Abstract
Background
Hydromorphone is a potent μ-opioid selective agonist that has an onset time within 5 minutes and reaches peak effect between 10 and 20 minutes. However, it may show immediate analgesic effect to rocuronium-induced pain because of its peripheral analgesic property and also may attenuate noxious stimuli from tracheal intubation during induction. The opioid receptors are known to be present in peripheral sensory nerve terminals as well as in the dorsal root ganglion and the central terminal of primary afferent nerves. Therefore, we hypothesized that hydromorphone may be considered a potent pretreatment or adjuvant drug during the induction of anesthesia with its peripherally and centrally mediated analgesia.
Objective
The aim of this study was to compare the effects of pretreatment with hydromorphone in reducing rocuronium-induced withdrawal movements and hemodynamic changes during tracheal intubation with the effects of fentanyl and normal saline.
Methods
In this double-blind, randomized, controlled study, consecutive adult patients aged 20 to 70 years who were scheduled to undergo general anesthesia for elective gastric or colorectal surgery at the Samsung Seoul Hospital (Seoul, Republic of Korea) were randomly assigned to receive 5 mL hydromorphone 0.03 mg/kg or fentanyl 2 μg/kg or normal saline. Thirty seconds after administering the study drug, anesthesia was induced with 2.5% thiopental sodium 5 mg/kg. After loss of consciousness, rocuronium 0.6 mg/kg was injected and immediate withdrawal movements were recorded. Two minutes after rocuronium injection, tracheal intubation was performed and hemodynamic changes were observed.
Results
A total of 194 patients were enrolled, with 65 in the hydromorphone group, 67 in the fentanyl group, and 62 in the saline group. The overall incidence of withdrawal movements was significantly lower in the hydromorphone group (2 patients; 3.1%) and the fentanyl group (5 patients; 7.5%) (both, P < 0.001) than in the saline group (36 patients; 58.1%). The mean arterial pressure (MAP) and heart rate (HR) after intubation (median [interquartile range]) in the fentanyl group (101.5 [84−115] mm Hg; 93.5 [82−102] beats per minute [bpm]) and the hydromorphone group (93.0 [83−106] mm Hg; 90.0 [86.3−93.6] bpm) were significantly lower than these measures in the saline group (111.5 [105−123] mm Hg; 103.5 [96−113] bpm) (fentanyl group MAP and HR, P < 0.001; hydromorphone group MAP and HR, P < 0.001).
Conclusions
Pretreatment with hydromorphone and fentanyl may have similar effectiveness in reducing withdrawal movements in response to rocuronium injection pain and inducing immediate general anesthesia.
Key words: hydromorphone, induction of anesthesia, injection pain, rocuronium, withdrawal movement
Introduction
Hydromorphone, a potent μ-opioid selective agonist with a systemic analgesic onset time of 5 minutes and peak effect time within 10 to 20 minutes, has been used widely for the management of acute postoperative and cancer-related pain.
Opioid receptors are known to be present in peripheral sensory nerve terminals as well as in the dorsal root ganglion and the central terminal of primary afferent nerves.1,2 In this regard, opioids with longer blood-brain equilibrium and hysteresis (ie, the time lag between peak concentration in the plasma and the effect site) may show immediate analgesic effect via the peripheral opioid receptors at the veins,3 unlike their known delayed onset of action.
The peripherally mediated immediate analgesic property of hydromorphone may work to reduce intravenous rocuronium injection pain by inhibiting the activation of the peripheral nociceptors,4,5 and, with its centrally mediated analgesic effect, may also produce earlier systemic effect than expected. Therefore, we investigated the effectiveness of hydromorphone as a pretreatment drug to reduce the withdrawal movements in response to injection of rocuronium and to attenuate hemodynamic changes to tracheal intubation compared with that of fentanyl and saline.
