Remifentanil versus alfentanil in a balanced anesthetic technique for total abdominal hysterectomy

ELSEVIER

Remifentanil versus Alfentanil in a Balanced Anesthetic Technique for Total Abdominal Hysterectomy Anthony L. Kovac, MD,* Said S. Azad, MD,? Phyllis Steer, MD, * Thomas Witkowski, MDJ Randal Batenhorst, PharmD,O Sally McNeal, BA$j Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS; Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA; Glaxo-Wellcome, Inc., Research Triangle Park, NC.

*Associate Professor of Anesthesiology, versity of Kansas Medical Center

Uni-

iclinical Professor of Anesthesiology, Thomas Jefferson University @ssistant Professor of Anesthesiology, Thomas Jefferson University ODirector, International Anesthesia/Analgesia Clinical Research, Glaxo-Wellcome, Inc. §Clinical Research come, Inc.

Scientist,

Glaxo-Well-

Address reprint requests to Dr. Kovac at the Department of Anesthesiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7415, USA. Supported by a grant from Glaxo-Wellcome, Inc., Research Triangle Park, NC. Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Atlanta, GA, October 21-25, 1995. Received for publication January 15, 1997; revised manuscript accepted for publication May 14, 199’7.

Study Objectives: To compare the intraoperative effects and recovery characteristics of remzfentanil hydrochloride and alfentanil when administered as part of balanced anesthesia, and to assess the effects of an additional remifntanil infusion administered as analgesic pretreatment before remoual of the uterus. Design: Multicentw, double-blind, randomized, parallel-group study. Setting: Two university hospitals. Patients: 35 ASA physical status 6 II, and III women scheduled for elective total abdominal hysterectomy with general endotracheal anesthesia. Interventions: Patients were premeditated with midazolam 0.05 mg/kg intravenously (n/). Anesthesia was induced with thiopenta12 mg/kg, vecuronium 0.15 mg/kg, and a single dose of opioid over 60 seconds (Pump 1): remifntanil2 Fg/kg (Remi/Placebo and Remi/Remi groups) or alfentanil50 pg/kg (Alf/Placebo group). Anesthesia was maintained with a nitrous oxide/oxygen mixture (66:34 ratio) and a continuous opioid infusion: remifentanilO.25 pg/kg/ min (Remi/Placebo and Remi/Remi) or alfentani10.5 pg/kg/min (Alf/Placebo). At skin incision, a second blinded drug infusion was also initiated (Pump 2): remifentanil 0.25 pg/kg/ min (Remi/Remi) or saline placebo (Remi/Placebo and Alf/Placebo). Intraoperative responses were controlled with single doses of opioid and/or rate titrations via Pump 1. Pump 2 was terminated on removal of the uterus. Pump 1 was terminated at skin closure. Measurements and Main Results: The mean (*SD) opioid infusion rates administered for the duration of Pump 2 to suppress responses to removal of the uterus were 0.49 t 0.27 Fg/kg/min, 1.99 -t 1.34 pg/kg/min, and 0.49 2 0.07 pg/kg/min for the Remi/ Placebo, Alf/Placebo, and Remi/Remi groups, respectively. At these rates, similar proportions of patients in the Remi/Placebo (670/o) and the Alf/Placebo (60%) groups had responses. Fewer patients had responses in the Remi/Remi group (8 7%) compared with the Remi/Placebo and Alf/Placebo groups (p < 0.05). The mean total opioid doses used during maintenance were 84.6 pg/kg (Remi/Placebo), 393 pg/kg (AlJ/Placebo), and 68.7 pg/kg (Remi/Remi). Awakening times were signz~icantly shorter (p < 0.05) in the remifntanil population compared with the alfentanilpopulation, but discharge times were similar. More patients received naloxone to reverse opioid effects in the alfentanil population (60%) than in the remifentanil population (20%) (p < 0.05). Conclusions: A mean remijentanil infusion of 0.49 pg/kg/min is as effective as a mean alfntanil infusion of 1.99 pg/kg/ min in suppressing intraoperative responses. Doubling of the remifentanil infusion to 0.5 pg/kg/ min before the major stress event improves suppression of responses and lowers intraoperative use of remzfentanil without prolonging

.Journal of Clinical Anesthesia 9:532-541, 1997 -0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

095%8180/97/$17.00 PI1 SO952-SlSO(97)00140-2

Remifentanil vs. aljhtanil

balanced anesllzesiajv

TAH: Kouac et al.

