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Prophylactic phenylephrine infusion for the prevention of hypotension after spinal anesthesia in the elderly: a randomized controlled clinical trial
Journal of Clinical Anesthesia (2016) 35, 99–106
Original contribution
Prophylactic phenylephrine infusion for the prevention of hypotension after spinal anesthesia in the elderly: a randomized controlled clinical trial☆,☆☆,★ Fabrice Ferré MD a,⁎, Philippe Marty MD a , Laura Bruneteau MD a , Virgine Merlet MD a , Benoît Bataille MD b , Anne Ferrier MD a , Claude Gris MD a , Matt Kurrek MD c , Olivier Fourcade MD, PhD a , Vincent Minville MD, PhD a a
Department of Anesthesiology and Critical Care Medicine, Purpan University Hospital, Toulouse, France Department of Critical Care Medicine, Narbonne Hospital, Narbonne, France c Department of Anesthesia, University of Toronto, 150 College St, Room 121, Fitzgerald Bldg, Toronto, Ontario, M5S 3E2, Canada b
Received 1 September 2015; revised 10 June 2016; accepted 8 July 2016
Keywords: Hypotension; Phenylephrine; Spinal anesthesia
Abstract Study objective: Hypotension frequently occurs during spinal anesthesia (SA), especially in the elderly. Phenylephrine is effective to prevent SA-induced hypotension during cesarean delivery. The objective of this study was to evaluate the efficacy and safety of prophylactic infusion of phenylephrine after SA for orthopedic surgery in the elderly. Design: This prospective, randomized, double-blind, and placebo-controlled study included 54 patients older than 60 years undergoing elective lower limb surgery under SA (injection of 10 mg of isobaric bupivacaine with 5 μg of sufentanyl). Intervention: Patients were randomized to group P (100-μg/mL solution of phenylephrine solution at 1 mL/min after placement of SA) or the control group C (0.9% isotonic sodium chloride solution). The flow of the infusion was stopped if the mean arterial blood pressure (MAP) was higher than the baseline MAP and maintained or restarted at 1 mL/min if MAP was equal to or lower than the baseline MAP. Heart rate and MAP were collected throughout the case. Measurements: Hypotension was defined by a 20% decrease and hypertension as a 20% increase from baseline MAP. Bradycardia was defined as a heart rate lower than 50 beats per minute.
☆ The abstract of this article has already been presented in oral communication at the French National Congress of Anesthesia and Critical Care Medicine (SFAR) in September 2013. ☆☆ Conflicts of interest: none declared. ★ Funding: none. ⁎ Corresponding author at: Department of Anesthesiology and Critical Care Medicine, Purpan University Hospital, Hôpital Purpan, Place du Dr Baylac, TSA 40 031, 31059 Toulouse CEDEX 9, France. Tel.: +33 0 5 61 77 99 88. E-mail address: [email protected] (F. Ferré).
http://dx.doi.org/10.1016/j.jclinane.2016.07.020 0952-8180/© 2016 Elsevier Inc. All rights reserved.
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F. Ferré et al. Main results: Twenty-eight patients were randomized to group P and 26 patients to group C. MAP was higher in group P than in group C (92 ± 2 vs 82 ± 2 mm Hg, mean ± SD, Pb .001). The number of hypotensive episodes per patient was higher in group C compared with group P (9 [0-39] vs 1 [0-10], median [extremes], Pb .01), but the number of hypotensive patients was similar between groups (19 [73%] vs 20 [71%], P= 1). The time to onset of the first hypotension was shorter in group C (3 [1-13] vs 15 [1-95] minutes, P= .004). The proportion of patients without hypotension (cumulative survival) was better in group P (P= .04). The number of hypertensive episodes per patient and the number of bradycardic episodes per patient were similar between groups (P= not significant). Conclusion: Prophylactic phenylephrine infusion is an effective method of reducing SA-induced hypotension in the elderly. Compared with a control group, it delays the time to onset of hypotension and decreases the number of hypotensive episodes per patient. More data are needed to evaluate clinical outcomes of such a strategy. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Orthopedic surgery is the most common operation among patients older than 60 years [1], and lower extremities surgery represents 24% of all interventions among patients older than 75 years [2,3]. Spinal anesthesia (SA) is frequently chosen by anesthesiologists [4,5] but often associated with arterial hypotension [6]. This phenomenon is caused by the block of preganglionic sympathetic nerve fibers and is due to a decrease of both the systemic vascular resistance [7] as well as the cardiac output (stemming from a lower preload due to diminished venous return) [8-10]. Contrary to SA-induced hypotension for cesarean deliveries (where the effects of uteroplacental hypoperfusion can be directly assessed by the degree of fetal acidosis through umbilical cord pH) [11], the clinical effects and significance of mild hypotension after SA for other procedures are more difficult to evaluate and continue to be a matter of debate.1 Nevertheless, the high incidence of hypotension after SA in the elderly represents a significant anesthetic concern because this patient population frequently suffers from various comorbid conditions and is at high risk for hypoperfusion of organs with already decreased functional reserve [12-17]. The prevention of arterial hypotension after SA presents a challenging task, and the routine bolus administration of crystalloid fluids is not always effective and can quickly lead to volume overload and signs of congestive heart failure when the effects of SA dissipate [18,19]. For that reason, a number of authors have instead proposed the use of vasopressors, but agents such as ephedrine, a direct and indirect alpha adrenergic agent, increase heart rate and myocardial oxygen consumption, which can lead to adverse cardiovascular effects in elderly patients [7,20]. Phenylephrine, on the other hand, is a pure direct alpha-1 receptor agonist without a direct effect on heart rate, and its beneficial effect during SA for cesarean delivery has been well demonstrated [11,21-23]. Nishikawa et al [24] demonstrated that a prophylactic intramuscular injection of 1 Neal JM. Hypotension and bradycardia during spinal anesthesia: significance, prevention, and treatment. Techniques in Regional Anesthesia & Pain Management 2000;4(4):148-54.
phenylephrine in elderly patients undergoing surgical repair of hip fracture under SA could reduce the incidence of hypotension. However, the effects of intramuscular vasopressors are often more difficult to predict, and such a route of administration is generally not the first choice of most clinicians who usually favor repeated small doses of intravenous (IV) agents. The principal goal of our study was to evaluate the effectiveness of prophylactic IV phenylephrine infusion on the prevention of hypotension following SA in patients older than 60 years undergoing elective orthopedic surgery. We also intended to measure safety by evaluating the incidence of adverse events (hypertension and bradycardia) of the study medication. Cardiac and neurologic complications that can be associated with arterial hypotension were also recorded.
