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Effects of different BP management strategies on postoperative delirium in elderly patients undergoing hip replacement: A single center randomized controlled trial
Journal of Clinical Anesthesia 62 (2020) 109730
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Journal of Clinical Anesthesia journal homepage: www.elsevier.com/locate/jclinane
Original Contribution
Effects of different BP management strategies on postoperative delirium in elderly patients undergoing hip replacement: A single center randomized controlled trial
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XingMei Xu, XianWen Hu , Yun Wu, Yun Li, Ye Zhang, MuChun Zhang, QingQing Yang Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei 230032, China Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Anhui 230032, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Blood pressure Hip replacement Regional cerebral oxygen saturation Postoperative delirium
Study objective: Postoperative delirium (POD) is a common after hip replacement. Intraoperative blood pressure management may affect postoperative delirium. The aim of this study was to compare the effects of different blood pressure management strategies on POD. Design: A single center randomized controlled trial. Setting: The Second Hospital of Anhui Medical University, Hefei, China. Patients: A total of 150 patients aged 65–80 years underwent hip arthroplasty. Interventions: A random number table was used to divide the patients into three groups: mean blood pressure (MAP) was maintained from 10% to 20% below the baseline (group D), MAP was maintained from baseline to 10% below the baseline (group M), and MAP was maintained from baseline to 10% above the baseline (group H). Measurements: The primary endpoint was POD at 1–3 days. The secondary endpoint was the intraoperative MAP and regional cerebral oxygen saturation (rSO2) value, MAP, Visual Analogue Scale (VAS score) 1–3 days after surgery, the lengths of post anesthesia care unit (PACU) stay and hospital stay and emergence agitation were recorded. Main results: Patients in group H showed a lower incidence of POD on the first day than those in groups D and M (22% and 16% vs 4%; P = 0.031). There is no difference of incidence of POD on the 2rd and 3rd day postoperatively. Patients in group H received a higher MAP as well as rSO2 during the operation compared the other two groups (P < 0.05). Compared with groups D and M, emergence agitation was significantly reduced (P = 0.029) and the lengths of PACU stay (P = 0.018) and hospital stay (P = 0.008) were shortened in group H. Conclusions: Maintenance of intraoperative blood pressure from baseline to 10% above the baseline helps to reduce the incidence of POD and emergence agitation and shorten the lengths of PACU stay and hospital stay, and it may be related to increased rSO2 during the operation.
1. Introduction Postoperative delirium (POD) is defined as an acute (and fluctuating) disturbance in attention and cognition, which is not based on a pre-existing neurocognitive disorder [1]. Given the association between osteoarthritis, trauma and age, most of the patients who undergo elective total hip arthroplasty are elderly and at high risk for postoperative delirium [2], with the mobility as high as 55.9%, mostly occur 3 days postoperatively [3,4]. POD has a negative impact on the prognosis of patients, which leading to prolonged hospitalization, increased postoperative mortality, increased risk of early postoperative cognitive dysfunction (POCD), and increased burden on the family and
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society [5]. The risk of POD is multifactorial. In addition to age and postoperative pain, intraoperative blood pressure has been shown to be a risk factor for delirium in orthopedic patients. Yang L and colleagues showed that if intraoperative hypertension persists, the incidence of POD would also increase [6]. It is also suggested that intraoperative continuous hypotension may lead to an increased incidence of POD, which may be related to perioperative cerebral ischemia and hypoxia, resulting in insufficient cerebral blood supply and further leading to hippocampal cell damage and mitochondrial structure and function disorders [7]. Regional cerebral oxygen saturation (rSO2) monitoring is a non-invasive method for assessing the balance between cerebral
Corresponding author at: Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei 230032, China. E-mail address: [email protected] (X. Hu).
https://doi.org/10.1016/j.jclinane.2020.109730 Received 29 September 2019; Received in revised form 17 December 2019; Accepted 18 January 2020 0952-8180/ © 2020 Elsevier Inc. All rights reserved.
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Fig. 1. CONSORT flowchart.
within half a year before admission; visual, auditory, or language communication disorders; liver and kidney dysfunction; and long-term alcohol abuse. The preoperative simple mini-mental state scale (MMSE) score was calculated after excluding those who could not co-operate with the scoring measurement and whose scores were lower than the lowest score of the corresponding educational level MMSE score assessed before the study, and patients who failed to pass the exam (patients who were illiterate and obtained a score ≤ 17, those with primary school education who obtained a score ≤ 20, those with middle school education who obtained a score ≤ 22, those with university education who obtained a score ≤ 22, and those with university education who obtained a score ≤ 23) were also excluded since the cognitive dysfunction would exist preoperatively. Patients were divided into 3 groups according to the blood pressure level: patients with the MAP maintained from 10% to 20% below the baseline were set to group D, MAP maintained from baseline to 10% below the baseline were set to group M, and MAP maintained from baseline to 10% above the baseline were set to group H. If the MAP did not reach the target blood pressure level for 10 min, the patients was also excluded.
oxygen supply and consumption [8]. The rSO2 value is a very sensitive indicator of cerebral hypoxia, and intraoperative hypotension can cause cerebral perfusion insufficiency [9,10], which can lead to POD. Perioperative blood pressure maintained at ± 20% of the base value is often the ideal control target [11,12], but there is no unified conclusion on the influence of perioperative blood pressure on delirium incidence after hip replacement. In this study, blood pressure was controlled in the range of −20% to +10% near the baseline MAP value, and we compared the incidence of delirium of the elderly after hip surgery in 3 groups randomized to low, normal or high blood pressure. The primary outcome was POD incidence every 3 days postoperatively, and we hypothesized that maintenance of MAP was maintained from baseline to 10% above the baseline would reduce the incidence of POD, which linking to a raised rSO2.
2. Materials & methods 2.1. Study design
2.2. Management of general anesthesia and analgesia
This randomized clinical, three-arm parallel study was performed according to the Declaration of Helsinki principles between April 2019 and September 2019. The study was approved by the Ethics Committee for Clinical Trials of the Second Affiliated Hospital of Anhui Medical University, Hefei, China [approval no.: PJ-YX2018-048(F1)]. The trial was registered in the Chinese Clinical Trial Registry before patient enrollment (ChiCTR1900022411). All patients gave written informed consent. Patients undergoing elective hip replacement with the American Society of Anesthesiologists (ASA) physical status II or III and New York Heart Association Functional Classification (NYHA) class II or III were included in this study. All patients were between 65 and 80 years of age, and were excluded from the study if they met any of the following criteria: diseases of brain tumor disease; history of cerebrovascular accident; history of mental diseases and taking psychotropic drugs
All patients fasted for 8 h and did not receive any sedative or analgesic medications before the induction of anesthesia. After arrival to the operation room, intravenous access was established, and all patients received lactated Ringer's solution (5–7 ml/kg) maintained at a rate of 5–7 ml/kg/h. Vital parameters, including invasive radial arterial pressure (for clinical reasons), non-invasive blood pressure, heart rate, electrocardiogram, pulse oximetry, and end-tidal carbon dioxide partial pressure, were monitored using a Drager monitor (model: A7, Hefei unity medical co.). Stroke volume variation (SVV) was monitored by the continuous non-invasive arterial pressure monitoring system (CNAP) (model: CANP™ Monitor 500, Guangzhou Xinju Science and Trade Co.). For measuring the rSO2 value, two sensors for near-infrared spectroscopy (model: egos-600a, Suzhou Aiqin Bio-Medical Electronics 2
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0.2 mg·kg−1, and muscle relaxation was achieved with cisatracurium 0.2 mg·kg−1. Laryngeal mask airway (LMA) was inserted in the patients, and mechanical ventilation was set to target a PETCO2 in the 35–45 mmHg range and SpO2 > 95%. The baseline inspiratory gas was a mixture of 60/40% oxygen/air. Anesthesia was maintained with sevoflurane (1%–2%), propofol (4–8 mg·kg−1·h−1), remifentanil (0.1–0.3 μg·kg−1·min−1), and cisatracurium (0.1–0.2 mg·kg−1·h−1). The BIS values were maintained between 40 and 60. The patient's body temperature was monitored by a nasal thermometer (Shen Zhen, Mecun, healthcare co.) and maintained between 36.0 °C and 37.0 °C. Cisatracurium besylate infusion and sevoflurane inhalation were terminated about 30 min before the end of the surgery and sufentanil was administered with 5 μg to provide the analgesia postoperatively. Propofol and remifentanil were discontinued at the end of surgery. After surgery, early recovery was managed in a postanesthesia care unit (PACU), and patients was send back to the ward with a Steward resuscitation score of above 6 [13]. All patients used IV patient-controlled analgesia postoperatively for 48 h. The IV patient-controlled analgesia opioid consisted of 2.5 μg·kg−1 sufentanil and 2 mg granisetron (total volume of 100 ml, including 0.9% normal saline, basal rate 2 ml/h, bolus 2 ml, and lockout time 15 min).
