- Email: [email protected]
Hydromorphone vs fentanyl for epidural analgesia and anesthesia
The American Journal of Surgery (2016) -, -–-
Hydromorphone vs fentanyl for epidural analgesia and anesthesia Melissa N. Nguyen, Pharm.D., B.C.P.S.a, Lisa Hall Zimmerman, Pharm.D., B.C.P.S., B.C.N.S.P., B.C.C.C.P., F.C.C.M.a,*, Kathy Meloche, B.S.N., R.N.-B.C.b, Heather S. Dolman, M.D., F.A.C.S.c, Alfred E. Baylor, M.D., F.A.C.S.c, Samir Fuleihan, M.D.d, Robert F. Wilson, M.D., F.A.C.S., M.C.C.M.c, James G. Tyburski, M.D., F.A.C.S.c a
Department of Pharmacy Services, Detroit Receiving Hospital, 4201 St. Antoine Blvd, UHC-1B, Detroit, MI 48201, USA; bDepartment of Anesthesia, Harper University Hospital/Hutzel Women’s Hospital, Detroit, MI, USA; cDepartment of Surgery, Wayne State University/Detroit Receiving Hospital, Detroit, MI, USA; dDepartment of Anesthesiology, Detroit Medical Center, Harper University Hospital, Detroit, MI, USA
KEYWORDS: Analgesia; Epidural; Anesthesia; Hydromorphone; Fentanyl
Abstract BACKGROUND: Epidural analgesia/anesthesia is used during surgery because it dramatically relieves pain and attenuates the stress response. Because limited data exist regarding the relative merits of hydromorphone (HM) and fentanyl (FENT), the objective was to determine which was more safe and effective. METHODS: Prospective case-matched, observational study evaluated elective surgery patients: 30 HM and 60 FENT. Variables were measured perioperatively. RESULTS: Of the 90 patients, mean age was 52 years; simplified acute physiology score was 26 6 10; and American Society of Anesthesiologists score was 2.4 HM vs 2.7 FENT, P 5 .03. HM patients were more apt to be excessively sedated (16% HM vs 1% FENT, P 5 .007) and have poor mental unresponsiveness (6% HM vs 0% FENT, P 5 .04). The incidence of hypotension was not different, 76% HM vs 80% FENT, not significant. CONCLUSIONS: In a closely case-matched population, FENT caused less excessive sedation and unresponsiveness. FENT patients had better intraoperative urine output and tended to have less repeated episodes of hypotension. Ó 2016 Elsevier Inc. All rights reserved.
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. The study was performed at Detroit Receiving Hospital, Harper University Hospital, Detroit, Michigan * Corresponding author. Tel.: 11-586-943-5994; fax: 11-313-745-2965. E-mail address: [email protected] Manuscript received July 12, 2015; revised manuscript December 9, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.12.003
Acute pain generally occurs because of tissue damage or inflammation. Inadequate postoperative pain relief has been identified as an important predictor of long-term morbidity and mortality.1–4 In an effort to improve postoperative pain management, in 2001 The Joint Commission implemented standards for pain management that made it a medical priority and stated that all patients have the right to pain assessment and treatment.5 In addition, numerous
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organizations have published guidelines to help improve pain management.6,7 The pain of major surgery induces a stress response that leads to pathophysiologic changes in all major organs as well as alterations in hemodynamics, metabolism, immunology, and hemostasis.8 Previous studies and metaanalyses have shown epidural analgesia and anesthesia (EAA) to be advantageous to parenteral opioids for pain management in the perioperative period.2,9 We could not find any studies comparing the efficacy and safety of the 2 most commonly used opioids in epidurals, hydromorphone (HM) and fentanyl (FENT). Consequently, we chose to evaluate these 2 opioids in the setting of perioperative EAA. The primary objective was to determine which was safer and more effective, FENT or HM.
epidural therapy was discontinued. The Anesthesia Pain Service managed the epidural dosing throughout and also determined when to discontinue the epidural catheter. A significant decrease in blood pressure was defined as a decline in systolic blood pressure 20 -mm Hg or more from the baseline.9 A reduction in blood pressure was anticipated after induction of general anesthesia. Hence, analysis of blood pressure variations occurred after hemodynamic stabilization after general anesthesia induction. Repeated episodes of decreases in blood pressure or hypotension were defined as occurrences 2 or more events. To be deemed as repeated episodes, the initial hypotensive event had to recover to normal blood pressure and maintained recovery for at least 6 hours. The level of pain was evaluated both at rest and during activity by the visual analoge scale (VAS) score. Pain with activity was assessed during the time the patient was standing out of bed or ambulating. Inadequate pain control was defined as a VAS score of 5 or more, plus the need for medication interventions. These interventions included increasing the epidural infusion rate or providing intravenous opioids, specifically morphine. An epidural failure was defined as the need for intravenous opioids or increase in the epidural infusion rate. Complications evaluated included hypotension, pruritus, extremity paresthesias, excessive sedation (Modified Ramsey Sedation Score [MRSS] R 4), nausea/vomiting, chest pain, and unresponsiveness (MRSS 5 6).10 Statistical analyses were performed using the Statistical Package for the Social Sciences, version 21.0. Descriptive statistics, Chi-square, Fisher’s exact, Mann-Whitney U, and t tests were used as appropriate. Multiple regression analyses were performed to determine whether there were any variables that had a positive correlation to decreases in blood pressure or increases in epidural dose requirements. A power analysis was performed a priori and found that at least 28 patients would be needed for the primary objective. Statistical significance was determined by a P value less than .05.