2. Methods This prospective, randomized, double-blind, and placebocontrolled study was approved by the local research ethics board (protocol number 09.001.03, favorable opinion of the CPP Sud-Ouest et Outre-Mer 1 dated January 19, 2011) and carried out between September 2011 and January 2013. This trial was registered at ClinicalTrials.gov (NCT01533662). All study subjects gave informed consent. Patients older than 60 years undergoing SA for elective orthopedic surgery on the lower extremities at the local university department (Centre Hospitalier Universitaire Rangueil de Toulouse, France) were eligible for inclusion. Exclusion criteria included uncontrolled hypertension, hyperthyroidism, dementia, symptomatic coronary artery disease, anemia with a hemoglobin b10 g/dL, or any contraindications to SA or administration of vasoconstrictors. The subjects were randomized to either treatment with IV phenylephrine (group P) or control (group C). According to routine practice at our institution, antihypertensive medications were discontinued the day before surgery except β-blockers. The usual criteria of fasting (6 hours for solids and 2 hours for nonparticulate liquids) were observed. Patients received no premedication before arrival in the operating room.
Prophylactic phenylephrine infusion during spinal anesthesia All patients were monitored in accordance with current guidelines, including noninvasive blood pressure as well as continuous electrocardiogram (ECG) and pulse oximetry (SpO2). Before placement of spinal anesthesia, all patients received an IV bolus of 8 mL/kg of Lactated Ringer’s [25]. The baseline mean arterial blood pressure (MAP) was calculated as the average of 3 consecutive measurements before placement of the SA. After placement of the SA, the patient's heart rate and noninvasive blood pressure were obtained every minute for 20 minutes and thereafter, in accordance with standard clinical practice, every 5 minutes until the end of surgery. Hemodynamics were defined as follows: hypotension: MAP drop of at least 20% from baseline; severe hypotension: MAP drop of at least 30% from baseline; hypertension: MAP increase of at least 20% from baseline; bradycardia: heart rate of less than 50/min. A hypotensive, hypertensive, or bradycardic patient is a patient who developed at least 1 episode of hypotension, hypertension, or bradycardia throughout the case. An independent co-investigator carried out the randomization by sealed envelopes and prepared the syringes containing either 100 μg/mL of phenylephrine (group P) or 0.9% isotonic sodium chloride solution (group C). Neither the
101 anesthesiologist of the case nor the patient knew the results of the randomization. Spinal anesthesia (midline puncture) was performed in the lateral decubitus position by a staff anesthetist at L3-L4 or L4-L5 with a 25-gauge Withacre needle (BD, Franklin Lakes, NJ) injecting 10 mg of isobaric 0.5% bupivacaine (2 mL) with 5 μg of sufentanil (1 mL for a total volume of 3 mL). After injection, the patients remained in the lateral decubitus position for 5 minutes and were then turned supine. The dermatome level of the sensory block (assessed by the loss of cold sensation using an alcohol-soaked gauze pad bilaterally) was checked every 5 minutes for 20 minutes. The modified Bromage scale (0 = no motor block, 1 = straight leg hip flexion blocked, 2 = knee flexion blocked, 3 = complete motor block) was used to quantify the degree of motor block at 20 minutes. Immediately following intrathecal injection of the local anesthetic, the infusion of phenylephrine (or isotonic sodium chloride solution) was started via infusion pump at 1 mL/min on the closest port of a patient's IV dedicated line. The infusion rate was adjusted (stopped if the MAP was higher than baseline or restarted/maintained at 1 mL/min if the MAP was equal to or lower than baseline) after every blood pressure (BP) measurement (every minute during the first 20 minutes
Enrollment Assessed for eligibility (n=64)
Excluded (n=7) ¨ Not meeting inclusion criteria (n= 4) ¨ Declined to participate (n= 1) ¨ Other reasons (n= 2) Randomized (n= 57)
Allocation 29 were allocated to receive phenylephrine -
28 received phenylephrine
-
1 did not receive phenylephrine (SA failure)
28 were allocated to receive normal saline -
28 received normal saline
-
Follow-Up Lost to follow-up (n=0)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Discontinued intervention (n=0)
Analysis 28 were included in 48 hours analysis
26 were included in 48 hours analysis (n=2 were excluded from analysis because of protocol violation)
Chart 1 Randomization and follow-up of patients. A total of 54 patients, older than 60 years, undergoing SA for elective orthopedic surgery were followed for 48 hours after surgery and included in the analysis.
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Table 1 Patient demographics, sensory and motor block, baseline hemodynamic parameters, and length of surgery for group P (phenylephrine) and group C (control) Variable
Group P
Group C
P
n Age (y) Sex (female-male) Weight (kg) Height (cm) ASA (1/2/3/4) Known hypertension Heart rate at baseline (beat per min) MAP at baseline (mm Hg) Sensory level Bromage score Surgery Foot Knee (TKA) Hip (THA) Other Length of surgery (min)
28 71.2 ± 7.6 17:11 77.7 ± 20.2 164 ± 10 5/20/3/0 12 (43%) 70 ± 12 94 ± 13 T7 (T3-T12) 3 (1-3)
26 73.5 ± 9.1 14:12 75.5 ± 17.3 166 ± 9 1/20/5/0 15 (58%) 68 ± 16 96 ± 9 T6 (T3-T12) 3 (1-3)
NS NS NS NS NS NS NS NS NS NS
8 15 (10) 4 (4) 1 100 (25-145)
3 15 (9) 4 (4) 4 102.5 (20-140)
NS
ASA = American Society of Anesthesiologists; TKA = total knee arthroplasty; THA = total hip arthroplasty; NS = not significant. Values are expressed as mean ± SD, median (extremes), or as percentage of total group (%).