PERIOPERATIVE EVENTS

Reml/Pla group

Remifentanll

2 kgkg

over 1 min

Remifentanil

0.25 pgkglm~n

’

RemliRemi

Remifentanil

2 @kg

over 1 men +

Remifentanil

0.25 pgIkg/min

1

group

Alf/Pla group

Alfentanil

Alfentanil

50 pgkg over 1 rnln

RemriPla group RemilRemi

group

AlfiPla group

0.5 pgkglmin

100% (limit 2 pgiKg/mln)

5 3 single doses (1 pgkg)

over 1 mm: < 3 rate pby

5 3 single doses (1 @kg)

over 1 min; 5 3 rate 1‘ by 100% (limit 2 wgk@nin)

5 3 single doses (7 pg/kg); 5 3 rate T by 100% (limit 4 pgkg/min)

4 ALL GROUPS: - Pump 1 rate -

by 50%

Phenylephrinelatropine

ALL GROUPS: - Thiopental

Ix.~_____*s

PUMP 2 INFUSION PERIOD -I_l-l-l__-___y”_---_

Figure 1. Schematic of study design. Remi = remifentanil; infusion rate decrease. (See text for further details).

allows faster awakening times than alfentanil, but preemptive administration of postoperative analgesics is recommended to facilitate discharge. 0 1997 by Elsevier Science Inc. f-ecoveq times. Remifentanil

Keywords: Alfentanil; anesthesia, balanced, hysterectomy, total abdominal; remifentanil.

Zmglkg IV

emergence;

Introduction Numerous intraoperative events (such as tracheal intubation, surgical incision, manipulation of visceral organs, and extubation) may occur during surgery. These events cause abrupt increases in epinephrine, norepinephrine, glucagon, cortisol, human growth hormone, antidiuretic hormone, and other hormone levels.’ This increase in stress hormone levels can promote hemodynamic instability. Therefore, controlling the intraoperative responses helps to maintain cardiovascular stability and may reduce perioperative morbidity and mortality in some patients.’ The balanced anesthetic technique,

Alf = alfentanil;

Pla = placebo;

T = infusion

rate increase;

1 =

incorporating the use of nitrous oxide, oxygen, opioids, and muscle relaxants, is commonly used for general anesthesia.* With this technique, acute hemodynamic changes can be controlled by varying the rate and dose of opioid administration in response to changes in the surgical stimuli. Alfentanil is frequently used as an opioid in a balanced anesthesia technique.3 However, with alfentanil and with a number of other opioids, increasing the dose of opioid to suppress intraoperative responses may prolong postoperative recovery. Recently, a new 4anilidopiperidine derivative, remifentanil hydrochloride (UltivaB, Glaxo Wellcome Inc.; formerly GI8’7084B) has been approved for clinical use as an intravenous (IV) drug for induction and maintenance of anesthesia. The pharmacodynamic profile for remifentanil is similar to other p,-opioid agonists of the 4anilidopiperidine class. 4-6 However unlike other opioids, remifentanil has a rapid offset of action due to its metabolism by nonspeciflc blood and tissue esterases.4-” Remifentanil has a short effective biological half-life of 3 to 6 minutes,7-g allowing for rapid titratability in response to varying levels J. Clin. Anesth., vol. 9, November 1997

533

Original Conttibutions

of intraoperative stress and for administration in relatively higher doses compared with other opioids to provide maximal suppression of intraoperative responses. The duration of action of remifentanil does not increase with prolonged administration of infusion and, therefore, the risk of prolonged recovery is minimal compared with other fentanyl analogs.4*7-g The specific objectives of this study were to compare the intraoperative effects and recovery characteristics of remifentanil hydrochloride and alfentanil when administered as part of a balanced anesthetic technique and to assess the effects of an additional remifentanil infusion administered as analgesic pretreatment before the removal of the uterus.