Methods This was a human investigations committee-approved, prospective, observational study of patients who had an epidural catheter placed for perioperative analgesia and anesthesia at an academic medical center. Elective nontrauma surgery patients age 18 years or older who received EAA perioperatively were included for evaluation. Obstetric patients, patients with only a nerve block, and surgical cases with inadequate numbers of patients to case match were excluded. Patients were case matched according to the surgical procedure and divided in a 1:2 ratio, HM vs FENT, which was decided a priori. For example, 1 gastric bypass HM patient was matched to 2 gastric bypass FENT patients. Most of the patients received FENT epidurals for surgical procedures. Hence, the intent was to control for sparse data problems which might exist between the 2 opioids which could allow the data to favor FENT based on outcomes. All patients received concomitant epidural bupivacaine with concentrations of .0625% and .075% with no difference between the groups. The adequacy of pain control was compared to the typically described dosage ranges for epidural HM .15 to .3 mg/hr and FENT .5 to 1.0 mcg/kg/hr.8 Weight-based dosing (mcg/kg/hr) exists for FENT based in the pharmacokinetic properties of this synthetic opioid. FENT is highly lipophilic crossing the blood brain barrier easily. Weight-based dosing is used to prevent under or overdosing which can lead to ineffectiveness or over sedation, respectively. HM is a more hydrophilic opioid and dosed in mg/hr based on the efficacy data. Baseline characteristics and severity of illness scores were collected. The rates and severity of decreases in blood pressure and other epidural-related complications possibly related to the EAA were evaluated. Blood pressure was evaluated before placement of the epidural, then every 15 minutes after the initiation of the epidural during the operative theater and in the postanesthesia care unit. Then, blood pressure was evaluated hourly for 2 hours, then every 2 hours for 16 hours, and then every 4 hours until the
Results Of the 409 patients evaluated for inclusion, only 90 elective, nontrauma surgery patients met inclusion criteria and case matching. The primary reasons for exclusion were due to patients receiving an epidural for obstetrical reasons and limited numbers of patients receiving HM to case match based on the surgical procedure. The most frequent surgeries performed were total abdominal hysterectomy (36%), exploratory laparotomy with resection (34%), gastric bypass (13%), and genitourinary procedures (9%). Baseline characteristics were similar between the groups regarding age, sex, race, and simplified acute physiology score (Table 1). The epidural catheter was placed at a thoracic site in 53% of the patients and at a lumbar site in 47%. Initiation of the epidural catheter was primarily
M.N. Nguyen et al. Table 1
Hydromorphone vs fentanyl for epidural pain control
3
Baseline characteristics
Demographics
All n 5 90
HM n 5 30
FENT n 5 60
P value
Age (y), mean 6 SD Female sex, n (%) African American, n (%) BMI (kg/m2), mean 6 SD Height (cm), mean 6 SD Weight (kg), mean 6 SD Physical status ASA score, mean 6 SD SAPS II Score Epidural location Thoracic, n (%) Lumbar, n (%)
52 6 13 64 (71) 57 (63) 33 6 11 167 6 11 91 6 28
52 6 11 19 (63) 16 (53) 35 6 12 166 6 9 89 6 29
51 6 14 45 (75) 41 (69) 32 6 11 167 6 12 94 6 25
.70 .25 .16 .40 .84 .31
2.5 6 0.6 26 6 10
2.4 6 0.6 28 6 7
2.7 6 0.5 26 6 11
.03 .27
48 (53) 42 (47)
17 (57) 13 (43)
31 (52) 29 (48)
.99 .99
ASA 5 American Society of Anesthesiologists; BMI 5 body mass index; FENT 5 fentanyl; HM 5 hydromorphone.
during the preoperative phase of care with the mean duration of the epidural catheter being 2.0 6 .7 days. Patients in the HM and FENT groups had similar episodes of moderate pain, VAS 6 to 8, 66% HM vs 58% FENT, P 5 .46; and severe pain, VAS 9 to 10, 36% HM vs 26% FENT, P 5 .32. However, the patients in the HM group tended to require more supplemental intravenous opioids to help control their pain, 30% HM vs 16% FENT, P 5 .14 suggesting a higher failure rate. No difference was seen in increases in epidural rates between the groups. The incidence of 2 or more epidural complications (eg, hypotension, pruritus, lower extremity paresthesias, nausea/
Table 2
vomiting, chest pain, excessive sedation [MRSS R 4], unresponsiveness [MRSS 5 6], tended to be higher with HM, [67% vs 48%, P 5 .10; Table 2]) Although the frequency of at least 1 episode of hypotension was similar in both groups, HM patients tended to have 2 or more episodes of decreased blood pressure during the time of epidural administration (50% vs 30%, P 5 .17). No significant correlation was observed between the incidence of a decrease in blood pressure and the site of epidural catheter placement between the groups. Comparing the hypotension between the groups based on epidural location in the thoracic spine, there were no differences (82% HM vs 90% FENT, P 5 .65).