Patients and Methods
This double-blind, randomized, controlled study was conducted at the Samsung Seoul Hospital, Samsung Medical Center in Seoul, Korea. This study was approved by the Samsung Seoul Medical Center's institutional review board (No. 2008-06-051) and was registered in the Australian New Zealand Clinical Trials Registry (ANZCTR, ACTRN12610000316000). Written, informed consent was obtained from all subjects. Patients aged 20 to 70 years who had an American Society of Anesthesiologists physical status I or II and were undergoing general anesthesia for elective gastric or colorectal surgery from August 2008 to January 2009 were enrolled consecutively in this study. Enrollment of patients was evaluated through preanesthetic rounds and determined by 2 anesthesiologists (E.Y.J. and B.S.S.). Patients with a history of hypertension were included in the study only if confirmed to be of medically well-controlled status with blood pressure <140/90 mm Hg with or without antihypertensive medication.6,7 These patients were instructed to continue treatment even on the day of surgery. The exclusion criteria were as follows: known allergy and contraindication to opioids; history of diabetes mellitus, asthma, or neurological deficit; pregnancy; or use of analgesics or sedatives within the 24 hours before surgery. Random allocation of patients into 1 of 3 groups to receive 5 mL of either IV hydromorphone hydrochloride⁎ 0.03 mg/kg (n = 65) or IV fentanyl citrate 2 μg/kg (n = 67; Gu Ju Pharm, Seoul, Korea) or IV saline (n = 62; sodium chloride, Joong Wae Pharm, Seoul, Korea) was facilitated by using a computer-generated random number concealed in an envelope. One of 2 anesthesiologists (S.Y.L. and W.S.S.) unsealed the envelope in a preparatory room outside the operating theater and prepared the drug or placebo (normal saline) in a syringe accordingly, in the absence of the study participants. The syringes for both study drug and placebo were identical, labeled “study drug” to conceal treatment group allocation. The anesthesiologist (S.Y.L. or W.S.S.) who prepared the drug syringe then handed it over to the anesthesiologists in the operating room, blinded to the treatment allocation, to carry out the induction of anesthesia. The anesthesiologists (S.Y.L. and W.S.S.) who prepared the study drug syringes did not participate in the induction of anesthesia and left the operating room. The patient and 2 anesthesiologists carrying out the induction and recording the outcomes were all blinded to treatment group. The syringes were stored at room temperature.
Premedication was not administered before surgery. On arrival at the operating room, the intravenous cannulation site and its patency were confirmed by the anesthesiologist. Patients with intravenous cannulation located elsewhere than at the veins of the forearm were excluded from the study. All patients received continuous electrocardiography, noninvasive arterial pressure, capnography, and end-tidal sevoflurane monitoring. All drugs were injected through the proximal rubber port connected to the intravenous cannula with a free flow of intravenous lactated Ringer solution. During preoxygenation with 100% oxygen, the study drug was injected over 30 seconds, and an investigator blinded to the study drug observed for signs of adverse events, such as apnea and coughing for 30 seconds, and questioned patients about adverse events just before injection of thiopental sodium. Then, 2.5% thiopental sodium 5 mg/kg was injected over 5 seconds. After loss of consciousness and eyelash reflexes, when the appropriate end-tidal carbon dioxide curve appeared on capnography upon trial of mask ventilation with inspired oxygen fraction 1.0, rocuronium 0.6 mg/kg was injected over 5 seconds. The time interval between the study drug injection and rocuronium injection was set at <90 seconds in all patients. Two anesthesiologists, the one who administered the study drug and another to conduct anesthetic induction, assessed the patient response during and immediately after rocuronium injection. The 2 investigators were educated beforehand to grade patients' responses according to the scale proposed by Shevchenko and colleagues8: 1 = no movement; 2 = movement at the wrist only; 3 = movement/withdrawal involving the arm only (elbow/shoulder); 4 = generalized response, withdrawal or movement in more than 1 extremity.
Sevoflurane was started after the rocuronium injection and was adjusted to maintain an end-tidal concentration of 2.5 to 3.0 vol% in 100% oxygen. Two minutes after the rocuronium injection, the anesthesiologist, who had more than 4 years of experience in anesthetic practice, performed tracheal intubation and applied controlled ventilation to maintain normocarbia without ballooning the cuff for 1 minute to avoid stimulation. Patient movement and status of vocal cord relaxation were observed during tracheal intubation. Anesthesia was maintained with sevoflurane (end-tidal concentration of 2 to 3 vol%). The time interval between the study drug injection and intubation was designed to be within 3 to 4 minutes in all patients. The intubation time, defined as the time from mouth opening to obtaining the appropriate capnographic trace, was measured in all patients. The mean arterial pressure (MAP) and heart rate (HR) were measured on arrival at the operating room, 1 minute before intubation, and 1 minute after tracheal intubation. If there was an increase in HR (>40% in baseline) and/or increased blood pressure with ST change in electrocardiography after intubation, IV esmolol (0.3 mg/kg) was available for administration.