and then every 5 minutes until the end of surgery). The total volume of solution infused was recorded at the end of surgery. Further treatment for hemodynamic derangements was carried out as follows: hypotension: 100 μg phenylephrine bolus IV; bradycardia (heart rate less than 50/min) with hypertension: hold syringe pump; and bradycardia with hypotension: atropine 10 μg/kg bolus IV. Serial ECGs and troponin Ic levels were performed postoperatively at 6, 24, and 48 hours. Myocardial ischemic disturbances were defined as follows: T-wave changes, STsegment elevation or depression, pathological Q waves or new left bundle-branch block on ECGs, and increase in
Table 2
serum troponin Ic (≥0.006 ng/mL). Simultaneously, all patients were screened by neurological examination (obvious clinical sign of stroke: facial paralysis, aphasia, upper limb monoplegia, or hemiplegia) and standardized confusion assessment method [26] for the diagnosis of postoperative delirium. Given the incidence of SA-induced hypotension in the elderly of almost 80% [27], we calculated the number of patients needed to detect a 40% difference in the incidence of hypotension between the 2 groups (with an α of 5% and a power of 90%) to be 26 in each group. Normal distribution of quantitative variables was verified by Kolmogorov-
Hemodynamic parameters for group P (phenylephrine) and group C (control)
Variable
Group P (n = 28)
Group C (n = 26)
P
MAP (mm Hg) No. of hypotensive episodes per patient No. of severe hypotensive episodes per patient No. of patients with hypotension Minimal MAP (mm Hg) Maximal MAP (mm Hg) Time to first hypotensive episode (min) No. of hypertensive episodes per patient No. of patients with hypertension No. of bradycardic episodes per patient No. of patients with bradycardia Cumulative dose of phenylephrine (μg) Volume of fluid intraoperatively administered (mL)
91.6 ± 1.8 1 (0-10) 0 (0-3) 20 (71%) 75.5 (50-97) 105.5 (68-146) 15 (1-95) 0 (0-6) 12 (43%) 0 (0-17) 8 (29%) 2570 (0-12 000) 750 (200-1500)
82.3 ± 1.9 9.5 (0-39) 0 (0-29) 19 (73%) 71 (44-88) 101.5 (80-159) 3 (1-13) 0 (0-3) 6 (23%) 0 (0-9) 3 (12%) 600 (0-2200) 600 (250-1500)
b.0001 .006 .12 1 .13 .41 .004 .08 .15 .17 .17 b.001 .69
Values are expressed as mean ± SD, median (extremes), or as percentage of total group (%). Number of patients with hypotension/hypertension/bradycardia = number of patients who developed at least 1 episode of hypotension/hypertension/bradycardia.
Prophylactic phenylephrine infusion during spinal anesthesia Smirnov test, and results expressed as mean ± SD or median (extremes). Comparisons were carried out with a mixed linear model or the Mann-Whitney test, and categorical variables were compared using the Fisher exact test. Changes in MAP over time were analyzed with a repeated-measure analysis of variance; and the cumulative proportion of patients without hypotension, by Kaplan-Meier analysis and Tarone-Ware test. Patients who did not have any episode of hypotension were treated as censored. A P value of b .05 was considered statistically significant. All calculations were carried out using SPSS version 20 (Armonk, NY).
3. Results Fifty-seven patients were randomized. One of them did not receive allocated intervention because of spinal anesthesia failure, and 2 of them were secondarily excluded because of protocol violation (Chart). A total of 54 patients completed the study successfully and were included in the analysis. Twenty-eight patients received phenylephrine (group P), and 26 patients isotonic sodium chloride solution (group C). There was no difference between groups in their demographics, sensory and motor block, baseline hemodynamic parameters, or length of surgery (Table 1). The MAP was higher in group P than in group C (91.6 ± 1.8 vs 82.3 ± 1.9 mm Hg, Pb .0001) (Table 2), and the variations of MAP over the first 20 minutes of the intervention (time of the shortest surgical intervention) showed higher MAPs in group P when compared with group C (P= .05). The number of hypotensive patients was not statistically different between the control group and the phenylephrine group (73% vs 71%, P= 1) (Table 2), but the number of hypotensive episodes per patient was significantly higher (9.5 [039] in group C vs 1 [0-10] in group P, P= .006) (Fig. 1). Neither the degree of hypotension (minimum MAP, P= .13) nor the number of severe hypotensive episodes per patient (MAP decrease to less than 30% below baseline, P = .12) was different between the phenylephrine and the control groups (Table 2). The time until the first hypotensive episode was shorter in the control group than in the phenylephrine group (3 [1-13] vs 15 [1-95] minutes, P= .004). The proportion of patients without hypotension (“cumulative survival over time”) was higher in group P compared with group C (P= .04, Fig. 2). The number of hypertensive episodes per patient was similar between groups (0 [0-3] in group C vs 0 [0-6] in group P, P= .08). The number of patients who became hypertensive was higher in group P, but this did not reach statistical significance (43% vs 23%, P= .15). The maximal MAP was not statistically different between both groups (P= .41). The increase in the number of bradycardic episodes per patient and the increase in the number of patient who became bradycardic between both groups did not reach statistical significance (Table 2).
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*
Fig. 1 Number of hypotensive episodes per patient for group P (phenylephrine) and group C (control). Values are expressed as median, interquartiles, and extremes (*P= .006).
The total phenylephrine dose was significantly higher in group P (2570 [0-12 000] vs 600 [0-2200] μg in group C, Pb .001). Postoperatively, no new focal neurologic deficit or delirium was detected. Only 1 patient in the control group showed repolarization abnormalities at 48 hours, and although a higher proportion of patients in the control group showed a postoperative elevation of troponin Ic at 6, 24, and 48 hours, none of these changes reached statistical significance (Table 3).