Intraoperative data and complications
Characteristic Operative data Operative time*, h EBL*, ml/h Crystalloids*, ml/kg/h OR urine output*, ml/kg/h Intraoperative and postoperative hemodynamics Onset of hypotension*, h Hypotension† Decrease in SBP from epidural start to first hypotensive event, mm Hg* R2 episodes hypotension† Duration of hypotension, h* Hypotension requiring vasopressors† Hypotension with lumbar placement of epidural† Other complications† Chest pain Excessive sedation Extremity paresthesia Nausea and/or vomiting Pruritus Unresponsiveness
HM n 5 30
FENT n 5 60
P value
3.0 6 0.9 102 6 73 11.9 6 5.0 .8 6 0.5
2.7 6 1.2 102 6 141 13.3 6 6.6 1.6 6 2.0
.38 .99 .30 .05
2.0 6 2.7 23 (76) 43 6 14 15 (50) 3.6 6 9.7 14 (47) 9 (31)
2.3 6 4.6 48 (80) 44 6 18 21 (30) 2.7 6 4.5 22 (37) 2 (3)
.81 .71 .85 .17 .37 .36 .02
0 (0) 5 (16) 11 (36) 5 (16) 10 (33) 2 (6)
1 (1) 1 (1) 16 (28) 6 (10) 21 (36) 0 (0)
.47 .01 .42 .36 .75 .04
EBL 5 estimated blood loss; h 5 hours; kg 5 kilogram; ml 5 milliliters; OR 5 operative; SBP 5 systolic blood pressure; SD 5 standard deviation. *Expressed as mean 6 SD. † N (%).
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Intraoperative fluids, blood loss, operative time, and urine output were evaluated to determine if there was an impact on the decrease in blood pressure, but there was no difference between the groups. However, the FENT patients had a better urine output, P 5 .05. Patients with repeated episodes of decreases in blood pressure also tended to have longer hospital lengths of stay (6.2 6 4.0 HM vs 5.4 6 4.5 FENT days, P 5 .06). Overall, excessive sedation (MRSS R 4) occurred more frequently with HM, 16% vs 1% FENT, P 5 .007. Specifically, more sedation was seen in HM patients with lumbar placed epidurals, 31% HM vs 3% FENT, P 5 .02. The incidence of unresponsiveness (MRSS 5 6) was also higher with HM, 6% HM vs 0% FENT, P 5 .04. Evaluating the sedation episodes in patients receiving adjunct therapy, the sedation did not occur after supplemental morphine was given. No spinal hematomas were noted during the study period.
in the epidural infusion rate along with more supplemental intravenous opioids. Hence, we believe HM had a higher incidence of failure which may have been because of a technical reason. From our review, an epidural can have many variable causing failure and include anatomical catheter location, patient positioning, puncture site, and localization of the epidural space to name a few. FENT patients received slightly more operative intravenous fluids despite almost identical blood loss. There was some concern that the reduced amount of fluid volume administered to the HM patients might impact the frequency and severity of hypotension. However, when comparing patients who experienced hypotension, repeated episodes of hypotension or needed vasopressors, no differences in fluid intake were found. In addition, intraoperative urine output was significant with the FENT group. Limitations of this study include the fact that we were not able to correlate dosing requirements and efficacy to plasma and cerebral spinal fluid opioid concentrations. Considering this is an observational study, the location of the epidural catheter was selected based on the prescribing anesthesiologist. Hence, these data cannot be extrapolated to all surgical procedures.
Comments EAA is one of the best ways to control pain and to attenuate the stress response of major surgery. This technique has been shown to reduce complications, and decrease morbidity and mortality postoperatively compared with systemic opioid administration.2 A recent metaanalysis showed the superiority of epidural analgesia vs patient-controlled analgesia.4 Overall, epidurals containing opioids provided more analgesia when comparing VAS scores. However, the meta-analysis did not compare HM vs FENT individually.4 At our institution, the choice of an anesthetic/analgesic agent is based on provider preference, drug properties, and patient variables such as age and risk for decreases in blood pressure. To our knowledge, this is the 1st article comparing HM and FENT under these circumstances. FENT, a synthetic opioid with greater potency and lipophilic properties than morphine and HM, is the oldest meperidine-like agonist.11 FENT provides rapid, potent analgesia and provides a relatively quick onset of action and short duration of effect (.5 to 1 hour). Comparatively, HM has a fairly quick onset and longer duration of action. Hence, the short duration of FENT’s activity may be the reason our patient population did not have as much sedation and unresponsiveness. FENT does not demonstrate histaminereleasing properties which is known to cause vasodilation and subsequent hypotension.12 Although both HM and FENT do not exert a histamine release, FENT tended to be less likely to provide repeated episodes of hypotension. Equianalgesic dosing is known for HM and FENT for the intravenous route systemically. HM and FENT have been studied independently in the spinal fluid; however, no direct equivalence with HM and FENT has been established via the epidural route. Although the VAS scores were similar between the groups, HM patients appeared to have less adequate pain relief, requiring more frequent increases
Conclusions Overall, in a closely case-matched population, this study evaluated the 2 most commonly used opioids in combination with bupivacaine for epidural analgesia. Our FENT patients were relatively sicker based on their preoperative American Society of Anesthesiologists scores. However, we found relatively no statistical differences in major adverse effects such as hypotension between FENT and HM. FENT patients had better intraoperative urine output and tended to have less repeated episodes of hypotension. FENT epidural patients also had less excessive sedation and unresponsiveness in this closely case-matched surgical population and required less pain rescue maneuvers. Thus, these findings favor FENT over HM as the epidural opioid of choice.
References 1. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg 2007;104:689–702. 2. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg 2003;238:663–73. 3. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomized trials. BMJ 2000;321:1493–7. 4. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology 2005;103:1079–88. 5. Gordon DB, Rees SM, McCausland MP, et al. Improving reassessment and documentation of pain management. Joint Comm J Qual Patient Saf 2008;34:509–17.