Statistical Analysis
Statistical analyses were carried out using SPSS 12.0 for Windows (SPSS Inc, Chicago, Illinois). The data are reported as mean (SD), median (interquartile range), or number (proportion) of patients. Patient characteristics and intravenous cannulation sites were compared using χ2 test, Fisher exact test, Kruskal-Wallis test, or 1-way ANOVA where appropriate. The incidence of withdrawal movements was analyzed using Fisher exact test. The changes in MAP and HR within each group from the baseline to before and after tracheal intubation were analyzed by repeated-measures ANOVA with Bonferroni adjustment.
The hemodynamic parameters among groups, including MAP and HR differences before and after intubation, were compared using Kruskal-Wallis test with post hoc analysis by Tukey test using ranking. P value was corrected by Bonferroni adjustment because of multiple testing. The incidence of patient movements and the status of vocal cord relaxation during tracheal intubation were analyzed using χ2 test and Fisher exact test, respectively. The intubation time was compared using Kruskal-Wallis test with post hoc analysis by Tukey test using ranking.
The number of patients in the study was determined based on a pilot study, with an estimated incidence of 45% and 15% withdrawal movement in the saline and hydromorphone groups, respectively. At least 53 patients were required for each group to achieve a 30% reduction in the withdrawal movement at the significance level of 5% and power of 90%, and considering the possibility of unanticipated exclusions (10%). P < 0.05 was considered significant.
Results
A total of 194 patients (hydromorphone group, n = 65; fentanyl group, n = 67; and saline group, n = 62) were enrolled consecutively between August 2008 and January 2009. Among the 194 patients, 3 patients in the fentanyl group and 1 patient in the saline group did not complete the study because they met exclusion criteria during the study process. Exclusion criteria were patients with laryngeal view grade 3 or 4 with no visualization of the vocal cords during tracheal intubation,9 or any other conditions that would affect vocal cord assessment such as vocal cord spasm, and patients with an intravenous route other than the forearm. One patient (fentanyl group) had a percutaneously inserted central catheter instead of a peripheral intravenous line, another developed vocal cord spasm (saline group), and 2 patients (fentanyl group) did not show the vocal cords during intubation. Therefore, 190 patients (hydromorphone group, n = 65; fentanyl group, n = 64; and saline group, n = 61) (mean [SD] age, 54.6 [10.3] years; height, 163.2 [8.0] cm; weight, 62.1 [9.7] kg) completed the study.
However, for an intent-to-treat analysis, the 194 initially enrolled patients were analyzed. Figure 1 summarizes the enrollment, randomization, and subsequent exclusion process. This randomized trial was carried out and reported in accordance to the CONSORT statement10 and the CONSORT explanation and elaboration document.11 The patients' characteristics were similar in all groups (Table I). The intravenous cannulation sites at the forearm were similar in all 3 groups. The most common intravenous cannulation site was the cephalic vein. The number of patients with intravenous cannulation at the cephalic vein were 45, 42, and 46 in the hydromorphone, fentanyl, and saline groups, respectively. The next most common sites were accessory cephalic vein, basilic vein, and median antebrachial vein. An 18-gauge intravenous cannula was used for all patients except 1 patient in the saline group who had a 20-gauge intravenous line.
Figure 1.
CONSORT flowchart for patient allocation and participation in this study.
Table I.
Patients' characteristics (N = 194).⁎
| Hydromorphone (n = 65) | Fentanyl (n = 67) | Saline (n = 62) | |
|---|---|---|---|
| Age, mean (SD), y | 53.5 (11.1) | 57.2 (10.1) | 53.6 (9.5) |
| Sex, M : F, no. (%) | 39 (60):26 (40) | 39 (58):28 (42) | 35 (56):27 (44) |
| Height, mean (SD), cm | 165.0 (7.8) | 162.2 (7.9) | 163.0 (8.4) |
| Weight, mean (SD), kg | 63.0 (10.4) | 63.3 (9.6) | 60.4 (8.9) |
| ASA status I/II, no. (%) | 49 (75)/16 (25) | 46 (72)/18 (28) | 47 (77)/14 (23) |
| Hypertension, no. (%) | 12 (18.5) | 17 (25.4) | 11 (17.7) |
ASA = American Society of Anesthesiologists.