Materials

and Methods

Patient Selection The study was conducted in 38 adult women, no more than 30% above ideal body weight, ASA physical status I, II, or III, who were scheduled for elective total abdominal hysterectomy (TAH) with general anesthesia. Exclusion criteria were known hypersensitivity to opioids; significant psychiatric, cardiovascular, renal, or hepatic disease; exposure to anesthesia or parenteral opioid within 2 weeks prior to surgery; exposure to oral opioids within 12 hours prior to the surgery; chronic exposure to benzodiazepines, tricyclic antidepressants, anticonvulsants, B-blockers, or cw,-adrenergic agonists; history of alcohol or drug abuse; pregnancy (as determined by positive urine pregnancy test); or lactating condition.

Study Design This randomized, double-blind, parallel-group study was approved by the institutional review boards at the University of Kansas Medical Center and at the Jefferson Medical College. All patients provided written informed consent. One patient was enrolled in each study group to receive open-label study drugs during the pilot phase of this study to familiarize the investigators with study procedures. The open-label patients were not included in the efficacy analyses. After the pilot phase, randomization schedules generated by SAS version 6.08 (SAS Institute, Car-y, NC) for each study site were used to assign eligible patients sequentially to one of three treatment groups: Remi/ Placebo, Alf/Placebo, and Remi/Remi. An overview of the study design is presented in Figure 1. Two infusion pumps were used to administer the opioids during the study: Pump 1 was used during the induction and maintenance periods, and Pump 2 was used to deliver the second blinded infusion (pretreatment) at the current Pump 1 rate from skin incision until excision of the uterus. During anesthesia induction, all groups received an initial dose of opioid infused over a l-minute period (remifentanil 2 pg/kg for the Remi/Placebo and Remi/Remi groups, and alfentanil 50 kg/kg for the Alf/Placebo group). During maintenance, remifentanil 0.25 kg/kg/ min was initiated for the Remi/Placebo and Remi/Remi 534

J. Clin. Anesth., vol. 9, November

1997

groups, and alfentani10.5 pg/kg/min was initiated for the Alf/Placebo group. The second blinded drug infusion was initiated for the duration of the major stress event, defined as the removal of the uterus. The duration for removal of the uterus was from entry into the abdominal cavity (ie, pulling apart of the abdominal recti muscles) until the uterus was completely excised. Opioid infusion syringes were prepared by the hospital pharmacy according to the randomization schedules. The hospital pharmacy prepared different blinded syringes for each stage of the surgical procedure, and each syringe was labeled accordingly (induction [Pump 11, maintenance [Pump 11, single-dose [Pump 11, and pretreatment [Pump 21). The concentrations of remifentanil were 20 pg/ml (for the induction and single-dose syringes) and 250 p,g/ml (for the maintenance and pretreatment syringes) . The concentrations of alfentanil were 500 kg/ml (for the induction and maintenance syringes) and 140 pg/ml (for the single-dose syringe).

Preinduction All patients received midazolam 0.05 mg/kg IV in the preoperative holding area. All patients had two peripheral venous catheters: one for infusing study opioids and fluids, and the other for infusing other intraoperative medications. To minimize the amount of dead space in the N catheter used to administer study opioids and to accommodate two infusion pumps, a double stopcock was connected to the catheter at the insertion site. The leads for a standard lead II EGG were placed, and ECG and heart rate (HR) were continuously monitored. Continuous direct measurements of arterial systolic and diastolic blood pressures (SBP and DBP) were made via a radial arterial catheter. Oxyhemoglobin saturation (S,O,) was continuously monitored by pulse oximetry. End-tidal carbon dioxide concentration (P,,CO,) was monitored continuously by capnometry and maintained between 29 mmHg and 40 mmHg throughout the intraoperative period.

Induction

of Anesthesia

Patients breathed 100% oxygen for 3 minutes by mask. At the start of induction, infusion Pump 1 was attached to one stopcock to deliver the initial opioid dose via the induction syringe. Immediately afterward, the induction syringe was replaced with the maintenance syringe to initiate the continuous opioid infusion. Bolus doses of thiopental 2 mg/kg IV were administered after the end of the initial opioid dose to facilitate endotracheal intubation and loss of consciousness (LOC). Patients were then asked every 5 to 10 seconds to open their eyes and take a deep breath. Failure to respond to three consecutive commands was equated with LOC. Vecuronium 0.15 mg/kg IV was administered after LOC and tracheal intubation was attempted 2 to 5 minutes later after loss of twitch response, as indicated by the train-of-four monitor. Additional bolus doses of thiopental 2 mg/kg IV were given when intubation was not successfully completed on the first attempt.