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Hydromorphone vs fentanyl for epidural pain control
6. Apfelbaum JL, Ashburn MA, Connis RT, et al. Practice guidelines for acute pain management in the perioperative setting an updated report by the American Society of Anesthesiologists task force on acute pain management. Anesthesiology 2012;116:248–73. 7. Gross JB, Bailey PL, Connis RT, et al. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96: 1004–17. 8. de Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia: what are the choices? Anesth Analg 1996;83:867–75. 9. Bijker JB, van Klei WA, Kappen TH, et al. Incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007;107:213–20. 10. Ramsay M, Savege T, Simpson BR, et al. Controlled sedation with alphaxalone/alphadolone. BMJ 1974;2:656–9. 11. Tuman KJ, McCarthy RJ, March RJ, et al. Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991;73:696–704. 12. Grossman M, Abiose A, Tangphao O, et al. Morphine-induced venodilation in humans. Clin Pharmcol Thera 1996;60:554–60.
Discussion Discussant Dr. Jeffrey Bender (Oklahoma City, OK): I don’t understand the methodology that led to a one-to-two case match ratio. Why not just one-to-one? I would have liked to have seen the actual data on the number of cases and how they were divided between the 2 groups. The amount of I.V. fluid given intraoperatively was statistically the same in both groups, but the Fentanyl (FENT) patients had better urine output, twice the urine output. To me this implies that the FENT patients were better resuscitated during their operation. Could this explain why there was less postoperative hypotension in FENT group? Did you control for variance among anesthesia attendings? Could more experienced or, dare I say it, better anesthesia attendings be using FENT more often? While the amount was severe pain was the same in both group, the Hydromorphone (HM) patients got more supplemental opioids. Why was this? Dr. Zimmerman: Regarding the case matching, when we looked at all our patients, we have probably more than a thousand patients that are receiving epidurals over the 12-month period of time. When we looked at those, we actually recognized that most of those patients were receiving FENT and very few were receiving HM. So our intent was in that case matching, 1 to 2 ratio was try to eliminate any confounders that might be present in actually the practice with the FENT. To your 2nd question, these patients were elective cases who were placed on nothing by mouth after midnight. We anticipated the anesthesia attendings to administer consistent fluids perioperatively. These were not trauma patients who would receive aggressive resuscitation resulting in an
5
increase in urine output. We did not expect to find FENT patients with an increased urine output. The 3rd question was, do we control for anesthesia attendings? We did not look at that. That’s certainly something we can go back and review. I appreciate that comment. Regarding the last question about the patients receiving HM and more supplemental opioids, I think that’s certainly something we can go back and review. We didn’t understand why that was occurring, as well. We postulated that perhaps there are pharmacokinetic profile differences between FENT and HM that we’re just not seeing because it’s being delivered in an epidural fashion. Dr. Donn M. Schroder (Grosse Pointe, MI): I’m curious on the timing of the administration of the epidural. You stated that the delayed dose of FENT really had no advantage over the HM. And was that due to preemptive analgesia effect where perhaps it was preemptive when it was 1st given intraoperatively and that’s what made a statistical difference and it was not later? What was the timing of the intraoperative dosing of the FENT epidural? Was it at the beginning of the operation or was it toward the end? Dr. Zimmerman: As far as when the epidurals were placed, typically, most of them were placed in our preoperative holding area. After anesthesia induction, the epidural infusion was initiated between 30 minutes to an hour from the time in which induction had occurred. Dr. William C. Cirocco (Columbus, OH): I am curious, why epidural? Who’s pushing for this? Is it anesthesia or your surgeons? What operations are these? Which of your surgical faculty? You don’t get into much of the complicationsdpotential complications of epidural. For instance, there’s literature suggesting postoperative bilious and anastomotic leak in the colorectal population, for instance. Dr. Zimmerman: That’s a great question. One of the reasons why we chose to look at this is that we had 10 different FENT-bupivacaine and 6 different HM-bupivacaine concentrations. As you know, the National Patient Safety initiative encourages that we minimize any potential risk to the patient. With 16 different concentrations available, potential risk exists that the patient could receive the wrong drug concentration which could lead to harm. Through this evaluation, our intent was to streamline the number of epidural concentrations available by evaluating safety and efficacy to minimize potential risk to the patient. Dr. Cirocco: So, again, why epidural? I was at an institution where it was pushed by anesthesia. They got paid more than I got paid for the operation. The epidural came out in a day or two. These patients were in the hospital a week to 10 days recovering. So we went right back to a patient controlled analgesia. It made no sense to me in the population that I deal with. Dr. Zimmerman: Our surgeons work with anesthesia to determine the type of postoperative pain control best for the patient based on the procedure performed. So that was usually a conversation with the surgeon.
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Dr. Michael White (Detroit, MI): It is my understanding that the anesthesia got to choose what they wanted to use each patient and it was just an observational study you were matching for the different two; is that correct? Dr. Zimmerman: Yes. Dr. White: My question would be, what made them choose one over the other? You didn’t really present any of that data. That could influence partly what your outcome was, because, again, it wasn’t adyou tried to case match. But, again, it wasn’t a randomized study, so it would be interesting to have seen that data, what made maybe them choose FENT vs HM for their case.
Dr. Zimmerman: Through the selection of and evaluating that data, that was not anything that was clear in the chart or record that I could ascertain. Dr. Abdelkader Hawasli (Detroit, MI): This is revisiting old things from more than 10 years ago. And the question is always, what is the effect of the ileus postop from the anesthetic this way, and the increase in the length of stay, you have not contributed to that effect on the total cost to the institution. Dr. Zimmerman: So looking at bowel function, we did look at that comparing the 2 groups and there was not any difference between return of bowel function based on which opioids that was used. We did not compare any cost data through this group.