Fig. 2 Cumulative survival (Kaplan-Meier) curves show the proportion of patients in each group without hypotension. The censored observations represent patients who have not had any hypotensive episodes by the time their surgery finished. The difference between group P (phenylephrine) and group C (control) is statistically significant (P= .04).
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Table 3 Postoperative cardiac outcomes compared between group P (phenylephrine) and group C (control) Group P (n = 28) Cardiac outcomes Ischemic changes on ECG 6h 0 24 h 0 48 h 0 Increase in troponin Ic 6h 3 (11%) 24 h 3 (11%) 48 h 6 (21%)
Group C (n = 26)
P
0 0 1 (4%) 4 (15%) 7 (27%) 6 (23%)
.4 .07 .9
Values are expressed as percentage of group total (%).
4. Discussion We found that infusing phenylephrine during orthopedic surgery in patients older than 60 years, beginning immediately after the placement of an SA, was effective in decreasing both the lag time to first as well as the number of hypotensive episodes per patient. The use of alpha-agonists to treat hypotension associated with neuraxial anesthesia has been studied extensively in obstetrics, and the current opinion favors phenylephrine over ephedrine as the pressor of choice due to its effectiveness and beneficial effect on umbilical pH and fetal acid-base balance [21,28,29]. Whereas the optimal regimen for prophylactic administration, that is, bolus vs infusion, is still being investigated [30], it would seem that the intramuscular injection, as studied by certain authors [24], may not be the first choice because the pharmacokinetic profile of slower systemic absorption could entail more unpredictable and delayed effects, such as hypertension and bradycardia. In our study, 70% of patients became hypotensive, and this figure is consistent with other published results [27]. Even though we did not show a difference between the overall total proportions of patients that became hypotensive, we did observe a significant reduction in hypotensive episodes per patient in the phenylephrine group, indicating that the total time of hypotension for any given patient with hypotension was less. Bijker et al [31] recently found that, for elderly patients, the mortality risk increases when the duration of intraoperative hypotension becomes long enough, suggesting that lower BPs are tolerated for shorter durations. We also found that the cumulative proportion of patients over time who were hypotensive (using the Kaplan-Meier survival approach) was less and that the time to the first hypotensive episode was longer in the phenylephrine group. All patients in the control group suffered their first episode of hypotension in the first 13 minutes after SA, and this period, corresponding with the sudden development of the sympathetic block causing a decrease in afterload and cardiac filling pressures, is traditionally a time of high workload for most anesthesiologists.
Different mechanisms could explain the fact that the Kaplan-Meier curves for both the phenylephrine and the control group seemed to merge over time, such as, for example, a decrease of its effect over time (tachyphylaxis), even though this is probably unlikely and to our knowledge has never been demonstrated for phenylephrine. The findings could also be due to our BP measurement protocol, which after an initial period of frequent BP checks every minute consisted of taking the BP only every 5 minutes. This latter measurement frequency (chosen to mirror clinical practice) could have led to greater swings in BP and thus more hypotensive episodes, in both groups, during this relatively long time interval. The use of a closed-loop infusion system may be optimal and confer a number of advantages (decrease interventions, decrease MAP fluctuations), and such a system has already been studied for this purpose in patients undergoing cesarean deliveries under SA [32,33]. We believe that where no closed-loop infusion systems are available, an infusion rate of 50 μg/min could perhaps provide better hemodynamic stability compared with a rate of 100 μg/min and decrease the number of required interventions by the practitioner, like it has been shown for use with SA during cesarean deliveries [34]. The safety of prophylactic phenylephrine infusion is an important factor. Even though we found a greater number of hypertensive patients in the phenylephrine group, this difference was not statistically significant. Moreover, the number of hypertensive episodes per patient, the number of bradycardic patients, and the number of bradycardia per patient were not statistically different between the phenylephrine and the control groups (Table 2). Our results are in keeping with the findings of Nishikawa et al [24] and suggest that the prophylactic phenylephrine infusion may be considered relatively safe with respect to its effect on hypertension and bradycardia despite the use of a high cumulative dose at the infusion rate of 100 μg/min. Although there is clearly an association between intraoperative hypotension and poor outcome, the efficacy of any intervention cannot be answered definitively. Thiele et al [35,36] define a tangible bias as our tendency to “favor what we can see and understand over what we cannot” and argue that the use of phenylephrine is driven by this bias by favoring less important but immediately measurable variables, such as MAP, over more important but less measurable variables, such as tissue oxygen delivery. This bias unfortunately runs through much of our regular resuscitation practices [37]. Finally, does a “cosmetic” improvement of BP change the prognosis of patients? The question still remains. The incidence of delirium ranges from 5% to approximately 10% following elective surgery, and perioperative hypotension may be a contributing factor [38]. We did not find any case of postoperative delirium among the 54 elective patients in our study, and a much larger sample size would have to be studied to evaluate postoperative neurologic complications. A study of the effect on delirium could focus on certain high-risk populations, such as patients with hip fractures who experience postoperative delirium in almost 35% of the cases [16].
Prophylactic phenylephrine infusion during spinal anesthesia Elevation of troponin value may represent a warning myocardial insult [39]. Indeed, among adults undergoing noncardiac surgery, myocardial injury after noncardiac surgery is common and associated with substantial mortality [40]. We did not observe statistically significant differences of myocardial injury after noncardiac surgery between groups. A much larger sample size would have to be studied to evaluate postoperative cardiac complications that could be associated with intraoperative hypotension. The prophylactic infusion of phenylephrine prevents hypotension probably by limiting the duration spent below the threshold of hypotension after SA in the elderly population. A larger study would allow evaluating the optimal dosing regimen (perhaps including a closed-loop infusion pump), as well as the effect on less frequent postoperative outcomes.