Table 1 Demographic characteristic of study patients. Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
20(40) 69(8) 25(4)
19(38) 69(8) 24(4)
21(42) 68(6) 23(3)
0.977 0.606 0.277
38(76) 12(24) 6(2)
36(72) 14(28) 6(2)
38(76) 12(24) 6(2)
0.917 0.917 0.975
11(22) 39(78) 28(56)
14(28) 36(72) 25(50)
12(24) 38(76) 26(52)
0.840 0.840 0.829
13(26)
16(32)
14(28)
0.853
4(8) 27(54)
7(14) 26(52)
5(10) 23(46)
0.716 0.769
Grade of hypertension (n) I 15(30) II 12(24)
13(26) 13(26)
11(22) 12(24)
0.660 0.965
11(22) 5(10) 9(18) 3(6) 5(10) 6(12) 124(15) 35(10–52)
0.890 0.411 0.627 0.576 0.757 0.950 0.495 0.976
Gender (n) Male Age (years) BMI (kg·m−2) ASA score (n) II III Preoperative waiting time (d) Types of surgery (n) Hemiarthroplasty Total hip arthroplasty Dependence on smoking (n) Alcohol abuse (n) Comorbidity (n) Coronary heart disease Hypertension
Types of antihypertensive ACEI/ARB Beta-blocker Calcium blocker Diuretic Diabetes mellitus Others Preoperative Hb (g/L) Preoperative CRP (mg/ L)
medication (n) 12(24) 10(20) 7(14) 3(6) 11(22) 13(26) 5(10) 6(12) 8(16) 7(14) 5(10) 7(14) 122(15) 120(18) 34(9–36) 35(11–45)
2.3. Intraoperative hemodynamic monitoring and management The baseline of MAP was recorded as the mean value of MAP measured at 10 a.m. every 3 days before surgery. Blood pressure was recorded every 3 min intermittently using the non-invasive manometry. Volume management was directed by SVV, which had an upper limit of 12% to eliminate the volume effect on MAP. Blood loss was corrected by Ringer's sodium lactate and hydroxyethyl starch electrolyte at a ratio of 2:1. MAP was controlled 5 min after induction (T1) until the end of surgery (T5). During the operation, MAP in different groups, as well as heart rate were adjusted by the vasoactive agents on the basis of the appropriate depth of anesthesia and volume therapy. If the MAP was still lower than the target range, phenylephrine (40 μg) was administered with further adjustment of 0.1–0.3 μg·kg−1·min−1. If MAP was still higher than the target range, urapidil bolus (0.2–0.5 mg kg−1) was administered. Similarly, heart rate was adjusted either with atropine of 0.05 mg in case of lower than 50 beats/min, or esmolol of 20 mg in case of 100 beats/min furtherly.
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation for the data normally distributed or as median [interquartile range] for the data non-normally distributed. ASA = American Society of Anesthesiologists; BMI = body mass index; Hb = hemoglobin; CRP = C-reactive protein.
Co.) were pasted on the left and right sides of the forehead. The patient's baseline rSO2 data were acquired before an aesthetic induction while the patient breathed room air. For BIS monitoring (the America, Covidien IIc Co.), a single-use, disposable BIS sensor was applied to the forehead after the skin was wiped with alcohol swabs. 100% oxygen provided with mask before intubation. General anesthesia was induced with sufentanil 0.5 μg·kg−1 and etomidate
2.4. Outcome measures The primary endpoint was the incidence of POD on every 3 days postoperatively, which was evaluated once daily in the afternoon by a systematic training member who is blinded to group assignment, POD assessment was guided by the Confusion Assessment Method -Chinese
Table 2 Surgical data with outcomes. Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
Surgical profiles Anesthesia duration (min) Surgery duration (min) MAP holding time (min)
160(41) 122(38) 165(41)
148(29) 112(26) 153(29)
149(42) 112(36) 154(42)
0.206 0.211 0.206
Fluid balance Phenylephrine (μg) Urapidil (n) Fluid volume (ml) Total blood loss (ml) Length of PACU stay (min) Length of hospital stay (days)
345[0–690] 5(10) 1036(285) 175(80) 92(65) 15(5)
486[0–800] 6(12) 1046(191) 174(116) 94(61) 15(5)
688[0–1150] 3(6) 1036(149) 173(95) 63(50)⁎ 12(4)⁎
0.057 0.686 0.966 0.996 0.018 0.008
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation or as median [interquartile range]. PACU = post anesthesia care unit. Anesthesia duration refers to the time from the beginning of anesthesia to the end of anesthesia. Surgery duration refers to from the beginning of surgery to the end of surgery. MAP holding time refers to from 5 min after induction of anesthesia to the end of surgery. ⁎ P < 0.05 vs Group D. 3
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Table 3 Incidence of POD. Group D (n = 50) POD
1 day postoperative (n) 2 days postoperative (n) 3 days postoperative (n)
Group M (n = 50)
11(22) 4(8) 2(4)
8(16) 3(6) 1(2)
Group H (n = 50) 2(4) 1(2) 0
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P value 0.031 0.397 0.360
Noncontinuous variables are presented as number of subjects (percentage). POD = postoperative delirium. ⁎ P < 0.05 vs Group D.
Fig. 2. Continuous variables are presented as mean ± standard deviation. Compared to T0, rSO2 values at T2-T6 were statistically significant (*P < 0.05). Compared with group D, intraoperative MAP values were increased at T1-T6 in group H (**P < 0.05) (a); compared to T0, MAP values at T1-T6 were statistically significant (*P < 0.05) Compared with group D, intraoperative MAP value were increased at T1-T6, and bilateral rSO2 values were increased at T2-T6 in group H (**P < 0.05) (b); there was no statistical difference in the HR and BIS valve among the three groups (c, d). rSO2, regional cerebral oxygen saturation; MAP, mean blood pressure; HR, heart beat; and BIS, bispectral index.