No significant differences were found between the groups.
Table II lists the incidence and grade of the withdrawal movements. The overall incidence of withdrawal movements was significantly lower in the hydromorphone group (2 patients; 3.1%) and the fentanyl group (5 patients; 7.5%) (both, P < 0.001) than in the saline group (36 patients; 58.1%). The incidence of wrist, arm, and generalized movements was higher in the fentanyl group (1.5%, 3.0%, and 3.0%, respectively) than in the hydromorphone group (1.5%, 0%, and 1.5%, respectively), but without statistical significance.
Table II.
Incidence and grade of withdrawal movements associated with the rocuronium injection. Data are shown as number (%) of patients.
| Grade of Withdrawal Movements⁎ | Hydromorphone (n = 65) | Fentanyl (n = 67) | Saline (n = 62) |
|---|---|---|---|
| 1 (No withdrawal) | 63 (97.0)† | 59 (92.2)† | 25 (41.0) |
| 2 (Wrist withdrawal) | 1 (1.5) | 1 (1.6) | 5 (8.2) |
| 3 (Arm withdrawal only) | 0 (0) | 2 (3.1) | 20 (32.8) |
| 4 (Generalized movement) | 1 (1.5) | 2 (3.1) | 11 (18.0) |
Proposed by Shevchenko et al.8
P < 0.001 versus the saline group.
Figure 2 presents MAP and HR variables. There were statistically significant changes in MAP and HR from baselines after intubation in all groups except changes in MAP after intubation in the hydromorphone group. MAP and HR (median [interquartile range]) after intubation in the fentanyl group (101.5 [84−115] mm Hg; 93.5 [82–102] bpm) and the hydromorphone group (93.0 [83–106] mm Hg; 90.0 [86.3−93.6] bpm) were significantly lower than those in the saline group (111.5 [105–123] mm Hg; 103.5 [96–113] bpm) (fentanyl group MAP and HR, P < 0.001; hydromorphone group MAP and HR, P < 0.001). Changes in MAP before and after intubation were significant in the fentanyl and hydromorphone groups compared with those in the saline group (both, P = 0.002). Changes in HR before and after intubation were significantly less in the hydromorphone group compared with the saline group. (P = 0.006). No patients required administration of IV esmolol after intubation.
Figure 2.
This figure delineates the (A) mean arterial pressure (MAP) and (B) heart rate (HR) on arrival (baseline) and before (1 min BI) and after (1 min AI) tracheal intubation. This box and whisker plot shows median values with interquartile ranges. There were statistically significant changes in the MAP and HR from the baseline after intubation in all groups except for the changes in the MAP after intubation in the hydromorphone group. The MAP and HR after intubation in the fentanyl (median [interquartile range]) (101.5 [84−115] mm Hg; 93.5 [82–102] beats per minute [bpm]) and hydromorphone (93.0 [83−106] mm Hg; 90.0 [86.3−93.6] bpm) groups were significantly lower than those in the saline group (111.5 [105−123] mm Hg; 103.5 [96−113] bpm) (fentanyl group MAP and HR: P < 0.001; hydromorphone group MAP and HR: P < 0.001). Baseline = upon arrival at the operating room; 1 min BI = 1 minute before intubation; 1 min AI = 1 minute after intubation. *P values compared with the baseline value within the group; †P values compared with the saline group; ‡P values compared with the fentanyl group.
Table III shows the incidence of patient movements, status of vocal cord relaxation during tracheal intubation, and intubation time. No significant between-group differences were found in the incidence of movements during intubation (12 patients [18.5%] in the hydromorphone group; 12 [17.9%] in the fentanyl group; and 20 [32.3%] in the saline group). The status of vocal cord relaxation during tracheal intubation was similar in all groups (full/partial relaxation: 59/6 patients [91%/9%] in the hydromorphone group; 61/5 [91%/9%] in the fentanyl group; and 52/9 [85%/15%] in the saline group). The intubation time (median [interquartile range]) in the hydromorphone group (15.0 [14−18] sec), fentanyl group (15.0 [13−18] sec), and saline group (17.0 [15−20] sec) were significantly different in the Kruskal-Wallis test (P = 0.032) but without intergroup differences in the Tukey test with ranking.