Remifentanil vs. alfentanil balanced anesthesia@ TAH: Kovac et al.

Maintenance Anesthesia was maintained with 66% nitrous oxide in oxygen, the assigned opioid infusion, and additional doses of vecuronium as needed to maintain adequate muscle relaxation (two twitches by train-of-four) for the duration of the procedure. Patients were observed for responses to intubation, removal of the uterus, and light anesthesia. Light anesthesia was characterized by hemodynamic (SBP 2 15% increase above preoperative baseline for 21 min, or 2 20% increase above prestress baseline for 22 min after the major stress event, or HR > 90 beats/min for 21 min), somatic (movement, eye opening, or grimacing), or autonomic (tearing or sweating) changes. Signs of light anesthesia that were considered transient were first treated with single doses of opioid administered via single-dose syringes (1 pg/kg remifentanil for the Remi/Placebo or Remi/Remi groups, or 7 pg/kg alfentanil for the Alf/Placebo group) and separated by at least 1 minute (Figure 1). If three sequential single doses did not control the response, then up to three infusion rate increases could be made via the maintenance syringe (doubling of the current infusion rate up to a maximum infusion rate of remifentanil 2 p,g/kg/min or alfentani14 pg/kg/min) . A supplemental dose of thiopenta12 mg/kg IV was administered if the response persisted. Patients who required supplemental thiopental were judged to be inadequately anesthetized but were included in the data analyses. At skin incision or approximately 5 minutes before Table

1

entry into the abdominal cavity, infusion Pump 2 was attached to the second stopcock to deliver the second blinded infusion (remifentanil at the current Pump 1 rate for the Remi/Remi group; saline placebo for the Remi/ Placebo and Alf/Placebo groups) (Fig-ure 1). This procedure effectively doubled the remifentanil infusion rate in the Remi/Remi group. If hypotension occurred (SBP < 80 mmHg) before Pump 2 was initiated, the maintenance infusion rate controlled by Pump 1 was decreased by 50% between the current and previous infusion rate. If SBP did not exceed 80 mmHg within 2 minutes after the infusion rate decrease, then phenylephrine 25 to 100 mg IV and/or atropine 0.5 mg IV was administered. If hypotension occurred after Pump 2 was initiated, the infusion in Pump 2 was terminated and the Pump 1 infusion rate was decreased by 50% between the current and previous infusion rate. After stabilization of SBP following removal of the uterus, the maintenance infusion in Pump 1 was decreased by 50% every 10 minutes to a final rate that provided adequate anesthesia (a priori targets of 0.25 kg/kg/min for each remifentanil group and 0.5 kg/kg/ min for the alfentanil group).

Emergence/Recovery After return of two or more twitches, residual neuromuscular blockade was reversed with neostigmine 2.5 to 5.0 IV

Demographic and Anesthetic Characteristics Treatment Alf/Placebo

(n = 10)

Age b-s)

51.3 + 13.6

Weight (kg) ASA physical status, n (%) ASA I

69.4 + 7.1 0

ASA III Anesthesia duration (hours) Thiopental induction dose (mg/kg) * Time to intubation (min) Time to skin incision (min) Duration of infusion of Pump 2 (min) Lag time (min)? Study opioid consumption Total bolus dose (pg/kg) Total infusion dose (pg/kg) Total bolus + infusion dose (kg/kg) Maintenance opioid dose adjustmentsf Intraoperative rate increases Intraoperative single doses

Remi/Placebo

(n = 12)

44.2 + 5.4 66.8 I 13.9 2 (17%) 10 (83%)

9 (90%)

ASA II

Groups

0

1 (10%)

2.3 t 3.1 +

0.5

Remi/Remi

(n = 13)

42.5 t- 12.1 72 IL 14.2 2 (15%) 9 (69%) 2 (15%) 2.7 t- 0.8 3.0 2 1.2

2.5 + 2.7 t

0.6 0.8

6.9 ?