Table 4 Postoperative pain and blood pressure and postoperative complications Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
VAS score 24 h postoperative 48 h postoperative 72 h postoperative
2.2(2.0–2.8 0.8) 1.5(0.7) 1.2(0.5)
2.4(0.9) 1.6(0.7) 1.2(0.4)
2.3(0.9) 1.5(0.7) 1.1(0.4)
0.522 0.658 0.597
Blood pressure 24 h postoperative (mmHg) 48 h postoperative (mmHg) 72 h postoperative (mmHg) Emergence agitation (n)
90(7.7) 90(7.2) 91(8.1) 12(24)
90(9.4) 90(8.6) 91(8.1) 11(22)
90(5.9) 89(6.3) 90(5.1) 3(6)⁎
0.957 0.495 0.827 0.029
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation. VAS = Visual Analogue Scale. ⁎ P < 0.05 vs other two groups. 4
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3. Results
Reversion (CAM-CR) scale, which used the original 11 items of the CAM but developed 4 points evaluation for each item [14]. The items of CAM-CR include acute onset, attention deficit, disorientation, memory deficit, perceptual deficit, excitement, hysteresis, fluctuation of illness, and change in the sleep-wake cycle. Assessment criteria were as follows: < 19 points indicate that the patient does not have delirium, 20–22 points indicate that the patient has suspected delirium, and > 22 points indicate that the patient has delirium. Apart from the baseline, MAP and rSO2 were also recorded at the following endpoints, which were continuously measured and recorded before the induction of anesthesia (T0); 5 min after induction of anesthesia (T1); 5 min, 30 min, and 60 min after incision (T2-T4); at the end of surgery (T5); and 5 min after surgery (T6). Additionally, intraoperative fluid balance, duration of anesthesia and operation, lengths of PACU stay [15] and hospital stay, emergence agitation, VAS score, and postoperative analgesics were recorded.
The CONSORT diagram is shown in Fig. 1. From among the 200 patients, 44 patients were excluded (33 did not meet the inclusion criteria, 9 chose not to participate in the study, and 2 did not complete the study). One patient was lost to follow-up, 3 initially randomized patients were excluded from data analysis (intraoperative MAP was not within the target range), and 2 refuse to postoperative assessment. Finally, 150 patients were randomly assigned to the following three groups: MAP was maintained from 10% to 20% below the baseline (group D), MAP was maintained from baseline to 10% below the baseline (group M), and MAP was maintained from baseline to 10% above the baseline (group H). 3.1. Patients' characteristics and operative data No differences in gender, age, BMI, ASA, preoperative waiting time (from admission to surgery), types of surgery, nicotine dependence, alcohol abuse, comorbidity, grade of hypertension, types of antihypertensive medication, and preoperative hemoglobin (Hb) and CReactive Protein (CRP) valves were observed among the three groups (Table 1). The three groups exhibited comparable surgical profiles, including the volume of crystalloid infusion and the lengths of PACU stay and hospital stay. No differences in anesthesia duration, surgery duration, MAP holding time, and the use of vasoactive agents (e.g., urapidil, phenylephrine) were found among the three groups. Compared with group D, the lengths of PACU stay(min) and hospital stay (days) [92(65) and vs 63(50); P = 0.017; 15(5) vs 12(4); P = 0.003] were significantly shortened in group H (Table 2). There was no statistical difference in hospital stay and the lengths of PACU stay between group D and group M.
2.5. Randomization and blinding Once consent was received, participants were assigned by the research assistant to three groups according to a random allocation sequence. An online random list generation was utilized to perform blocked randomization in a 60:60:60 ratio. The anesthesiologist was not blinded to the trials because the anesthesiologist should know the MAP target to which each participant has been assigned to make proper adjustment in the therapy to achieve the target blood pressure level. Outcome assessment and statistical analyses were performed by independent researchers. Outcome assessor and the surgical team were blinded to the study allocation status of participants.
2.6. Sample size and statistical analyses
3.2. Primary endpoint
The sample size was estimated as a minimum of 60 subjects in each study group to find a 30% difference among the groups based on a previous study [13,14], at a significance level of 5% and a power of 95%. The sample size in present study was calculated by using PASS 2008 (NCSS, LLC. Kaysville, Utah, USA) software. The degrees of freedom and effect size for the incidence of POD among the three groups as a primary outcome were 2 and 0.3, respectively. A sample size of 50 patients per group would allow for detecting a significant difference with a power of 80% and an α-coefficient of 0.05. The final sample size in present study was determined to be 60 patients per group, when considered a 10% dropout rate and higher power. Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). The measurement data were tested for normal distribution with Kolmogorov-Smirnov and homogeneity test of variances with Levene. Normally distributed continuous data were presented as mean ± standard deviation, and abnormal distributions were expressed as median (25%–75% percentile). Categorical variables were expressed as number (%). Categorical variables including sex, ASA classification, type of surgery, dependence on smoking, alcohol abuse, postoperative agitation, and incidence of POD and were analyzed using χ2 test. Group comparisons of age, body mass index, preoperative waiting time, preoperative Hb and CRP, surgical profiles, fluid balance, length of PACU stay and hospital stay, postoperative VAS score and blood pressure, and CAM-CR score, Continuous data were performed using one-way analysis of variance (ANOVA). Post-hoc analysis in ANOVA with Bonferroni correction was performed. For intraoperative hemodynamic parameters (rSO2, MAP, BIS, HR), univariate analysis was performed using Independent-sample t-test was employed to compare continuous variables between every two groups, and repeated measures one-way ANOVA was adopted for in-group comparisons.
Patients in group H showed a lower incidence of POD on the first day than those in groups D [11 (22) vs 2 (4); P = 0.007]. There was no statistical difference in the incidence of POD on the first day between group D and group M (Table 3). 3.3. Secondary endpoints and postoperative characteristics Compared with the baseline values, the timepoint after intubation induced comparable changes in all hemodynamic parameters among the three groups (Fig. 2). Postoperative VAS score and blood pressure, and postoperative complications, including emergence agitation, nausea and vomiting, and fever (Table 4), were comparable among the three groups. Compared with groups D, the incidence of emergence agitation (n) [12 (24) vs 3 (6); P = 0.011] was significantly shortened in group H (4). There was no statistical difference in the incidence of emergence agitation between group D and group M (Table 4). 4. Discussion In this prospective randomized study of the association between MAP changes and POD in elderly patients undergoing hip arthroplasty surgery, maintenance of the MAP within 10% higher than the baseline (group H) was found to be associated with a reduced incidence of POD on the first day after surgery. Hip replacement is a common orthopedic surgery in elderly patients and majority of women. Tzimas and colleagues indicated that patients undergoing joint arthroplasty are vulnerable to develop POD ranging from 7% to 75% [16]. Therefore, elderly patients undergoing hip arthroplasty were selected as subjects in this study to observe the effect of intraoperative blood pressure on POD. The effect of blood pressure on POD is inconclusive. It is suggested 5
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difference (Table 4); therefore, POD due to pain factors can be excluded during hip replacement. Although we have excluded the influence of these factors on POD, we still need to continue analyzing these factors affecting POD. However, the following are a few limitations of our study: (1) a small sample size, there was a lack of blood indicators to monitor POD, for example: IGF-I, IL-6, and S100B, and (3) we only used one method to assess POD, which may have led to differences in assessment.