Hydromorphone vs fentanyl for epidural analgesia and anesthesia Melissa N. Nguyen, Pharm.D., B.C.P.S.a, Lisa Hall Zimmerman, Pharm.D., B.C.P.S., B.C.N.S.P., B.C.C.C.P., F.C.C.M.a,*, Kathy Meloche, B.S.N., R.N.-B.C.b, Heather S. Dolman, M.D., F.A.C.S.c, Alfred E. Baylor, M.D., F.A.C.S.c, Samir Fuleihan, M.D.d, Robert F. Wilson, M.D., F.A.C.S., M.C.C.M.c, James G. Tyburski, M.D., F.A.C.S.c a
Department of Pharmacy Services, Detroit Receiving Hospital, 4201 St. Antoine Blvd, UHC-1B, Detroit, MI 48201, USA; bDepartment of Anesthesia, Harper University Hospital/Hutzel Women’s Hospital, Detroit, MI, USA; cDepartment of Surgery, Wayne State University/Detroit Receiving Hospital, Detroit, MI, USA; dDepartment of Anesthesiology, Detroit Medical Center, Harper University Hospital, Detroit, MI, USA
KEYWORDS: Analgesia; Epidural; Anesthesia; Hydromorphone; Fentanyl
Abstract BACKGROUND: Epidural analgesia/anesthesia is used during surgery because it dramatically relieves pain and attenuates the stress response. Because limited data exist regarding the relative merits of hydromorphone (HM) and fentanyl (FENT), the objective was to determine which was more safe and effective. METHODS: Prospective case-matched, observational study evaluated elective surgery patients: 30 HM and 60 FENT. Variables were measured perioperatively. RESULTS: Of the 90 patients, mean age was 52 years; simplified acute physiology score was 26 6 10; and American Society of Anesthesiologists score was 2.4 HM vs 2.7 FENT, P 5 .03. HM patients were more apt to be excessively sedated (16% HM vs 1% FENT, P 5 .007) and have poor mental unresponsiveness (6% HM vs 0% FENT, P 5 .04). The incidence of hypotension was not different, 76% HM vs 80% FENT, not significant. CONCLUSIONS: In a closely case-matched population, FENT caused less excessive sedation and unresponsiveness. FENT patients had better intraoperative urine output and tended to have less repeated episodes of hypotension. Ó 2016 Elsevier Inc. All rights reserved.
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. The study was performed at Detroit Receiving Hospital, Harper University Hospital, Detroit, Michigan * Corresponding author. Tel.: 11-586-943-5994; fax: 11-313-745-2965. E-mail address: [email protected] Manuscript received July 12, 2015; revised manuscript December 9, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.12.003
Acute pain generally occurs because of tissue damage or inflammation. Inadequate postoperative pain relief has been identified as an important predictor of long-term morbidity and mortality.1–4 In an effort to improve postoperative pain management, in 2001 The Joint Commission implemented standards for pain management that made it a medical priority and stated that all patients have the right to pain assessment and treatment.5 In addition, numerous
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The American Journal of Surgery, Vol -, No -, - 2016
organizations have published guidelines to help improve pain management.6,7 The pain of major surgery induces a stress response that leads to pathophysiologic changes in all major organs as well as alterations in hemodynamics, metabolism, immunology, and hemostasis.8 Previous studies and metaanalyses have shown epidural analgesia and anesthesia (EAA) to be advantageous to parenteral opioids for pain management in the perioperative period.2,9 We could not find any studies comparing the efficacy and safety of the 2 most commonly used opioids in epidurals, hydromorphone (HM) and fentanyl (FENT). Consequently, we chose to evaluate these 2 opioids in the setting of perioperative EAA. The primary objective was to determine which was safer and more effective, FENT or HM.
epidural therapy was discontinued. The Anesthesia Pain Service managed the epidural dosing throughout and also determined when to discontinue the epidural catheter. A significant decrease in blood pressure was defined as a decline in systolic blood pressure 20 -mm Hg or more from the baseline.9 A reduction in blood pressure was anticipated after induction of general anesthesia. Hence, analysis of blood pressure variations occurred after hemodynamic stabilization after general anesthesia induction. Repeated episodes of decreases in blood pressure or hypotension were defined as occurrences 2 or more events. To be deemed as repeated episodes, the initial hypotensive event had to recover to normal blood pressure and maintained recovery for at least 6 hours. The level of pain was evaluated both at rest and during activity by the visual analoge scale (VAS) score. Pain with activity was assessed during the time the patient was standing out of bed or ambulating. Inadequate pain control was defined as a VAS score of 5 or more, plus the need for medication interventions. These interventions included increasing the epidural infusion rate or providing intravenous opioids, specifically morphine. An epidural failure was defined as the need for intravenous opioids or increase in the epidural infusion rate. Complications evaluated included hypotension, pruritus, extremity paresthesias, excessive sedation (Modified Ramsey Sedation Score [MRSS] R 4), nausea/vomiting, chest pain, and unresponsiveness (MRSS 5 6).10 Statistical analyses were performed using the Statistical Package for the Social Sciences, version 21.0. Descriptive statistics, Chi-square, Fisher’s exact, Mann-Whitney U, and t tests were used as appropriate. Multiple regression analyses were performed to determine whether there were any variables that had a positive correlation to decreases in blood pressure or increases in epidural dose requirements. A power analysis was performed a priori and found that at least 28 patients would be needed for the primary objective. Statistical significance was determined by a P value less than .05.