1.1

1.7 10.4 2 9.5

22.4 + 4.2 73.0 + 29.1 51.1 ? 26.6

25.1 + 8.4 51.5 2 12.8 58.3 2 22.4

30.6 +- 16.6 69.2 t 34.8 61.2 2 26.7

76.1 316.9 393.0

8.5 76.1 84.6

5.2 63.5 68.7

2 (1 to 4) 3 (1 to 15)

2 (1 to 6) 3 (1 to 16)

I (1 to 4) 3 (1 to 12)

8.1 t

3.4

Note: Values are mean !z SD. Alf = alfentanil; Remi = remifentanil “Total

dose required

for loss of consciousness.

iTime between the termination IMedian (range) given.

of Pump 2 and termination

of Pump 1.

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535

Original Contributions

mg and glycopyrrolate 0.5 mg before discontinuation of nitrous oxide. At the end of the surgical procedure (last surgical suture), the Pump 1 infusion and nitrous oxide were discontinued simultaneously. Patients breathed normally or were ventilated with 100% oxygen for 5 minutes. If patients had not achieved adequate respiration by 10 minutes after the discontinuation of nitrous oxide, naloxone 0.1 to 0.4 mg IV was administered every 2 to 3 minutes until a respiratory rate (RR) of at least 8 breaths/min and/or P,,CO, no greater than 50 mmHg was achieved.

Outcome Measurements The primary efficacy endpoint was the proportion of patients with light anesthesia responses to the removal of the uterus. The proportion of patients with light anesthesia responses to endotracheal intubation and skin incision were also noted. The times from discontinuation of nitrous oxide to the time of achievement of the following recovery parameters were recorded by an individual blinded to the treatment assignment: spontaneous respiration, adequate respiration (oxygen saturation [S,O,] > 90% on room air, RR > 8 breaths/min, or P,rCO, 2 50 mmHg), response to verbal command, satisfactory extubation, and postanesthesia care unit (PACU) discharge. Safety was assessed by monitoring clinical adverse events (defined as any untoward medical events) including muscle rigidity during induction, nausea and emesis, and patient recall of operating room events (assessed on postoperative day 1). Muscle rigidity was assessed by the investigator, and it was rated on a four-point scale (O=none, l=mild, 2=moderate, and 3=severe). Patients were assessed by an individual blinded to study treatment for the presence of nausea or emesis within 15 minutes of PACU admission, 60 minutes later, and at the time of discharge from the PACU. Nausea assessments were obtained by asking patients whether they were nauseated, and severity was graded on a four-point scale (O=none, 1 =mild, 2=moderate, and 3=severe).

differences between the remifentanil and alfentanil populations. The Cox’s semi-parametric proportional hazards model was used to compare differences between groups for the emergence parameters, censoring patients who received naloxone.”

Results After studying three patients in the open-label pilot portion of the study, 35 patients were randomized into the study and included in the efficacy analyses. One patient who was scheduled for TAH had a vaginal hysterectomy instead. Treatment groups were comparable with regard to demographic characteristics, the total dose of thiopental required to achieve loss of consciousness, times to intubation and skin incision, anesthesia duration, duration of infusion of Pump 2 (hysterectomy), and the time between the termination of Pump 2 and the end of surgery (lag time) (Table 1).

Study Opioid Consumption The mean (+-SD) opioid infusion rates administered for the duration of Pump 2 to suppress responses to removal of the uterus were 0.49 rfr 0.27 kg/kg/min, 1.99 f 1.34 yg/kg/min, and 0.49 + 0.07 kg/kg/min for the Remi/ Placebo, Alf/Placebo, and Remi/Remi groups, respectively. The mean (range) opioid infusion rates for the duration of maintenance were: 0.54 (0.25 to 1.41) pg/kg/ min (Remi/Placebo), 2.02 (0.5 to 5.10) kg/kg/min (Alf/ Placebo), and 0.38 (0.19 to 0.63) pg/kg/min (Remi/ Remi). The mean opioid infusion rates administered to each group at five different times during the maintenance infusion period are presented in Figure 2.