that Intraoperative hypotension can lead to stroke and ischemia-reperfusion injury [17,18] which may promote the occurrence of POD. When intraoperative MAP is < 60 mmHg or intraoperative MAP decreases by 40% compared with MAP before anesthesia induction, and if the duration of hypotension is > 30 min, it will lead to postoperative myocardial injury and POD [19]. When blood pressure > 160/ 90 mmHg was used to define perioperative hypertension [20]. And intraoperative hypertension is primarily caused by sympathetic mediated vasoconstriction, hypercarbia, hypoxia [21]. Increased MAP found in the POD patients may have led to sympathetic activation and parasympathetic inhibition that subsequently resulted in a decreased release of acetylcholine. Decreased acetylcholine can enhance neuroinflammation and cause to POD [22]. At present, the range of intraoperative blood pressure maintenance in elderly patients undergoing hip replacement is still controversial. Perioperative blood pressure maintained at ± 20% of the base value is often the ideal control target, but the ideal range of intraoperative blood pressure in elderly patients has not been determined. Therefore, in this study, blood pressure was controlled in the range of −20% and ± 10% around the baseline value of MAP, and a certain gradient value was set to observe the intraoperative POD incidence among the three groups. In our study, fewer subjects developed POD on the first day in group H compared to groups D and M. Intraoperative cerebral ischemia and cerebral oxygen desaturation have been proposed as possible mechanisms of postoperative delirium and postoperative cognitive dysfunction [23,24]. Wang X and colleagues found that rSO2 desaturation were significantly associated with hypotensive and hypoperfusion state, resulting to profound delirium [10]. In our study, we used rSO2 to reflect the effect of intraoperative blood pressure on POD. In this study, there was no statistically significant difference in preoperative hemoglobin content among the three groups, and the inhaled oxygen concentration was controlled at 60% during surgery. Perioperative PETCO2 was controlled at 35–45 mmHg, and the intraoperative body temperature was maintained constant, so as to eliminate the interference by other factors in the rSO2 value. In our study, intraoperative MAP values were increased at T1-T6 and bilateral rSO2 values were increased at T2-T6 in group H (P < 0.05) (Fig. 2(a) and (b)). And it is consisted with the study of Hayashi, which suggested that the intraoperative rSO2 value can increase with an MAP elevation [25]. The study results suggest that rSO2 valve may start to change after MAP was controlled 5 min after incision (T2). In this study, MAP was controlled from the beginning of anesthesia, and the starting time of the operation in this study was 30 min after the beginning of anesthesia. Thus, we can conclude that the fluctuation of MAP within a small range within 30 min had no effect on the rSO2 value, and the rSO2 value can change after controlling the MAP value for > 30 min. Therefore, when perioperative blood pressure is controlled in the range of −20% and ± 10% near the baseline value of MAP, MAP holding time over 30 min can affect intraoperative rSO2 value and the incidence of POD. Emergence agitation (EA) refers to the transient state of consciousness and behavior separation in the process of patients from anesthesia to full consciousness, which can be manifested as emotional agitation, restlessness, and directional force obstruction. EA has also been referred to as emergence delirium or emergence excitement [26]. In this study, the incidence of EA was shorter in group H compared to groups D (Table 4). Therefore, we can conclude that intraoperative blood pressure may also affect the development of EA. There are many factors affecting POD. BIS at different depths may affect POD [27,28]. Slor and colleagues suggests that CRP plays a role in the inflammatory pathway of POD [29]. Postoperative pain is also a contributing factor to POD [30]. In this study, there were no statistically significant differences in preoperative blood pressure, age, ASA classification, BMI, preoperative waiting time (Table 1), and BIS valve (Fig. 2(d)) among the three groups, which ensured the comparability of the three groups. VAS scores in the three groups showed no statistical
5. Conclusion In summary, maintenance of MAP maintained from baseline to 10% above the baseline can reduce the incidence of POD during hip replacement, and it may be related to increased cerebral oxygen supply during the operation. CRediT authorship contribution statement XingMei Xu: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Writing - original draf. Xian Wen Hu: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Supervision, Writing - review & editing.Yun Wu: Formal analysis, Validation.Yun Li: Methodology, Resources.Ye Zhang: Methodology, Resources, Validation.MuChun Zhang: Funding acquisition, Investigation. QingQing Yang: Funding acquisition, Investigation, Visualization. Declaration of competing interest The authors declare that no grants/founding were involved in supporting this manuscript. Acknowledgment We acknowledge that the first and second authors had equal contribution to write and finalize this manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed Washington, DC: American Psychiatric Association; 2013. [2] Aziz KT, Best MJ, Naseer Z, Skolasky RL, Ponnusamy KE, Sterling RS, et al. The association of delirium with perioperative complications in primary elective total hip arthroplasty. Clin Orthop Surg 2018;10(3):286–91. [3] Zhao B, Ni Y, Tian X. Low plasma cholinesterase activity is associated with postoperative delirium after noncardiac surgery in elderly patients: a prospective observational study. Psychosomatics 2019;60(2):190–6. [4] Yang Y, Zhao X, Dong T, Yang Z, Zhang Q, Zhang Y. Risk factors for postoperative delirium following hip fracture repair in elderly patients: a systematic review and meta-analysis. Aging Clin Exp Res 2017;29(2):115–26. [5] Bickel H, Gradinger R, Kochs E. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord 2008;26(1):26–31. [6] Yang L, Sun DF, Han J, Liu R, Wang LJ, Zhang ZZ. Effects of intraoperative hemodynamics on incidence of postoperative delirium in elderly patients: a retrospective study. Med Sci Monit 2016;22:1093–100. [7] Nguyen DN, Huyghens L, Parra J, Schiettecatte J, Smitz J, Vincent JL. Hypotension and a positive fluid balance are associated with delirium in patients with shock. PLoS One 2018;13(8):e0200495. [8] Soh S, Shim JK, Song JW, Kim KN, Noh HY, Kwak YL. Postoperative delirium in elderly patients undergoing major spinal surgery: role of cerebral oximetry. J Neurosurg Anesthesiol 2017;29(4):426–32. [9] Green DW, Kunst, G. Cerebral oximetry and its role in adult cardiac, non-cardiac surgery and resuscitation from cardiac arrest. Anaesthesia 72 (Suppl. 1) 48–57. [10] Wang X, Feng K, Liu H, et al. Regional cerebral oxygen saturation and postoperative delirium in endovascular surgery: a prospective cohort study. Trials
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[20] Lien SF, Bisognano JD. Perioperative hypertension: defining at-risk patients and their management. Curr Hypertens Rep 2012;14(5):432–41. [21] Hanada S, Kawakami H, Goto T, Morita S. Hypertension and anesthesia. Curr Opin Anaesthesiol 2006;19(3):315–9. [22] Allen SR, Frankel HL. Postoperative complications: delirium. Send to Surg Clin North Am. 2012;92(2):409–31. [23] Lei L, KR FL, Carroll J, Poonawala H, Machina M, et al. Cerebral oximetry and postoperative delirium after cardiac surgery: a randomised, controlled trial. Anaesthesia 2017;72(12):1456–66. [24] Mailhot T, Cossette S, Lambert J, Cournoyer A, Denault AY. Cerebral oximetry as a biomarker of postoperative delirium in cardiac surgery patients. J Crit Care 2016;34:17–23. [25] Hayashi K, Tanabe K, Minami K, Sakata K, Nagase K, Iida H. Effect of blood pressure elevation on cerebral oxygen desaturation in the beach chair position. Asian J Anesthesiol 2017;55(1):13–6. [26] Begum U, Singh PR, Naithani B, Singh V, Singh GP, Tiwari T. Dexmedetomidine as bolus or low-dose infusion for the prevention of emergence agitation with sevoflurane anesthesia in pediatric patients. Anesth Essays Res 2019;13(1):57–62. [27] Chan MT, Cheng BC, Lee TM, Gin T. CODA trial group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013;25(1):33–42. [28] Xing L, Xin J, Suwei Y, Xia Y. The correlation of the depth of anesthesia and postoperative cognitive impairment: a meta-analysis based on randomized controlled trials. J Clin Anesth 2018;45:55–9. [29] Slor Chantal J, Joost W, Dimitrios A, Jansen RWMM, Houdijk APJ, van Gool WA, et al. The trajectory of C-reactive protein serum levels in older hip fracture patients with postoperative delirium. Int J Geriatr Psychiatry 2019;34(10):1438–46. [30] Subramaniam B, Shankar P, Shaefi S, Mueller A, O’Gara B, Banner-Goodspeed V, et al. Effect of intravenous acetaminophen vs placebo combined with propofol or dexmedetomidine on postoperative delirium among older patients following cardiac surgery: the DEXACET randomized clinical trial. JAMA 2019;321(7):686–96.