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F. Ferré et al. [39] Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators, Devereaux PJ, Chan MTV, AlonsoCoello P, Walsh M, Berwanger O, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA 2012;307:2295-304. [40] Botto F, Alonso-Coello P, Chan MTV, Villar JC, Xavier D, Srinathan S, et al. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology 2014;120:564-78.
Original contribution
Prophylactic phenylephrine infusion for the prevention of hypotension after spinal anesthesia in the elderly: a randomized controlled clinical trial☆,☆☆,★ Fabrice Ferré MD a,⁎, Philippe Marty MD a , Laura Bruneteau MD a , Virgine Merlet MD a , Benoît Bataille MD b , Anne Ferrier MD a , Claude Gris MD a , Matt Kurrek MD c , Olivier Fourcade MD, PhD a , Vincent Minville MD, PhD a a
Department of Anesthesiology and Critical Care Medicine, Purpan University Hospital, Toulouse, France Department of Critical Care Medicine, Narbonne Hospital, Narbonne, France c Department of Anesthesia, University of Toronto, 150 College St, Room 121, Fitzgerald Bldg, Toronto, Ontario, M5S 3E2, Canada b
Received 1 September 2015; revised 10 June 2016; accepted 8 July 2016
Keywords: Hypotension; Phenylephrine; Spinal anesthesia
Abstract Study objective: Hypotension frequently occurs during spinal anesthesia (SA), especially in the elderly. Phenylephrine is effective to prevent SA-induced hypotension during cesarean delivery. The objective of this study was to evaluate the efficacy and safety of prophylactic infusion of phenylephrine after SA for orthopedic surgery in the elderly. Design: This prospective, randomized, double-blind, and placebo-controlled study included 54 patients older than 60 years undergoing elective lower limb surgery under SA (injection of 10 mg of isobaric bupivacaine with 5 μg of sufentanyl). Intervention: Patients were randomized to group P (100-μg/mL solution of phenylephrine solution at 1 mL/min after placement of SA) or the control group C (0.9% isotonic sodium chloride solution). The flow of the infusion was stopped if the mean arterial blood pressure (MAP) was higher than the baseline MAP and maintained or restarted at 1 mL/min if MAP was equal to or lower than the baseline MAP. Heart rate and MAP were collected throughout the case. Measurements: Hypotension was defined by a 20% decrease and hypertension as a 20% increase from baseline MAP. Bradycardia was defined as a heart rate lower than 50 beats per minute.
☆ The abstract of this article has already been presented in oral communication at the French National Congress of Anesthesia and Critical Care Medicine (SFAR) in September 2013. ☆☆ Conflicts of interest: none declared. ★ Funding: none. ⁎ Corresponding author at: Department of Anesthesiology and Critical Care Medicine, Purpan University Hospital, Hôpital Purpan, Place du Dr Baylac, TSA 40 031, 31059 Toulouse CEDEX 9, France. Tel.: +33 0 5 61 77 99 88. E-mail address: [email protected] (F. Ferré).
http://dx.doi.org/10.1016/j.jclinane.2016.07.020 0952-8180/© 2016 Elsevier Inc. All rights reserved.
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F. Ferré et al. Main results: Twenty-eight patients were randomized to group P and 26 patients to group C. MAP was higher in group P than in group C (92 ± 2 vs 82 ± 2 mm Hg, mean ± SD, Pb .001). The number of hypotensive episodes per patient was higher in group C compared with group P (9 [0-39] vs 1 [0-10], median [extremes], Pb .01), but the number of hypotensive patients was similar between groups (19 [73%] vs 20 [71%], P= 1). The time to onset of the first hypotension was shorter in group C (3 [1-13] vs 15 [1-95] minutes, P= .004). The proportion of patients without hypotension (cumulative survival) was better in group P (P= .04). The number of hypertensive episodes per patient and the number of bradycardic episodes per patient were similar between groups (P= not significant). Conclusion: Prophylactic phenylephrine infusion is an effective method of reducing SA-induced hypotension in the elderly. Compared with a control group, it delays the time to onset of hypotension and decreases the number of hypotensive episodes per patient. More data are needed to evaluate clinical outcomes of such a strategy. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Orthopedic surgery is the most common operation among patients older than 60 years [1], and lower extremities surgery represents 24% of all interventions among patients older than 75 years [2,3]. Spinal anesthesia (SA) is frequently chosen by anesthesiologists [4,5] but often associated with arterial hypotension [6]. This phenomenon is caused by the block of preganglionic sympathetic nerve fibers and is due to a decrease of both the systemic vascular resistance [7] as well as the cardiac output (stemming from a lower preload due to diminished venous return) [8-10]. Contrary to SA-induced hypotension for cesarean deliveries (where the effects of uteroplacental hypoperfusion can be directly assessed by the degree of fetal acidosis through umbilical cord pH) [11], the clinical effects and significance of mild hypotension after SA for other procedures are more difficult to evaluate and continue to be a matter of debate.1 Nevertheless, the high incidence of hypotension after SA in the elderly represents a significant anesthetic concern because this patient population frequently suffers from various comorbid conditions and is at high risk for hypoperfusion of organs with already decreased functional reserve [12-17]. The prevention of arterial hypotension after SA presents a challenging task, and the routine bolus administration of crystalloid fluids is not always effective and can quickly lead to volume overload and signs of congestive heart failure when the effects of SA dissipate [18,19]. For that reason, a number of authors have instead proposed the use of vasopressors, but agents such as ephedrine, a direct and indirect alpha adrenergic agent, increase heart rate and myocardial oxygen consumption, which can lead to adverse cardiovascular effects in elderly patients [7,20]. Phenylephrine, on the other hand, is a pure direct alpha-1 receptor agonist without a direct effect on heart rate, and its beneficial effect during SA for cesarean delivery has been well demonstrated [11,21-23]. Nishikawa et al [24] demonstrated that a prophylactic intramuscular injection of 1 Neal JM. Hypotension and bradycardia during spinal anesthesia: significance, prevention, and treatment. Techniques in Regional Anesthesia & Pain Management 2000;4(4):148-54.
phenylephrine in elderly patients undergoing surgical repair of hip fracture under SA could reduce the incidence of hypotension. However, the effects of intramuscular vasopressors are often more difficult to predict, and such a route of administration is generally not the first choice of most clinicians who usually favor repeated small doses of intravenous (IV) agents. The principal goal of our study was to evaluate the effectiveness of prophylactic IV phenylephrine infusion on the prevention of hypotension following SA in patients older than 60 years undergoing elective orthopedic surgery. We also intended to measure safety by evaluating the incidence of adverse events (hypertension and bradycardia) of the study medication. Cardiac and neurologic complications that can be associated with arterial hypotension were also recorded.