Statistical Analysis Data were analyzed using SAS version 6.08 software. All statistical results were presented using two-sided p-values, and differences were considered to be statistically significant if the p-value was less than or equal to 0.05. Pair-wise comparisons were made using Fisher’s exact test for the percentage of patients with any response to removal of the uterus. Pairwise comparisons were also made using the Cochran-Mantel-Haenszel test” for the distribution of perioperative responses. The Fisher’s exact test was used to compare differences between groups for the percentage of patients who met the criteria for naloxone administration at 10 minutes after discontinuation of nitrous oxide and also for the incidence of emesis in the postoperative period. The Cochran-Mantel-Haenszel test was used to compare differences between groups for the incidence of nausea during the study. For the recovery parameters, plans were established a priori for testing 536

J. Clin. Anesth., vol. 9, November

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start Maintenance

Pre-Skin Incision

Start Pump 2

Measurement

Times During

End Pump 2

End Maintenance

Maintenance

Figure 2. Mean opioid infusion rates for the three groups at five measurement times during maintenance: start of maintenance (Start Maintenance); 5 minutes before skin incision (Pre-Skin Incision); combined initial rate of Pump 1 and Pump 2 (Start Pump 2); rate after Pump 2 was terminated (End Pump 2); and end of surgery (End Maintenance). The mean (range) opioid infusion rates for the duration of maintenance were: 0.54 (0.25 to 1.41) pg/kg/min (Remi/ Placebo), 2.02 (0.5 to 5.10) pg/kg/min (Alf/Placebo), and 0.38 (0.19 to 0.63) kg/kg/min (Remi/Remi). Remi = remifentanil; Alf = alfentanil.

Remifentanil us. aljentanil balanced anesthesia [or TAH: Kovac et al. Table 2 Surgical

Number (%) of Patients with Responses to Removal of the Uterus, Tracheal Intubation, and Skin Incision Events/Response

Alf/Placebo

Category

Skin incision Any intraoperative response* Hemodynamic response SBP t HRJ Tracheal intubation Any intraoperative response* Hemodynamic response SBP t

(n = 10)

Remi/Placebo

Remi/Remi

1 (10%)

0

0

1 (10%) 0

0 0

0 0

(n = 13)

5 (50%)

11 (92%)

5 (38%)

4 (40%)

10 (83%) 5 (42%)

5 (38%) 2 (15%)

1 (10%)

HRi

Removal of the uterus Any intraoperative response* Hemodynamic response SBP T HRl

(n = 12)

8 (67%)::

1(8%)

6 (60%)

8 (67%)

1 (10%)

0

1 (8%) 0

6 (6O%)t

Alf = alfentanil; Remi = remifentanil; SBP = systolic blood pressure; HR = heart rate. *Number (%) of patients m’ith any hemodynamic, somatic, or autonomic responses to the surgical event. lp = 0.018 for Alf/Placebo group us. Remi/Remi group. $p = 0.003 for Remi/Placebo group us. Remi/Remi group. t = increase j, = decrease The median frequency of opioid adjustments (rate increases or single doses) during the maintenance period was comparable among groups (Table 1). The incidence of hypotension (requiring decreases in opioid infusion rates) occurred in three patients in the remifentanil groups and none in the alfentanil group. Supplemental thiopental was administered to few patients across treatment groups (Remi/Placebo, 2; Alf/Placebo, 3; and Remi/Remi, 1).

Intraoperative Response Evaluations The proportion of patients with any responses (hemodynamic, somatic, or autonomic) to the removal of the uterus was similar in the Remi/Placebo (67%) and the Table 3

Distribution

Number

of responses

of Any Intraoperative

Alf/Placebo (60%) groups (Table 2). Fewer patients experienced hemodynamic responses in the Remi/Remi group (8%) compared with each of the other two groups (p < 0.05). Responses consisted primarily of SBP increases. One patient in the Alf/Placebo group experienced increases in both SBP and HR. iul of the responses to tracheal intubation and skin incision were hemodynamic in nature (Table 2). One patient in the Alf/Placebo group had an increase in SBP following skin incision but no patients in either remifentanil group responded to skin incision. The distribution of intraoperative responses (hemodynamic, somatic, or autonomic) is presented in Table 3. Fewer responses occurred intraoperatively in the Remi/

Response (Hemodynamic, Somatic, or Autonomic)

Alf/Placebo

(n = 10)

Remi/Placebo

0

0

1

0

ii

2 3 4 5 6 7

0 0 2 (20%) 0 0 0

0 0 0 1 (8%) 0 0

89

1 (10%)

i (25%) 5 (42%) 9

(25%)

(n = 12)

Remi/Remi 2 3 2 2 1 0 0 0

(n = 13)

(15%) (23%) (15%)

(15%) (8%)

0 210 Median

6 (60%) 12”

1 (8%) 2 (15%) 2

Alf = alfentanil; Remi = remifentanil. *p = 0.059 for Remi/Placebo vs. Remi/Remi.