2019;20(1):504. [11] Kristensen SD, Knuuti J, Saraste A, Anker S, Bøtker HE, De Hert S, et al. ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: the Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur J Anaesthesiol 2014;31(10):517–73. [12] Dodson GM, Bentley WE, Awad A, Muntazar M, Goldberg ME. Isolated perioperative hypertension: clinical implications & contemporary treatment strategies. Curr Hypertens Rev 2014;10(1):31–6. [13] Navarese EP, Austin D, Gurbel PA, et al. Drug-coated balloons in treatment of instent restenosis: a meta-analysis of randomised controlled trials. Clin Res Cardiol 2013;102(4):279–87. [14] Guo Y, Zhang Y, Jia P, Wang W, Zhou Q, Sun L, et al. Preoperative serum metabolites are associated with postoperative delirium in elderly hip-fracture patients. J Gerontol A Biol Sci Med Sci 2017;72(12):1689–96. [15] Hesse S, Kreuzer M, Hight D, et al. Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications. Br J Anaesth 2019;122(5):622–34. [16] Tzimas P, Samara E, Petrou A, Korompilias A, Chalkias A, Papadopoulos G. The influence of anesthetic techniques on postoperative cognitive function in elderly patients undergoing hip fracture surgery: general vs spinal anesthesia. Injury 2018;49(12):2221–6. [17] Bijker JB, Gelb AW. Review article: the role of hypotension in perioperative stroke. Can J Anaesth 2013;60(2):159–67. [18] Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology 2013;119(3):507–15. [19] Van Waes JA, van Klei WA, Wijeysundera DN, van Wolfswinkel L, Lindsay TF, Beattie WS. Association between intraoperative hypotension and myocardial injury after vascular surgery. Anesthesiology 2016;124(1):35–44.
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Original Contribution
Effects of different BP management strategies on postoperative delirium in elderly patients undergoing hip replacement: A single center randomized controlled trial
T
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XingMei Xu, XianWen Hu , Yun Wu, Yun Li, Ye Zhang, MuChun Zhang, QingQing Yang Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei 230032, China Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Anhui 230032, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Blood pressure Hip replacement Regional cerebral oxygen saturation Postoperative delirium
Study objective: Postoperative delirium (POD) is a common after hip replacement. Intraoperative blood pressure management may affect postoperative delirium. The aim of this study was to compare the effects of different blood pressure management strategies on POD. Design: A single center randomized controlled trial. Setting: The Second Hospital of Anhui Medical University, Hefei, China. Patients: A total of 150 patients aged 65–80 years underwent hip arthroplasty. Interventions: A random number table was used to divide the patients into three groups: mean blood pressure (MAP) was maintained from 10% to 20% below the baseline (group D), MAP was maintained from baseline to 10% below the baseline (group M), and MAP was maintained from baseline to 10% above the baseline (group H). Measurements: The primary endpoint was POD at 1–3 days. The secondary endpoint was the intraoperative MAP and regional cerebral oxygen saturation (rSO2) value, MAP, Visual Analogue Scale (VAS score) 1–3 days after surgery, the lengths of post anesthesia care unit (PACU) stay and hospital stay and emergence agitation were recorded. Main results: Patients in group H showed a lower incidence of POD on the first day than those in groups D and M (22% and 16% vs 4%; P = 0.031). There is no difference of incidence of POD on the 2rd and 3rd day postoperatively. Patients in group H received a higher MAP as well as rSO2 during the operation compared the other two groups (P < 0.05). Compared with groups D and M, emergence agitation was significantly reduced (P = 0.029) and the lengths of PACU stay (P = 0.018) and hospital stay (P = 0.008) were shortened in group H. Conclusions: Maintenance of intraoperative blood pressure from baseline to 10% above the baseline helps to reduce the incidence of POD and emergence agitation and shorten the lengths of PACU stay and hospital stay, and it may be related to increased rSO2 during the operation.
1. Introduction Postoperative delirium (POD) is defined as an acute (and fluctuating) disturbance in attention and cognition, which is not based on a pre-existing neurocognitive disorder [1]. Given the association between osteoarthritis, trauma and age, most of the patients who undergo elective total hip arthroplasty are elderly and at high risk for postoperative delirium [2], with the mobility as high as 55.9%, mostly occur 3 days postoperatively [3,4]. POD has a negative impact on the prognosis of patients, which leading to prolonged hospitalization, increased postoperative mortality, increased risk of early postoperative cognitive dysfunction (POCD), and increased burden on the family and
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society [5]. The risk of POD is multifactorial. In addition to age and postoperative pain, intraoperative blood pressure has been shown to be a risk factor for delirium in orthopedic patients. Yang L and colleagues showed that if intraoperative hypertension persists, the incidence of POD would also increase [6]. It is also suggested that intraoperative continuous hypotension may lead to an increased incidence of POD, which may be related to perioperative cerebral ischemia and hypoxia, resulting in insufficient cerebral blood supply and further leading to hippocampal cell damage and mitochondrial structure and function disorders [7]. Regional cerebral oxygen saturation (rSO2) monitoring is a non-invasive method for assessing the balance between cerebral
Corresponding author at: Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei 230032, China. E-mail address: [email protected] (X. Hu).
https://doi.org/10.1016/j.jclinane.2020.109730 Received 29 September 2019; Received in revised form 17 December 2019; Accepted 18 January 2020 0952-8180/ © 2020 Elsevier Inc. All rights reserved.
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Fig. 1. CONSORT flowchart.
within half a year before admission; visual, auditory, or language communication disorders; liver and kidney dysfunction; and long-term alcohol abuse. The preoperative simple mini-mental state scale (MMSE) score was calculated after excluding those who could not co-operate with the scoring measurement and whose scores were lower than the lowest score of the corresponding educational level MMSE score assessed before the study, and patients who failed to pass the exam (patients who were illiterate and obtained a score ≤ 17, those with primary school education who obtained a score ≤ 20, those with middle school education who obtained a score ≤ 22, those with university education who obtained a score ≤ 22, and those with university education who obtained a score ≤ 23) were also excluded since the cognitive dysfunction would exist preoperatively. Patients were divided into 3 groups according to the blood pressure level: patients with the MAP maintained from 10% to 20% below the baseline were set to group D, MAP maintained from baseline to 10% below the baseline were set to group M, and MAP maintained from baseline to 10% above the baseline were set to group H. If the MAP did not reach the target blood pressure level for 10 min, the patients was also excluded.
oxygen supply and consumption [8]. The rSO2 value is a very sensitive indicator of cerebral hypoxia, and intraoperative hypotension can cause cerebral perfusion insufficiency [9,10], which can lead to POD. Perioperative blood pressure maintained at ± 20% of the base value is often the ideal control target [11,12], but there is no unified conclusion on the influence of perioperative blood pressure on delirium incidence after hip replacement. In this study, blood pressure was controlled in the range of −20% to +10% near the baseline MAP value, and we compared the incidence of delirium of the elderly after hip surgery in 3 groups randomized to low, normal or high blood pressure. The primary outcome was POD incidence every 3 days postoperatively, and we hypothesized that maintenance of MAP was maintained from baseline to 10% above the baseline would reduce the incidence of POD, which linking to a raised rSO2.