Methods This was a human investigations committee-approved, prospective, observational study of patients who had an epidural catheter placed for perioperative analgesia and anesthesia at an academic medical center. Elective nontrauma surgery patients age 18 years or older who received EAA perioperatively were included for evaluation. Obstetric patients, patients with only a nerve block, and surgical cases with inadequate numbers of patients to case match were excluded. Patients were case matched according to the surgical procedure and divided in a 1:2 ratio, HM vs FENT, which was decided a priori. For example, 1 gastric bypass HM patient was matched to 2 gastric bypass FENT patients. Most of the patients received FENT epidurals for surgical procedures. Hence, the intent was to control for sparse data problems which might exist between the 2 opioids which could allow the data to favor FENT based on outcomes. All patients received concomitant epidural bupivacaine with concentrations of .0625% and .075% with no difference between the groups. The adequacy of pain control was compared to the typically described dosage ranges for epidural HM .15 to .3 mg/hr and FENT .5 to 1.0 mcg/kg/hr.8 Weight-based dosing (mcg/kg/hr) exists for FENT based in the pharmacokinetic properties of this synthetic opioid. FENT is highly lipophilic crossing the blood brain barrier easily. Weight-based dosing is used to prevent under or overdosing which can lead to ineffectiveness or over sedation, respectively. HM is a more hydrophilic opioid and dosed in mg/hr based on the efficacy data. Baseline characteristics and severity of illness scores were collected. The rates and severity of decreases in blood pressure and other epidural-related complications possibly related to the EAA were evaluated. Blood pressure was evaluated before placement of the epidural, then every 15 minutes after the initiation of the epidural during the operative theater and in the postanesthesia care unit. Then, blood pressure was evaluated hourly for 2 hours, then every 2 hours for 16 hours, and then every 4 hours until the
Results Of the 409 patients evaluated for inclusion, only 90 elective, nontrauma surgery patients met inclusion criteria and case matching. The primary reasons for exclusion were due to patients receiving an epidural for obstetrical reasons and limited numbers of patients receiving HM to case match based on the surgical procedure. The most frequent surgeries performed were total abdominal hysterectomy (36%), exploratory laparotomy with resection (34%), gastric bypass (13%), and genitourinary procedures (9%). Baseline characteristics were similar between the groups regarding age, sex, race, and simplified acute physiology score (Table 1). The epidural catheter was placed at a thoracic site in 53% of the patients and at a lumbar site in 47%. Initiation of the epidural catheter was primarily
M.N. Nguyen et al. Table 1
Hydromorphone vs fentanyl for epidural pain control
3
Baseline characteristics
Demographics
All n 5 90
HM n 5 30
FENT n 5 60
P value
Age (y), mean 6 SD Female sex, n (%) African American, n (%) BMI (kg/m2), mean 6 SD Height (cm), mean 6 SD Weight (kg), mean 6 SD Physical status ASA score, mean 6 SD SAPS II Score Epidural location Thoracic, n (%) Lumbar, n (%)
52 6 13 64 (71) 57 (63) 33 6 11 167 6 11 91 6 28
52 6 11 19 (63) 16 (53) 35 6 12 166 6 9 89 6 29
51 6 14 45 (75) 41 (69) 32 6 11 167 6 12 94 6 25
.70 .25 .16 .40 .84 .31
2.5 6 0.6 26 6 10
2.4 6 0.6 28 6 7
2.7 6 0.5 26 6 11
.03 .27
48 (53) 42 (47)
17 (57) 13 (43)
31 (52) 29 (48)
.99 .99
ASA 5 American Society of Anesthesiologists; BMI 5 body mass index; FENT 5 fentanyl; HM 5 hydromorphone.
during the preoperative phase of care with the mean duration of the epidural catheter being 2.0 6 .7 days. Patients in the HM and FENT groups had similar episodes of moderate pain, VAS 6 to 8, 66% HM vs 58% FENT, P 5 .46; and severe pain, VAS 9 to 10, 36% HM vs 26% FENT, P 5 .32. However, the patients in the HM group tended to require more supplemental intravenous opioids to help control their pain, 30% HM vs 16% FENT, P 5 .14 suggesting a higher failure rate. No difference was seen in increases in epidural rates between the groups. The incidence of 2 or more epidural complications (eg, hypotension, pruritus, lower extremity paresthesias, nausea/
Table 2
vomiting, chest pain, excessive sedation [MRSS R 4], unresponsiveness [MRSS 5 6], tended to be higher with HM, [67% vs 48%, P 5 .10; Table 2]) Although the frequency of at least 1 episode of hypotension was similar in both groups, HM patients tended to have 2 or more episodes of decreased blood pressure during the time of epidural administration (50% vs 30%, P 5 .17). No significant correlation was observed between the incidence of a decrease in blood pressure and the site of epidural catheter placement between the groups. Comparing the hypotension between the groups based on epidural location in the thoracic spine, there were no differences (82% HM vs 90% FENT, P 5 .65).