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Contributions

Figure 3. Mean A. systolic blood pressure (SBP), B. diastolic blood pressure, and C. heart rate over time. Values are means -C standard error. MSE = major stress event; Remi = remifentanil; Alf = alfentanil. Remi group (median of 2 responses) than in the Alf/ Placebo group (median of 11.5 responses) (p < 0.05). Mean blood pressure and HR values were stable during the intraoperative period (F@.~re 3).

Recovery Evaluations Five of 22 patients (20%) received naloxone to reverse opioid effects in the remifentanil population compared with 6 of 13 patients (60%) in the alfentanil population ($I 538

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< 0.05). The incidence of naloxone use was not related to the dose of remifentanil used (mean infusion rate, 0.25 to 2 pg/kg/min). Among the alfentanil patients who received naloxone, the last intraoperative maintenance rate ranged from 4 to 8 yg/kg/ min in three patients, and from 0.5 to 2 pg/kg/min in the remaining three patients. Times to recovery endpoints (verbal command, spontaneous and adequate respiration, and extubation) from the end of nitrous oxide discontinuation were significantly shorter for the remifentanil population than the alfentanil

Remijententanrl vs. aljentanil balanced anesthesia for TAH: Kovac et al. Table 4

Recovery Times Expressed as Medians (Range) Time

Recovery

Parameters

Response to verbal command Spontaneous respiration Adequate respiration Extubation PACU discharge

Alf/Placebo

10.5 13.5 14.0 14.5 123.0

(min) from Discontinuation (XI = 10)

(4,25) (2,19) (4,22) (4,25) (86,178)

of Nitrous

Remi/Placebo

4.0 4.5 6.5 7.0 115.0

Oxide

(n = 12)

(2,7)* (0,16)* (2,16)X (4,16)* (98,154)

to Recovery

Parameters Remi/Remi

3.0 3.0 6.0 8.0 123.0

(n = 13)

(1,9) (1,9) (1,12) (1,13) (74,191)

Alf = alfentanil; Remi = remifentanil; PACU = postanesthesia care unit. *p < 0.05 for remifentanil population us. alfentanil population.

population (p < 0.05) (Table 4). The median time to discharge from the PACU was approximately 2 hours across treatment groups. More patients who received remifentanil (40%) experienced moderate to severe postoperative pain within 10 minutes after response to verbal command than those who received alfentanil (10%). The majority of patients in each group received morphine sulfate to treat postoperative pain (Remi/Placebo, 92%; Alf/Placebo, 73%; Remi/ Remi, 79%).

Safety Evaluations During induction, similar proportions of patients across treatment groups developed muscle rigidity (Remi/Placebo, 52%; Alf/Placebo, 55%; Remi/Remi, 44%). The majority of muscle rigidity events (2 90%) in each group were rated mild to moderate in severity, with a median duration of 2.0 minutes. The proportion of patients who reported one or more episodes of nausea in the PACU was comparable among groups (Remi/Placebo, 46%; Alf/Placebo, 30%; Remi/ Remi, 42%). Nausea was generally mild to moderate in severity and was resolved by medical treatment. One patient in the Remi/Remi group had a severe episode that was not initially resolved by medical treatment but was resolved prior to discharge from the PACU. Similar proportions of patients in the remifentanil groups experienced emesis in the PACU (Remi/Remi, 23%; Remi/Placebo, 25%). At discharge from PACU, emesis was absent in all patients in the Remi/Remi group, but present in one patient in the Remi/Placebo group. Emesis did not occur in the alfentanil group. At least one half of the patients in each treatment group recalled entering the operating room when questioned on the day following surgery (Remi/Placebo, 50%; Alf/Placebo, 60%; Remi/Remi, 69%). No patients in any group recalled any aspect of the operation.