2. Materials & methods 2.1. Study design
2.2. Management of general anesthesia and analgesia
This randomized clinical, three-arm parallel study was performed according to the Declaration of Helsinki principles between April 2019 and September 2019. The study was approved by the Ethics Committee for Clinical Trials of the Second Affiliated Hospital of Anhui Medical University, Hefei, China [approval no.: PJ-YX2018-048(F1)]. The trial was registered in the Chinese Clinical Trial Registry before patient enrollment (ChiCTR1900022411). All patients gave written informed consent. Patients undergoing elective hip replacement with the American Society of Anesthesiologists (ASA) physical status II or III and New York Heart Association Functional Classification (NYHA) class II or III were included in this study. All patients were between 65 and 80 years of age, and were excluded from the study if they met any of the following criteria: diseases of brain tumor disease; history of cerebrovascular accident; history of mental diseases and taking psychotropic drugs
All patients fasted for 8 h and did not receive any sedative or analgesic medications before the induction of anesthesia. After arrival to the operation room, intravenous access was established, and all patients received lactated Ringer's solution (5–7 ml/kg) maintained at a rate of 5–7 ml/kg/h. Vital parameters, including invasive radial arterial pressure (for clinical reasons), non-invasive blood pressure, heart rate, electrocardiogram, pulse oximetry, and end-tidal carbon dioxide partial pressure, were monitored using a Drager monitor (model: A7, Hefei unity medical co.). Stroke volume variation (SVV) was monitored by the continuous non-invasive arterial pressure monitoring system (CNAP) (model: CANP™ Monitor 500, Guangzhou Xinju Science and Trade Co.). For measuring the rSO2 value, two sensors for near-infrared spectroscopy (model: egos-600a, Suzhou Aiqin Bio-Medical Electronics 2
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0.2 mg·kg−1, and muscle relaxation was achieved with cisatracurium 0.2 mg·kg−1. Laryngeal mask airway (LMA) was inserted in the patients, and mechanical ventilation was set to target a PETCO2 in the 35–45 mmHg range and SpO2 > 95%. The baseline inspiratory gas was a mixture of 60/40% oxygen/air. Anesthesia was maintained with sevoflurane (1%–2%), propofol (4–8 mg·kg−1·h−1), remifentanil (0.1–0.3 μg·kg−1·min−1), and cisatracurium (0.1–0.2 mg·kg−1·h−1). The BIS values were maintained between 40 and 60. The patient's body temperature was monitored by a nasal thermometer (Shen Zhen, Mecun, healthcare co.) and maintained between 36.0 °C and 37.0 °C. Cisatracurium besylate infusion and sevoflurane inhalation were terminated about 30 min before the end of the surgery and sufentanil was administered with 5 μg to provide the analgesia postoperatively. Propofol and remifentanil were discontinued at the end of surgery. After surgery, early recovery was managed in a postanesthesia care unit (PACU), and patients was send back to the ward with a Steward resuscitation score of above 6 [13]. All patients used IV patient-controlled analgesia postoperatively for 48 h. The IV patient-controlled analgesia opioid consisted of 2.5 μg·kg−1 sufentanil and 2 mg granisetron (total volume of 100 ml, including 0.9% normal saline, basal rate 2 ml/h, bolus 2 ml, and lockout time 15 min).
Table 1 Demographic characteristic of study patients. Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
20(40) 69(8) 25(4)
19(38) 69(8) 24(4)
21(42) 68(6) 23(3)
0.977 0.606 0.277
38(76) 12(24) 6(2)
36(72) 14(28) 6(2)
38(76) 12(24) 6(2)
0.917 0.917 0.975
11(22) 39(78) 28(56)
14(28) 36(72) 25(50)
12(24) 38(76) 26(52)
0.840 0.840 0.829
13(26)
16(32)
14(28)
0.853
4(8) 27(54)
7(14) 26(52)
5(10) 23(46)
0.716 0.769
Grade of hypertension (n) I 15(30) II 12(24)
13(26) 13(26)
11(22) 12(24)
0.660 0.965
11(22) 5(10) 9(18) 3(6) 5(10) 6(12) 124(15) 35(10–52)
0.890 0.411 0.627 0.576 0.757 0.950 0.495 0.976
Gender (n) Male Age (years) BMI (kg·m−2) ASA score (n) II III Preoperative waiting time (d) Types of surgery (n) Hemiarthroplasty Total hip arthroplasty Dependence on smoking (n) Alcohol abuse (n) Comorbidity (n) Coronary heart disease Hypertension
Types of antihypertensive ACEI/ARB Beta-blocker Calcium blocker Diuretic Diabetes mellitus Others Preoperative Hb (g/L) Preoperative CRP (mg/ L)
medication (n) 12(24) 10(20) 7(14) 3(6) 11(22) 13(26) 5(10) 6(12) 8(16) 7(14) 5(10) 7(14) 122(15) 120(18) 34(9–36) 35(11–45)
2.3. Intraoperative hemodynamic monitoring and management The baseline of MAP was recorded as the mean value of MAP measured at 10 a.m. every 3 days before surgery. Blood pressure was recorded every 3 min intermittently using the non-invasive manometry. Volume management was directed by SVV, which had an upper limit of 12% to eliminate the volume effect on MAP. Blood loss was corrected by Ringer's sodium lactate and hydroxyethyl starch electrolyte at a ratio of 2:1. MAP was controlled 5 min after induction (T1) until the end of surgery (T5). During the operation, MAP in different groups, as well as heart rate were adjusted by the vasoactive agents on the basis of the appropriate depth of anesthesia and volume therapy. If the MAP was still lower than the target range, phenylephrine (40 μg) was administered with further adjustment of 0.1–0.3 μg·kg−1·min−1. If MAP was still higher than the target range, urapidil bolus (0.2–0.5 mg kg−1) was administered. Similarly, heart rate was adjusted either with atropine of 0.05 mg in case of lower than 50 beats/min, or esmolol of 20 mg in case of 100 beats/min furtherly.
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation for the data normally distributed or as median [interquartile range] for the data non-normally distributed. ASA = American Society of Anesthesiologists; BMI = body mass index; Hb = hemoglobin; CRP = C-reactive protein.
Co.) were pasted on the left and right sides of the forehead. The patient's baseline rSO2 data were acquired before an aesthetic induction while the patient breathed room air. For BIS monitoring (the America, Covidien IIc Co.), a single-use, disposable BIS sensor was applied to the forehead after the skin was wiped with alcohol swabs. 100% oxygen provided with mask before intubation. General anesthesia was induced with sufentanil 0.5 μg·kg−1 and etomidate
2.4. Outcome measures The primary endpoint was the incidence of POD on every 3 days postoperatively, which was evaluated once daily in the afternoon by a systematic training member who is blinded to group assignment, POD assessment was guided by the Confusion Assessment Method -Chinese
Table 2 Surgical data with outcomes. Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
Surgical profiles Anesthesia duration (min) Surgery duration (min) MAP holding time (min)
160(41) 122(38) 165(41)
148(29) 112(26) 153(29)
149(42) 112(36) 154(42)
0.206 0.211 0.206
Fluid balance Phenylephrine (μg) Urapidil (n) Fluid volume (ml) Total blood loss (ml) Length of PACU stay (min) Length of hospital stay (days)
345[0–690] 5(10) 1036(285) 175(80) 92(65) 15(5)
486[0–800] 6(12) 1046(191) 174(116) 94(61) 15(5)
688[0–1150] 3(6) 1036(149) 173(95) 63(50)⁎ 12(4)⁎
0.057 0.686 0.966 0.996 0.018 0.008
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation or as median [interquartile range]. PACU = post anesthesia care unit. Anesthesia duration refers to the time from the beginning of anesthesia to the end of anesthesia. Surgery duration refers to from the beginning of surgery to the end of surgery. MAP holding time refers to from 5 min after induction of anesthesia to the end of surgery. ⁎ P < 0.05 vs Group D. 3
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Table 3 Incidence of POD. Group D (n = 50) POD
1 day postoperative (n) 2 days postoperative (n) 3 days postoperative (n)
Group M (n = 50)
11(22) 4(8) 2(4)
8(16) 3(6) 1(2)
Group H (n = 50) 2(4) 1(2) 0
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P value 0.031 0.397 0.360
Noncontinuous variables are presented as number of subjects (percentage). POD = postoperative delirium. ⁎ P < 0.05 vs Group D.