2. Methods This prospective, randomized, double-blind, and placebocontrolled study was approved by the local research ethics board (protocol number 09.001.03, favorable opinion of the CPP Sud-Ouest et Outre-Mer 1 dated January 19, 2011) and carried out between September 2011 and January 2013. This trial was registered at ClinicalTrials.gov (NCT01533662). All study subjects gave informed consent. Patients older than 60 years undergoing SA for elective orthopedic surgery on the lower extremities at the local university department (Centre Hospitalier Universitaire Rangueil de Toulouse, France) were eligible for inclusion. Exclusion criteria included uncontrolled hypertension, hyperthyroidism, dementia, symptomatic coronary artery disease, anemia with a hemoglobin b10 g/dL, or any contraindications to SA or administration of vasoconstrictors. The subjects were randomized to either treatment with IV phenylephrine (group P) or control (group C). According to routine practice at our institution, antihypertensive medications were discontinued the day before surgery except β-blockers. The usual criteria of fasting (6 hours for solids and 2 hours for nonparticulate liquids) were observed. Patients received no premedication before arrival in the operating room.
Prophylactic phenylephrine infusion during spinal anesthesia All patients were monitored in accordance with current guidelines, including noninvasive blood pressure as well as continuous electrocardiogram (ECG) and pulse oximetry (SpO2). Before placement of spinal anesthesia, all patients received an IV bolus of 8 mL/kg of Lactated Ringer’s [25]. The baseline mean arterial blood pressure (MAP) was calculated as the average of 3 consecutive measurements before placement of the SA. After placement of the SA, the patient's heart rate and noninvasive blood pressure were obtained every minute for 20 minutes and thereafter, in accordance with standard clinical practice, every 5 minutes until the end of surgery. Hemodynamics were defined as follows: hypotension: MAP drop of at least 20% from baseline; severe hypotension: MAP drop of at least 30% from baseline; hypertension: MAP increase of at least 20% from baseline; bradycardia: heart rate of less than 50/min. A hypotensive, hypertensive, or bradycardic patient is a patient who developed at least 1 episode of hypotension, hypertension, or bradycardia throughout the case. An independent co-investigator carried out the randomization by sealed envelopes and prepared the syringes containing either 100 μg/mL of phenylephrine (group P) or 0.9% isotonic sodium chloride solution (group C). Neither the
101 anesthesiologist of the case nor the patient knew the results of the randomization. Spinal anesthesia (midline puncture) was performed in the lateral decubitus position by a staff anesthetist at L3-L4 or L4-L5 with a 25-gauge Withacre needle (BD, Franklin Lakes, NJ) injecting 10 mg of isobaric 0.5% bupivacaine (2 mL) with 5 μg of sufentanil (1 mL for a total volume of 3 mL). After injection, the patients remained in the lateral decubitus position for 5 minutes and were then turned supine. The dermatome level of the sensory block (assessed by the loss of cold sensation using an alcohol-soaked gauze pad bilaterally) was checked every 5 minutes for 20 minutes. The modified Bromage scale (0 = no motor block, 1 = straight leg hip flexion blocked, 2 = knee flexion blocked, 3 = complete motor block) was used to quantify the degree of motor block at 20 minutes. Immediately following intrathecal injection of the local anesthetic, the infusion of phenylephrine (or isotonic sodium chloride solution) was started via infusion pump at 1 mL/min on the closest port of a patient's IV dedicated line. The infusion rate was adjusted (stopped if the MAP was higher than baseline or restarted/maintained at 1 mL/min if the MAP was equal to or lower than baseline) after every blood pressure (BP) measurement (every minute during the first 20 minutes
Enrollment Assessed for eligibility (n=64)
Excluded (n=7) ¨ Not meeting inclusion criteria (n= 4) ¨ Declined to participate (n= 1) ¨ Other reasons (n= 2) Randomized (n= 57)
Allocation 29 were allocated to receive phenylephrine -
28 received phenylephrine
-
1 did not receive phenylephrine (SA failure)
28 were allocated to receive normal saline -
28 received normal saline
-
Follow-Up Lost to follow-up (n=0)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Discontinued intervention (n=0)
Analysis 28 were included in 48 hours analysis
26 were included in 48 hours analysis (n=2 were excluded from analysis because of protocol violation)
Chart 1 Randomization and follow-up of patients. A total of 54 patients, older than 60 years, undergoing SA for elective orthopedic surgery were followed for 48 hours after surgery and included in the analysis.