Table III.
Incidence of patient movements, status of vocal cord relaxation during tracheal intubation, and intubation time.
| Hydromorphone (n = 65) | Fentanyl (n = 67) | Saline (n = 62) | |
|---|---|---|---|
| Movement, no. (%) | 12 (18.5) | 12 (17.9) | 20 (32.3) |
| Vocal cord relaxation full/partial, no. (%) | 59 (90.8)/6 (9.2) | 61 (92.4)/5 (7.6) | 52 (85.3)/9 (14.8) |
| Intubation time⁎, median (interquartile range), sec | 15 (14−18) | 15 (13−18) | 17 (15−20) |
| P | †P = 0.060 | †P = 0.057 | |
| ‡P = 1.0 |
Intubation time was defined as the time from mouth opening to obtaining an appropriate capnographic trace.
P values for intubation time compared with the saline group.
P values compared with the fentanyl group.
Discussion
This study suggests that hydromorphone may be as effective as fentanyl as a pretreatment drug in reducing withdrawal movements due to rocuronium injection pain and inducing general anesthesia without delay.
Hydromorphone has 5 to 7 times more potent analgesic efficacy than morphine, with a similar or lower incidence of adverse effects.12,13 This opioid is most commonly used for treating chronic cancer-related pain14,15 but it also has equivalent analgesic effects to other opioids for acute pain.16 Despite its wide applications in chronic and acute pain management, hydromorphone has not gained popularity in pre- or intraoperative use. MEDLINE was searched (inception to 2010) using the following terms: hydromorphone, induction, anesthesia, preoperative, intraoperative, and analgesia. The search did not identify any studies regarding the use of hydromorphone as an adjuvant agent for general anesthesia.
In terms of onset of action, hydromorphone may not be appropriate for procedures that require a rapid onset time. Hydromorphone has an onset time of 5 minutes and a peak effect time of 10 to 20 minutes.17 Therefore, using hydromorphone as an induction adjuvant or pretreatment drug may be controversial. However, we found that patients in the hydromorphone group had effectively diminished rocuronium injection pain within 90 seconds after injection and blunt cardiovascular responses to tracheal intubation with the same efficacy as fentanyl. This observation of instantaneous onset of pain subsidence to rocuronium injection may require explanations other than its centrally mediated analgesia, which take at least 5 minutes to be effective.
Opioid analgesia is obtained via the central and peripheral opioid receptors.2 The opioid receptors are found in peripheral terminals of the primary afferent neurons18 as well as in the dorsal root ganglia19 and the central terminal of primary afferent nerves.20 The rocuronium injection pain has been attributed to the direct activation of the C-nociceptor.4,5 It has been reported that venous occlusion using a venous tourniquet may provide sufficient time for adequate sequestration of pretreatment drugs; however, previous studies were conducted on drugs, such as lidocaine, with local anesthetic properties.8 The venous occlusion technique may be applied to opioid pretreatment to assure its adequate sequestration within the vein and allow it to interact with the venous nociceptors.1,8 Although this study did not use the venous occlusion technique while injecting the study drugs over 30 seconds, peripheral analgesic effects of hydromorphone may be one explanation for its prompt analgesic effects on rocuronium-induced pain within 90 seconds in this study. Additional application of venous tourniquets in future studies could be performed to verify the peripheral analgesic effects of hydromorphone. Therefore, if opioids with delayed onset displayed prompt analgesic effect on injection followed by immediate rocuronium administration, peripheral analgesia of opioid may be suspected more prominently. However, opioid pretreatments are used not only for reducing the withdrawal movement but also to attenuate hemodynamic changes due to tracheal intubation. Taking this into account, we used hydromorphone as the study agent to affect rocuronium withdrawal movement and hemodynamic profile.
The status of vocal cord relaxation and the incidence of patient movement during tracheal intubation showed no statistical difference among the 3 groups. However, patients in the saline group presented more movements during intubation than those in the hydromorphone and fentanyl groups. This finding may suggest that despite the reportedly adequate muscle relaxation with rocuronium 0.6 mg/kg, adjuvant drugs, such as hydromorphone and fentanyl, are required to deepen the level of anesthesia and suppress movement during the strong stimulus of tracheal intubation. The time to facilitate intubation was different among the groups (P = 0.032); however, their differences of approximately 2 seconds are not clinically significant.