Intraoperative data and complications
Characteristic Operative data Operative time*, h EBL*, ml/h Crystalloids*, ml/kg/h OR urine output*, ml/kg/h Intraoperative and postoperative hemodynamics Onset of hypotension*, h Hypotension† Decrease in SBP from epidural start to first hypotensive event, mm Hg* R2 episodes hypotension† Duration of hypotension, h* Hypotension requiring vasopressors† Hypotension with lumbar placement of epidural† Other complications† Chest pain Excessive sedation Extremity paresthesia Nausea and/or vomiting Pruritus Unresponsiveness
HM n 5 30
FENT n 5 60
P value
3.0 6 0.9 102 6 73 11.9 6 5.0 .8 6 0.5
2.7 6 1.2 102 6 141 13.3 6 6.6 1.6 6 2.0
.38 .99 .30 .05
2.0 6 2.7 23 (76) 43 6 14 15 (50) 3.6 6 9.7 14 (47) 9 (31)
2.3 6 4.6 48 (80) 44 6 18 21 (30) 2.7 6 4.5 22 (37) 2 (3)
.81 .71 .85 .17 .37 .36 .02
0 (0) 5 (16) 11 (36) 5 (16) 10 (33) 2 (6)
1 (1) 1 (1) 16 (28) 6 (10) 21 (36) 0 (0)
.47 .01 .42 .36 .75 .04
EBL 5 estimated blood loss; h 5 hours; kg 5 kilogram; ml 5 milliliters; OR 5 operative; SBP 5 systolic blood pressure; SD 5 standard deviation. *Expressed as mean 6 SD. † N (%).
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Intraoperative fluids, blood loss, operative time, and urine output were evaluated to determine if there was an impact on the decrease in blood pressure, but there was no difference between the groups. However, the FENT patients had a better urine output, P 5 .05. Patients with repeated episodes of decreases in blood pressure also tended to have longer hospital lengths of stay (6.2 6 4.0 HM vs 5.4 6 4.5 FENT days, P 5 .06). Overall, excessive sedation (MRSS R 4) occurred more frequently with HM, 16% vs 1% FENT, P 5 .007. Specifically, more sedation was seen in HM patients with lumbar placed epidurals, 31% HM vs 3% FENT, P 5 .02. The incidence of unresponsiveness (MRSS 5 6) was also higher with HM, 6% HM vs 0% FENT, P 5 .04. Evaluating the sedation episodes in patients receiving adjunct therapy, the sedation did not occur after supplemental morphine was given. No spinal hematomas were noted during the study period.
in the epidural infusion rate along with more supplemental intravenous opioids. Hence, we believe HM had a higher incidence of failure which may have been because of a technical reason. From our review, an epidural can have many variable causing failure and include anatomical catheter location, patient positioning, puncture site, and localization of the epidural space to name a few. FENT patients received slightly more operative intravenous fluids despite almost identical blood loss. There was some concern that the reduced amount of fluid volume administered to the HM patients might impact the frequency and severity of hypotension. However, when comparing patients who experienced hypotension, repeated episodes of hypotension or needed vasopressors, no differences in fluid intake were found. In addition, intraoperative urine output was significant with the FENT group. Limitations of this study include the fact that we were not able to correlate dosing requirements and efficacy to plasma and cerebral spinal fluid opioid concentrations. Considering this is an observational study, the location of the epidural catheter was selected based on the prescribing anesthesiologist. Hence, these data cannot be extrapolated to all surgical procedures.
Comments EAA is one of the best ways to control pain and to attenuate the stress response of major surgery. This technique has been shown to reduce complications, and decrease morbidity and mortality postoperatively compared with systemic opioid administration.2 A recent metaanalysis showed the superiority of epidural analgesia vs patient-controlled analgesia.4 Overall, epidurals containing opioids provided more analgesia when comparing VAS scores. However, the meta-analysis did not compare HM vs FENT individually.4 At our institution, the choice of an anesthetic/analgesic agent is based on provider preference, drug properties, and patient variables such as age and risk for decreases in blood pressure. To our knowledge, this is the 1st article comparing HM and FENT under these circumstances. FENT, a synthetic opioid with greater potency and lipophilic properties than morphine and HM, is the oldest meperidine-like agonist.11 FENT provides rapid, potent analgesia and provides a relatively quick onset of action and short duration of effect (.5 to 1 hour). Comparatively, HM has a fairly quick onset and longer duration of action. Hence, the short duration of FENT’s activity may be the reason our patient population did not have as much sedation and unresponsiveness. FENT does not demonstrate histaminereleasing properties which is known to cause vasodilation and subsequent hypotension.12 Although both HM and FENT do not exert a histamine release, FENT tended to be less likely to provide repeated episodes of hypotension. Equianalgesic dosing is known for HM and FENT for the intravenous route systemically. HM and FENT have been studied independently in the spinal fluid; however, no direct equivalence with HM and FENT has been established via the epidural route. Although the VAS scores were similar between the groups, HM patients appeared to have less adequate pain relief, requiring more frequent increases
Conclusions Overall, in a closely case-matched population, this study evaluated the 2 most commonly used opioids in combination with bupivacaine for epidural analgesia. Our FENT patients were relatively sicker based on their preoperative American Society of Anesthesiologists scores. However, we found relatively no statistical differences in major adverse effects such as hypotension between FENT and HM. FENT patients had better intraoperative urine output and tended to have less repeated episodes of hypotension. FENT epidural patients also had less excessive sedation and unresponsiveness in this closely case-matched surgical population and required less pain rescue maneuvers. Thus, these findings favor FENT over HM as the epidural opioid of choice.
References 1. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg 2007;104:689–702. 2. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg 2003;238:663–73. 3. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomized trials. BMJ 2000;321:1493–7. 4. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology 2005;103:1079–88. 5. Gordon DB, Rees SM, McCausland MP, et al. Improving reassessment and documentation of pain management. Joint Comm J Qual Patient Saf 2008;34:509–17.
M.N. Nguyen et al.