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Table 1 Patient demographics, sensory and motor block, baseline hemodynamic parameters, and length of surgery for group P (phenylephrine) and group C (control) Variable
Group P
Group C
P
n Age (y) Sex (female-male) Weight (kg) Height (cm) ASA (1/2/3/4) Known hypertension Heart rate at baseline (beat per min) MAP at baseline (mm Hg) Sensory level Bromage score Surgery Foot Knee (TKA) Hip (THA) Other Length of surgery (min)
28 71.2 ± 7.6 17:11 77.7 ± 20.2 164 ± 10 5/20/3/0 12 (43%) 70 ± 12 94 ± 13 T7 (T3-T12) 3 (1-3)
26 73.5 ± 9.1 14:12 75.5 ± 17.3 166 ± 9 1/20/5/0 15 (58%) 68 ± 16 96 ± 9 T6 (T3-T12) 3 (1-3)
NS NS NS NS NS NS NS NS NS NS
8 15 (10) 4 (4) 1 100 (25-145)
3 15 (9) 4 (4) 4 102.5 (20-140)
NS
ASA = American Society of Anesthesiologists; TKA = total knee arthroplasty; THA = total hip arthroplasty; NS = not significant. Values are expressed as mean ± SD, median (extremes), or as percentage of total group (%).
and then every 5 minutes until the end of surgery). The total volume of solution infused was recorded at the end of surgery. Further treatment for hemodynamic derangements was carried out as follows: hypotension: 100 μg phenylephrine bolus IV; bradycardia (heart rate less than 50/min) with hypertension: hold syringe pump; and bradycardia with hypotension: atropine 10 μg/kg bolus IV. Serial ECGs and troponin Ic levels were performed postoperatively at 6, 24, and 48 hours. Myocardial ischemic disturbances were defined as follows: T-wave changes, STsegment elevation or depression, pathological Q waves or new left bundle-branch block on ECGs, and increase in
Table 2
serum troponin Ic (≥0.006 ng/mL). Simultaneously, all patients were screened by neurological examination (obvious clinical sign of stroke: facial paralysis, aphasia, upper limb monoplegia, or hemiplegia) and standardized confusion assessment method [26] for the diagnosis of postoperative delirium. Given the incidence of SA-induced hypotension in the elderly of almost 80% [27], we calculated the number of patients needed to detect a 40% difference in the incidence of hypotension between the 2 groups (with an α of 5% and a power of 90%) to be 26 in each group. Normal distribution of quantitative variables was verified by Kolmogorov-
Hemodynamic parameters for group P (phenylephrine) and group C (control)
Variable
Group P (n = 28)
Group C (n = 26)
P
MAP (mm Hg) No. of hypotensive episodes per patient No. of severe hypotensive episodes per patient No. of patients with hypotension Minimal MAP (mm Hg) Maximal MAP (mm Hg) Time to first hypotensive episode (min) No. of hypertensive episodes per patient No. of patients with hypertension No. of bradycardic episodes per patient No. of patients with bradycardia Cumulative dose of phenylephrine (μg) Volume of fluid intraoperatively administered (mL)
91.6 ± 1.8 1 (0-10) 0 (0-3) 20 (71%) 75.5 (50-97) 105.5 (68-146) 15 (1-95) 0 (0-6) 12 (43%) 0 (0-17) 8 (29%) 2570 (0-12 000) 750 (200-1500)
82.3 ± 1.9 9.5 (0-39) 0 (0-29) 19 (73%) 71 (44-88) 101.5 (80-159) 3 (1-13) 0 (0-3) 6 (23%) 0 (0-9) 3 (12%) 600 (0-2200) 600 (250-1500)
b.0001 .006 .12 1 .13 .41 .004 .08 .15 .17 .17 b.001 .69
Values are expressed as mean ± SD, median (extremes), or as percentage of total group (%). Number of patients with hypotension/hypertension/bradycardia = number of patients who developed at least 1 episode of hypotension/hypertension/bradycardia.
Prophylactic phenylephrine infusion during spinal anesthesia Smirnov test, and results expressed as mean ± SD or median (extremes). Comparisons were carried out with a mixed linear model or the Mann-Whitney test, and categorical variables were compared using the Fisher exact test. Changes in MAP over time were analyzed with a repeated-measure analysis of variance; and the cumulative proportion of patients without hypotension, by Kaplan-Meier analysis and Tarone-Ware test. Patients who did not have any episode of hypotension were treated as censored. A P value of b .05 was considered statistically significant. All calculations were carried out using SPSS version 20 (Armonk, NY).
3. Results Fifty-seven patients were randomized. One of them did not receive allocated intervention because of spinal anesthesia failure, and 2 of them were secondarily excluded because of protocol violation (Chart). A total of 54 patients completed the study successfully and were included in the analysis. Twenty-eight patients received phenylephrine (group P), and 26 patients isotonic sodium chloride solution (group C). There was no difference between groups in their demographics, sensory and motor block, baseline hemodynamic parameters, or length of surgery (Table 1). The MAP was higher in group P than in group C (91.6 ± 1.8 vs 82.3 ± 1.9 mm Hg, Pb .0001) (Table 2), and the variations of MAP over the first 20 minutes of the intervention (time of the shortest surgical intervention) showed higher MAPs in group P when compared with group C (P= .05). The number of hypotensive patients was not statistically different between the control group and the phenylephrine group (73% vs 71%, P= 1) (Table 2), but the number of hypotensive episodes per patient was significantly higher (9.5 [039] in group C vs 1 [0-10] in group P, P= .006) (Fig. 1). Neither the degree of hypotension (minimum MAP, P= .13) nor the number of severe hypotensive episodes per patient (MAP decrease to less than 30% below baseline, P = .12) was different between the phenylephrine and the control groups (Table 2). The time until the first hypotensive episode was shorter in the control group than in the phenylephrine group (3 [1-13] vs 15 [1-95] minutes, P= .004). The proportion of patients without hypotension (“cumulative survival over time”) was higher in group P compared with group C (P= .04, Fig. 2). The number of hypertensive episodes per patient was similar between groups (0 [0-3] in group C vs 0 [0-6] in group P, P= .08). The number of patients who became hypertensive was higher in group P, but this did not reach statistical significance (43% vs 23%, P= .15). The maximal MAP was not statistically different between both groups (P= .41). The increase in the number of bradycardic episodes per patient and the increase in the number of patient who became bradycardic between both groups did not reach statistical significance (Table 2).
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*
Fig. 1 Number of hypotensive episodes per patient for group P (phenylephrine) and group C (control). Values are expressed as median, interquartiles, and extremes (*P= .006).