Fig. 2. Continuous variables are presented as mean ± standard deviation. Compared to T0, rSO2 values at T2-T6 were statistically significant (*P < 0.05). Compared with group D, intraoperative MAP values were increased at T1-T6 in group H (**P < 0.05) (a); compared to T0, MAP values at T1-T6 were statistically significant (*P < 0.05) Compared with group D, intraoperative MAP value were increased at T1-T6, and bilateral rSO2 values were increased at T2-T6 in group H (**P < 0.05) (b); there was no statistical difference in the HR and BIS valve among the three groups (c, d). rSO2, regional cerebral oxygen saturation; MAP, mean blood pressure; HR, heart beat; and BIS, bispectral index.
Table 4 Postoperative pain and blood pressure and postoperative complications Group D (n = 50)
Group M (n = 50)
Group H (n = 50)
P value
VAS score 24 h postoperative 48 h postoperative 72 h postoperative
2.2(2.0–2.8 0.8) 1.5(0.7) 1.2(0.5)
2.4(0.9) 1.6(0.7) 1.2(0.4)
2.3(0.9) 1.5(0.7) 1.1(0.4)
0.522 0.658 0.597
Blood pressure 24 h postoperative (mmHg) 48 h postoperative (mmHg) 72 h postoperative (mmHg) Emergence agitation (n)
90(7.7) 90(7.2) 91(8.1) 12(24)
90(9.4) 90(8.6) 91(8.1) 11(22)
90(5.9) 89(6.3) 90(5.1) 3(6)⁎
0.957 0.495 0.827 0.029
Noncontinuous variables are presented as number of subjects (percentage) and continuous variables are presented as mean ± standard deviation. VAS = Visual Analogue Scale. ⁎ P < 0.05 vs other two groups. 4
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3. Results
Reversion (CAM-CR) scale, which used the original 11 items of the CAM but developed 4 points evaluation for each item [14]. The items of CAM-CR include acute onset, attention deficit, disorientation, memory deficit, perceptual deficit, excitement, hysteresis, fluctuation of illness, and change in the sleep-wake cycle. Assessment criteria were as follows: < 19 points indicate that the patient does not have delirium, 20–22 points indicate that the patient has suspected delirium, and > 22 points indicate that the patient has delirium. Apart from the baseline, MAP and rSO2 were also recorded at the following endpoints, which were continuously measured and recorded before the induction of anesthesia (T0); 5 min after induction of anesthesia (T1); 5 min, 30 min, and 60 min after incision (T2-T4); at the end of surgery (T5); and 5 min after surgery (T6). Additionally, intraoperative fluid balance, duration of anesthesia and operation, lengths of PACU stay [15] and hospital stay, emergence agitation, VAS score, and postoperative analgesics were recorded.
The CONSORT diagram is shown in Fig. 1. From among the 200 patients, 44 patients were excluded (33 did not meet the inclusion criteria, 9 chose not to participate in the study, and 2 did not complete the study). One patient was lost to follow-up, 3 initially randomized patients were excluded from data analysis (intraoperative MAP was not within the target range), and 2 refuse to postoperative assessment. Finally, 150 patients were randomly assigned to the following three groups: MAP was maintained from 10% to 20% below the baseline (group D), MAP was maintained from baseline to 10% below the baseline (group M), and MAP was maintained from baseline to 10% above the baseline (group H). 3.1. Patients' characteristics and operative data No differences in gender, age, BMI, ASA, preoperative waiting time (from admission to surgery), types of surgery, nicotine dependence, alcohol abuse, comorbidity, grade of hypertension, types of antihypertensive medication, and preoperative hemoglobin (Hb) and CReactive Protein (CRP) valves were observed among the three groups (Table 1). The three groups exhibited comparable surgical profiles, including the volume of crystalloid infusion and the lengths of PACU stay and hospital stay. No differences in anesthesia duration, surgery duration, MAP holding time, and the use of vasoactive agents (e.g., urapidil, phenylephrine) were found among the three groups. Compared with group D, the lengths of PACU stay(min) and hospital stay (days) [92(65) and vs 63(50); P = 0.017; 15(5) vs 12(4); P = 0.003] were significantly shortened in group H (Table 2). There was no statistical difference in hospital stay and the lengths of PACU stay between group D and group M.
2.5. Randomization and blinding Once consent was received, participants were assigned by the research assistant to three groups according to a random allocation sequence. An online random list generation was utilized to perform blocked randomization in a 60:60:60 ratio. The anesthesiologist was not blinded to the trials because the anesthesiologist should know the MAP target to which each participant has been assigned to make proper adjustment in the therapy to achieve the target blood pressure level. Outcome assessment and statistical analyses were performed by independent researchers. Outcome assessor and the surgical team were blinded to the study allocation status of participants.
2.6. Sample size and statistical analyses
3.2. Primary endpoint
The sample size was estimated as a minimum of 60 subjects in each study group to find a 30% difference among the groups based on a previous study [13,14], at a significance level of 5% and a power of 95%. The sample size in present study was calculated by using PASS 2008 (NCSS, LLC. Kaysville, Utah, USA) software. The degrees of freedom and effect size for the incidence of POD among the three groups as a primary outcome were 2 and 0.3, respectively. A sample size of 50 patients per group would allow for detecting a significant difference with a power of 80% and an α-coefficient of 0.05. The final sample size in present study was determined to be 60 patients per group, when considered a 10% dropout rate and higher power. Statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). The measurement data were tested for normal distribution with Kolmogorov-Smirnov and homogeneity test of variances with Levene. Normally distributed continuous data were presented as mean ± standard deviation, and abnormal distributions were expressed as median (25%–75% percentile). Categorical variables were expressed as number (%). Categorical variables including sex, ASA classification, type of surgery, dependence on smoking, alcohol abuse, postoperative agitation, and incidence of POD and were analyzed using χ2 test. Group comparisons of age, body mass index, preoperative waiting time, preoperative Hb and CRP, surgical profiles, fluid balance, length of PACU stay and hospital stay, postoperative VAS score and blood pressure, and CAM-CR score, Continuous data were performed using one-way analysis of variance (ANOVA). Post-hoc analysis in ANOVA with Bonferroni correction was performed. For intraoperative hemodynamic parameters (rSO2, MAP, BIS, HR), univariate analysis was performed using Independent-sample t-test was employed to compare continuous variables between every two groups, and repeated measures one-way ANOVA was adopted for in-group comparisons.