Hydromorphone vs fentanyl for epidural pain control
6. Apfelbaum JL, Ashburn MA, Connis RT, et al. Practice guidelines for acute pain management in the perioperative setting an updated report by the American Society of Anesthesiologists task force on acute pain management. Anesthesiology 2012;116:248–73. 7. Gross JB, Bailey PL, Connis RT, et al. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96: 1004–17. 8. de Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia: what are the choices? Anesth Analg 1996;83:867–75. 9. Bijker JB, van Klei WA, Kappen TH, et al. Incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology 2007;107:213–20. 10. Ramsay M, Savege T, Simpson BR, et al. Controlled sedation with alphaxalone/alphadolone. BMJ 1974;2:656–9. 11. Tuman KJ, McCarthy RJ, March RJ, et al. Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 1991;73:696–704. 12. Grossman M, Abiose A, Tangphao O, et al. Morphine-induced venodilation in humans. Clin Pharmcol Thera 1996;60:554–60.
Discussion Discussant Dr. Jeffrey Bender (Oklahoma City, OK): I don’t understand the methodology that led to a one-to-two case match ratio. Why not just one-to-one? I would have liked to have seen the actual data on the number of cases and how they were divided between the 2 groups. The amount of I.V. fluid given intraoperatively was statistically the same in both groups, but the Fentanyl (FENT) patients had better urine output, twice the urine output. To me this implies that the FENT patients were better resuscitated during their operation. Could this explain why there was less postoperative hypotension in FENT group? Did you control for variance among anesthesia attendings? Could more experienced or, dare I say it, better anesthesia attendings be using FENT more often? While the amount was severe pain was the same in both group, the Hydromorphone (HM) patients got more supplemental opioids. Why was this? Dr. Zimmerman: Regarding the case matching, when we looked at all our patients, we have probably more than a thousand patients that are receiving epidurals over the 12-month period of time. When we looked at those, we actually recognized that most of those patients were receiving FENT and very few were receiving HM. So our intent was in that case matching, 1 to 2 ratio was try to eliminate any confounders that might be present in actually the practice with the FENT. To your 2nd question, these patients were elective cases who were placed on nothing by mouth after midnight. We anticipated the anesthesia attendings to administer consistent fluids perioperatively. These were not trauma patients who would receive aggressive resuscitation resulting in an
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increase in urine output. We did not expect to find FENT patients with an increased urine output. The 3rd question was, do we control for anesthesia attendings? We did not look at that. That’s certainly something we can go back and review. I appreciate that comment. Regarding the last question about the patients receiving HM and more supplemental opioids, I think that’s certainly something we can go back and review. We didn’t understand why that was occurring, as well. We postulated that perhaps there are pharmacokinetic profile differences between FENT and HM that we’re just not seeing because it’s being delivered in an epidural fashion. Dr. Donn M. Schroder (Grosse Pointe, MI): I’m curious on the timing of the administration of the epidural. You stated that the delayed dose of FENT really had no advantage over the HM. And was that due to preemptive analgesia effect where perhaps it was preemptive when it was 1st given intraoperatively and that’s what made a statistical difference and it was not later? What was the timing of the intraoperative dosing of the FENT epidural? Was it at the beginning of the operation or was it toward the end? Dr. Zimmerman: As far as when the epidurals were placed, typically, most of them were placed in our preoperative holding area. After anesthesia induction, the epidural infusion was initiated between 30 minutes to an hour from the time in which induction had occurred. Dr. William C. Cirocco (Columbus, OH): I am curious, why epidural? Who’s pushing for this? Is it anesthesia or your surgeons? What operations are these? Which of your surgical faculty? You don’t get into much of the complicationsdpotential complications of epidural. For instance, there’s literature suggesting postoperative bilious and anastomotic leak in the colorectal population, for instance. Dr. Zimmerman: That’s a great question. One of the reasons why we chose to look at this is that we had 10 different FENT-bupivacaine and 6 different HM-bupivacaine concentrations. As you know, the National Patient Safety initiative encourages that we minimize any potential risk to the patient. With 16 different concentrations available, potential risk exists that the patient could receive the wrong drug concentration which could lead to harm. Through this evaluation, our intent was to streamline the number of epidural concentrations available by evaluating safety and efficacy to minimize potential risk to the patient. Dr. Cirocco: So, again, why epidural? I was at an institution where it was pushed by anesthesia. They got paid more than I got paid for the operation. The epidural came out in a day or two. These patients were in the hospital a week to 10 days recovering. So we went right back to a patient controlled analgesia. It made no sense to me in the population that I deal with. Dr. Zimmerman: Our surgeons work with anesthesia to determine the type of postoperative pain control best for the patient based on the procedure performed. So that was usually a conversation with the surgeon.
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Dr. Michael White (Detroit, MI): It is my understanding that the anesthesia got to choose what they wanted to use each patient and it was just an observational study you were matching for the different two; is that correct? Dr. Zimmerman: Yes. Dr. White: My question would be, what made them choose one over the other? You didn’t really present any of that data. That could influence partly what your outcome was, because, again, it wasn’t adyou tried to case match. But, again, it wasn’t a randomized study, so it would be interesting to have seen that data, what made maybe them choose FENT vs HM for their case.
Dr. Zimmerman: Through the selection of and evaluating that data, that was not anything that was clear in the chart or record that I could ascertain. Dr. Abdelkader Hawasli (Detroit, MI): This is revisiting old things from more than 10 years ago. And the question is always, what is the effect of the ileus postop from the anesthetic this way, and the increase in the length of stay, you have not contributed to that effect on the total cost to the institution. Dr. Zimmerman: So looking at bowel function, we did look at that comparing the 2 groups and there was not any difference between return of bowel function based on which opioids that was used. We did not compare any cost data through this group.