The size and sites of the intravenous cannulas at 1 of the 6 superficial veins at the forearm were not different among groups. By investigating the selection of the venous cannulation at the forearm, it was expected that a difference in the withdrawal movement according to the selection of veins would be detected, but without significance.
This study had several limitations. First, there are no established recommended doses of hydromorphone for the induction of anesthesia. Therefore, equianalgesic doses of hydromorphone 0.03 mg/kg to fentanyl 2 μg/kg were used. Because the literature reports a hydromorphone-to-morphine equianalgesic potency of 1:5 to 1:7,12,13 a conversion ratio of 1:7 was used to select 0.03 mg/kg of hydromorphone. It is possible that hydromorphone 0.03 mg/kg might have a lower or higher analgesic effect than fentanyl 2 μg/kg. Second, the duration of hemodynamic monitoring was not long enough to fully evaluate the effects of hydromorphone on hemodynamic stability. The maximum onset of action for hydromorphone is 10 to 20 minutes17; therefore, a longer period of observation would have been appreciated. Third, the start of sevoflurane after rocuronium injection is not congruent with common clinical practice. This study was designed deliberately to turn sevoflurane on after rocuronium injection to rule out any potential confounding effect of sevoflurane on withdrawal movements. Fourth, hydromorphone is less emetogenic than the fentanyl derivatives12,21,22; however, we did not observe the incidence or severity of postoperative nausea and vomiting in this study.
Patients in the fentanyl and hydromorphone groups showed statistically significant hemodynamic stability compared with patients in the saline group; however, the patients in the latter group also did not show hemodynamic changes requiring esmolol administration. Although withdrawal movement occurred significantly more in patients in the saline group, it did not cause severe adverse outcomes such as loss of intravenous cannulation, prolongation of intubation time, or loss of correct endotracheal tube placement. In such respects, the benefits of using an opioid as a pretreatment or adjuvant agent may be questionable; however, clinical implication lies more in its use to debilitated patients in whom sympathetic stimulation might cause detrimental clinical consequences, such as myocardial ischemia or hypertensive events.23 Moreover, complications such as dislodgment of intravenous cannulation in children or debilitated patients or pulmonary aspiration due to sudden withdrawal movements could be life threatening even if occurring only rarely.24 Opioids, including fentanyl, are commonly used during induction with low or no risk of side effects and potent effect of blunting sympathetic stimulation to tracheal intubation25–28 or for reducing rocuronium injection pain.1,29 Therefore, considering fentanyl or hydromorphone as an adjuvant or a pretreatment drug during induction may be prudent, especially in patients at risk of developing cardiovascular events.
Conclusions
Compared with saline, hydromorphone produced immediate analgesia to rocuronium pain−induced withdrawal movement and reduced hemodynamic responses to tracheal intubation. These findings were comparable with pretreatment with fentanyl. These may be attributed both to central and peripheral antinociceptive effects of opioids. Because using hydromorphone as an adjuvant agent during induction and the intraoperative period is relatively novel, additional studies on the optimal use and doses of hydromorphone during the induction of anesthesia and intraoperative periods are needed.
Acknowledgments
The authors have indicated that they have no conflicts of interest regarding the content of this article. This manuscript was presented, in part, for poster presentation at the Canadian Anesthesiologists' Society 2010 Annual Meeting, Montreal, Quebec, Canada, June 2010.
Sang Hyun Lee was responsible for drafting and revising the article, conception, analysis of data, and final approval of the article. Chul Joong Lee was responsible for the conception, design, interpretation of data, drafting, revising and final approval of the article. Tae Hyeong Kim was responsible for the conception, data collection, revising and final approval of the article. Byung Seop Shin performed the study, analysis and interpretation of data, revising and final approval of the article. Suk Young Lee designed, performed the study, data analysis, revising and final approval of the article. Eun Young Joo was responsible for the conception, interpretation of data, revising and final approval of the article. Woo Seog Sim was responsible for the conception, design, interpretation of data, drafting, revising and final approval of the article.
Footnotes
Trademark: Dilid® (Hana Pharm Co, Ltd, Seoul, Korea)
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