The total phenylephrine dose was significantly higher in group P (2570 [0-12 000] vs 600 [0-2200] μg in group C, Pb .001). Postoperatively, no new focal neurologic deficit or delirium was detected. Only 1 patient in the control group showed repolarization abnormalities at 48 hours, and although a higher proportion of patients in the control group showed a postoperative elevation of troponin Ic at 6, 24, and 48 hours, none of these changes reached statistical significance (Table 3).
Fig. 2 Cumulative survival (Kaplan-Meier) curves show the proportion of patients in each group without hypotension. The censored observations represent patients who have not had any hypotensive episodes by the time their surgery finished. The difference between group P (phenylephrine) and group C (control) is statistically significant (P= .04).
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Table 3 Postoperative cardiac outcomes compared between group P (phenylephrine) and group C (control) Group P (n = 28) Cardiac outcomes Ischemic changes on ECG 6h 0 24 h 0 48 h 0 Increase in troponin Ic 6h 3 (11%) 24 h 3 (11%) 48 h 6 (21%)
Group C (n = 26)
P
0 0 1 (4%) 4 (15%) 7 (27%) 6 (23%)
.4 .07 .9
Values are expressed as percentage of group total (%).
4. Discussion We found that infusing phenylephrine during orthopedic surgery in patients older than 60 years, beginning immediately after the placement of an SA, was effective in decreasing both the lag time to first as well as the number of hypotensive episodes per patient. The use of alpha-agonists to treat hypotension associated with neuraxial anesthesia has been studied extensively in obstetrics, and the current opinion favors phenylephrine over ephedrine as the pressor of choice due to its effectiveness and beneficial effect on umbilical pH and fetal acid-base balance [21,28,29]. Whereas the optimal regimen for prophylactic administration, that is, bolus vs infusion, is still being investigated [30], it would seem that the intramuscular injection, as studied by certain authors [24], may not be the first choice because the pharmacokinetic profile of slower systemic absorption could entail more unpredictable and delayed effects, such as hypertension and bradycardia. In our study, 70% of patients became hypotensive, and this figure is consistent with other published results [27]. Even though we did not show a difference between the overall total proportions of patients that became hypotensive, we did observe a significant reduction in hypotensive episodes per patient in the phenylephrine group, indicating that the total time of hypotension for any given patient with hypotension was less. Bijker et al [31] recently found that, for elderly patients, the mortality risk increases when the duration of intraoperative hypotension becomes long enough, suggesting that lower BPs are tolerated for shorter durations. We also found that the cumulative proportion of patients over time who were hypotensive (using the Kaplan-Meier survival approach) was less and that the time to the first hypotensive episode was longer in the phenylephrine group. All patients in the control group suffered their first episode of hypotension in the first 13 minutes after SA, and this period, corresponding with the sudden development of the sympathetic block causing a decrease in afterload and cardiac filling pressures, is traditionally a time of high workload for most anesthesiologists.
Different mechanisms could explain the fact that the Kaplan-Meier curves for both the phenylephrine and the control group seemed to merge over time, such as, for example, a decrease of its effect over time (tachyphylaxis), even though this is probably unlikely and to our knowledge has never been demonstrated for phenylephrine. The findings could also be due to our BP measurement protocol, which after an initial period of frequent BP checks every minute consisted of taking the BP only every 5 minutes. This latter measurement frequency (chosen to mirror clinical practice) could have led to greater swings in BP and thus more hypotensive episodes, in both groups, during this relatively long time interval. The use of a closed-loop infusion system may be optimal and confer a number of advantages (decrease interventions, decrease MAP fluctuations), and such a system has already been studied for this purpose in patients undergoing cesarean deliveries under SA [32,33]. We believe that where no closed-loop infusion systems are available, an infusion rate of 50 μg/min could perhaps provide better hemodynamic stability compared with a rate of 100 μg/min and decrease the number of required interventions by the practitioner, like it has been shown for use with SA during cesarean deliveries [34]. The safety of prophylactic phenylephrine infusion is an important factor. Even though we found a greater number of hypertensive patients in the phenylephrine group, this difference was not statistically significant. Moreover, the number of hypertensive episodes per patient, the number of bradycardic patients, and the number of bradycardia per patient were not statistically different between the phenylephrine and the control groups (Table 2). Our results are in keeping with the findings of Nishikawa et al [24] and suggest that the prophylactic phenylephrine infusion may be considered relatively safe with respect to its effect on hypertension and bradycardia despite the use of a high cumulative dose at the infusion rate of 100 μg/min. Although there is clearly an association between intraoperative hypotension and poor outcome, the efficacy of any intervention cannot be answered definitively. Thiele et al [35,36] define a tangible bias as our tendency to “favor what we can see and understand over what we cannot” and argue that the use of phenylephrine is driven by this bias by favoring less important but immediately measurable variables, such as MAP, over more important but less measurable variables, such as tissue oxygen delivery. This bias unfortunately runs through much of our regular resuscitation practices [37]. Finally, does a “cosmetic” improvement of BP change the prognosis of patients? The question still remains. The incidence of delirium ranges from 5% to approximately 10% following elective surgery, and perioperative hypotension may be a contributing factor [38]. We did not find any case of postoperative delirium among the 54 elective patients in our study, and a much larger sample size would have to be studied to evaluate postoperative neurologic complications. A study of the effect on delirium could focus on certain high-risk populations, such as patients with hip fractures who experience postoperative delirium in almost 35% of the cases [16].
Prophylactic phenylephrine infusion during spinal anesthesia Elevation of troponin value may represent a warning myocardial insult [39]. Indeed, among adults undergoing noncardiac surgery, myocardial injury after noncardiac surgery is common and associated with substantial mortality [40]. We did not observe statistically significant differences of myocardial injury after noncardiac surgery between groups. A much larger sample size would have to be studied to evaluate postoperative cardiac complications that could be associated with intraoperative hypotension. The prophylactic infusion of phenylephrine prevents hypotension probably by limiting the duration spent below the threshold of hypotension after SA in the elderly population. A larger study would allow evaluating the optimal dosing regimen (perhaps including a closed-loop infusion pump), as well as the effect on less frequent postoperative outcomes.
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