Patients in group H showed a lower incidence of POD on the first day than those in groups D [11 (22) vs 2 (4); P = 0.007]. There was no statistical difference in the incidence of POD on the first day between group D and group M (Table 3). 3.3. Secondary endpoints and postoperative characteristics Compared with the baseline values, the timepoint after intubation induced comparable changes in all hemodynamic parameters among the three groups (Fig. 2). Postoperative VAS score and blood pressure, and postoperative complications, including emergence agitation, nausea and vomiting, and fever (Table 4), were comparable among the three groups. Compared with groups D, the incidence of emergence agitation (n) [12 (24) vs 3 (6); P = 0.011] was significantly shortened in group H (4). There was no statistical difference in the incidence of emergence agitation between group D and group M (Table 4). 4. Discussion In this prospective randomized study of the association between MAP changes and POD in elderly patients undergoing hip arthroplasty surgery, maintenance of the MAP within 10% higher than the baseline (group H) was found to be associated with a reduced incidence of POD on the first day after surgery. Hip replacement is a common orthopedic surgery in elderly patients and majority of women. Tzimas and colleagues indicated that patients undergoing joint arthroplasty are vulnerable to develop POD ranging from 7% to 75% [16]. Therefore, elderly patients undergoing hip arthroplasty were selected as subjects in this study to observe the effect of intraoperative blood pressure on POD. The effect of blood pressure on POD is inconclusive. It is suggested 5
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difference (Table 4); therefore, POD due to pain factors can be excluded during hip replacement. Although we have excluded the influence of these factors on POD, we still need to continue analyzing these factors affecting POD. However, the following are a few limitations of our study: (1) a small sample size, there was a lack of blood indicators to monitor POD, for example: IGF-I, IL-6, and S100B, and (3) we only used one method to assess POD, which may have led to differences in assessment.
that Intraoperative hypotension can lead to stroke and ischemia-reperfusion injury [17,18] which may promote the occurrence of POD. When intraoperative MAP is < 60 mmHg or intraoperative MAP decreases by 40% compared with MAP before anesthesia induction, and if the duration of hypotension is > 30 min, it will lead to postoperative myocardial injury and POD [19]. When blood pressure > 160/ 90 mmHg was used to define perioperative hypertension [20]. And intraoperative hypertension is primarily caused by sympathetic mediated vasoconstriction, hypercarbia, hypoxia [21]. Increased MAP found in the POD patients may have led to sympathetic activation and parasympathetic inhibition that subsequently resulted in a decreased release of acetylcholine. Decreased acetylcholine can enhance neuroinflammation and cause to POD [22]. At present, the range of intraoperative blood pressure maintenance in elderly patients undergoing hip replacement is still controversial. Perioperative blood pressure maintained at ± 20% of the base value is often the ideal control target, but the ideal range of intraoperative blood pressure in elderly patients has not been determined. Therefore, in this study, blood pressure was controlled in the range of −20% and ± 10% around the baseline value of MAP, and a certain gradient value was set to observe the intraoperative POD incidence among the three groups. In our study, fewer subjects developed POD on the first day in group H compared to groups D and M. Intraoperative cerebral ischemia and cerebral oxygen desaturation have been proposed as possible mechanisms of postoperative delirium and postoperative cognitive dysfunction [23,24]. Wang X and colleagues found that rSO2 desaturation were significantly associated with hypotensive and hypoperfusion state, resulting to profound delirium [10]. In our study, we used rSO2 to reflect the effect of intraoperative blood pressure on POD. In this study, there was no statistically significant difference in preoperative hemoglobin content among the three groups, and the inhaled oxygen concentration was controlled at 60% during surgery. Perioperative PETCO2 was controlled at 35–45 mmHg, and the intraoperative body temperature was maintained constant, so as to eliminate the interference by other factors in the rSO2 value. In our study, intraoperative MAP values were increased at T1-T6 and bilateral rSO2 values were increased at T2-T6 in group H (P < 0.05) (Fig. 2(a) and (b)). And it is consisted with the study of Hayashi, which suggested that the intraoperative rSO2 value can increase with an MAP elevation [25]. The study results suggest that rSO2 valve may start to change after MAP was controlled 5 min after incision (T2). In this study, MAP was controlled from the beginning of anesthesia, and the starting time of the operation in this study was 30 min after the beginning of anesthesia. Thus, we can conclude that the fluctuation of MAP within a small range within 30 min had no effect on the rSO2 value, and the rSO2 value can change after controlling the MAP value for > 30 min. Therefore, when perioperative blood pressure is controlled in the range of −20% and ± 10% near the baseline value of MAP, MAP holding time over 30 min can affect intraoperative rSO2 value and the incidence of POD. Emergence agitation (EA) refers to the transient state of consciousness and behavior separation in the process of patients from anesthesia to full consciousness, which can be manifested as emotional agitation, restlessness, and directional force obstruction. EA has also been referred to as emergence delirium or emergence excitement [26]. In this study, the incidence of EA was shorter in group H compared to groups D (Table 4). Therefore, we can conclude that intraoperative blood pressure may also affect the development of EA. There are many factors affecting POD. BIS at different depths may affect POD [27,28]. Slor and colleagues suggests that CRP plays a role in the inflammatory pathway of POD [29]. Postoperative pain is also a contributing factor to POD [30]. In this study, there were no statistically significant differences in preoperative blood pressure, age, ASA classification, BMI, preoperative waiting time (Table 1), and BIS valve (Fig. 2(d)) among the three groups, which ensured the comparability of the three groups. VAS scores in the three groups showed no statistical
5. Conclusion In summary, maintenance of MAP maintained from baseline to 10% above the baseline can reduce the incidence of POD during hip replacement, and it may be related to increased cerebral oxygen supply during the operation. CRediT authorship contribution statement XingMei Xu: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Writing - original draf. Xian Wen Hu: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Supervision, Writing - review & editing.Yun Wu: Formal analysis, Validation.Yun Li: Methodology, Resources.Ye Zhang: Methodology, Resources, Validation.MuChun Zhang: Funding acquisition, Investigation. QingQing Yang: Funding acquisition, Investigation, Visualization. Declaration of competing interest The authors declare that no grants/founding were involved in supporting this manuscript. Acknowledgment We acknowledge that the first and second authors had equal contribution to write and finalize this manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed Washington, DC: American Psychiatric Association; 2013. [2] Aziz KT, Best MJ, Naseer Z, Skolasky RL, Ponnusamy KE, Sterling RS, et al. The association of delirium with perioperative complications in primary elective total hip arthroplasty. Clin Orthop Surg 2018;10(3):286–91. [3] Zhao B, Ni Y, Tian X. Low plasma cholinesterase activity is associated with postoperative delirium after noncardiac surgery in elderly patients: a prospective observational study. Psychosomatics 2019;60(2):190–6. [4] Yang Y, Zhao X, Dong T, Yang Z, Zhang Q, Zhang Y. Risk factors for postoperative delirium following hip fracture repair in elderly patients: a systematic review and meta-analysis. Aging Clin Exp Res 2017;29(2):115–26. [5] Bickel H, Gradinger R, Kochs E. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn Disord 2008;26(1):26–31. [6] Yang L, Sun DF, Han J, Liu R, Wang LJ, Zhang ZZ. Effects of intraoperative hemodynamics on incidence of postoperative delirium in elderly patients: a retrospective study. Med Sci Monit 2016;22:1093–100. [7] Nguyen DN, Huyghens L, Parra J, Schiettecatte J, Smitz J, Vincent JL. Hypotension and a positive fluid balance are associated with delirium in patients with shock. PLoS One 2018;13(8):e0200495. [8] Soh S, Shim JK, Song JW, Kim KN, Noh HY, Kwak YL. Postoperative delirium in elderly patients undergoing major spinal surgery: role of cerebral oximetry. J Neurosurg Anesthesiol 2017;29(4):426–32. [9] Green DW, Kunst, G. Cerebral oximetry and its role in adult cardiac, non-cardiac surgery and resuscitation from cardiac arrest. Anaesthesia 72 (Suppl. 1) 48–57. [10] Wang X, Feng K, Liu H, et al. Regional cerebral oxygen saturation and postoperative delirium in endovascular surgery: a prospective cohort study. Trials
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