Discussion Results of this study indicate that a mean remifentanil infusion of 0.49 pg/kg/min is as effective as a mean alfentanil infusion of 1.99 pg/kg/min in suppressing intraoperative responses. Doubling of the remifentanil

infusion to 0.5 p,g/kg/min before the major stress event provides more effective control of intraoperative responses than rate increases or single doses of remifentanil or alfentanil initiated to control responses that occurred. The findings of this study appear to support the widespread clinical notion that it is much easier to prevent responses to noxious stimuli by preemptive administration of an increased dose of opioid than it is to control such responses once they are established. Furthermore, pretreatment of the major stress event results in lowering overall intraoperative opioid requirements (mean total opioid consumption of 68.71 Fg/kg VS. 84.64 kg/kg for the Remi/Remi group us. Remi/Placebo group) without compromising the level of anesthesia. Patients who received remifentanil experienced more rapid emergence from anesthesia than did those who received alfentanil, and discharge times were similar across all groups. The primary outcome measure in our study is a hemodynamic response to surgical manipulation. Although hemodynamic variables are often used as a guide for titration of anesthetics, there is a great deal of controversy as to whether changes in hemodynamic variables are an important and accurate reflection of the anesthetized state.i2 Clinical signs, including changes in hemodynamic variables, often vary with different surgical and anesthetic maneuvers. However, the advantage of using clinical signs is that they are major guides to the conduct of anesthesia in clinical practice.i3 In a classic study, Ausems et aL14 defended the assessment of anesthetic depth using clinical signs. As was done for Ausem et al.‘s study, we defined hemodynamic responses prospectively in terms of absolute changes in HR and blood pressure in order to ensure repeatability, reproducibility, and objectivity of measurements. The patient’s anesthetic state was also evaluated by assessing for the presence or absence of somatic and autonomic responses. Considered together, these steps can provide a reasonable estimate of anesthetic depth with results that would have direct clinical applicability. This study was designed using nonequipotent doses of remifentanil and alfentanil at the start of maintenance so as to evaluate the dose requirements of both opioids needed to suppress intraoperative responses without increasing the risk of prolonged recovery in the alfentanil patients. The doses of remifentanil used in the present study (0.25 or 0.5 pg/kg/min) were based on those J. Clin. Anesth., vol. 9, November 1997

539

Otiginal Contributions Table 5

Cost Comparison Total Dose Administered (mg)

Drug Alf/Placebo Remi/Placebo Remi/Remi

Cost/mg* $3.28 $9.00 $9.00

27.27 5.65 4.95

Final Cost $89.45 $50.85 $44.55

*Cost is based on average wholesale prices from Medi-Span [Indianopolis, IN (www.medispan.com) October 19961, and assumes no wastage. Cost per mg for alfentanil (Ah) is based on a 20 ml vial. Cost per mg for remifentanil (Remi) is based on a 5 mg vial.

identified from a previous study by Dershwitz et aL15 for suppression of responses to skin incision and intraoperative stimuli. We chose to evaluate a clinically acceptable dose of alfentanil (0.5 kg/kg/min) identified from a previous study by Monk et aL2 One limitation of our study is the absence of a fourth study arm involving alfentanil analgesic pretreatment in anticipation of the major stress event. Doubling the dose of alfentanil could provide improved control of intraoperative responses but could also increase the risk of delayed recovery and prolonged respiratory depression. As shown in the present study, the use of remifentanil provides recovery times that are predictable and are consistently shorter compared with those for alfentanil, even when intraoperative doses were as high as 1.41

sion at a lower infusion rate to allow for emergence from anesthesia while providing analgesia until PACU admission, and/or by the earlier introduction of analgesics to provide adequate postoperative analgesia before discontinuing the remifentanil infusion. In conclusion, remifentanil is a clinically useful alternative to alfentanil as an analgesic component of a balanced anesthetic technique with nitrous oxide when hemodynamic control and rapid, predictable emergence from anesthesia are desirable. Doubling of the remifentanil infusion to 0.5 pg/kg/min before the major

stress

event

resulted

in improved

suppression

of

intraoperative remifentanil,

responses, lower intraoperative use of and similar recovery times compared with

interventions

performed

in response

to noxious

stimuli.

Remifentanil provided faster awakening times than alfentanil, but preemptive administration of postoperative analgesics is recommended to facilitate PACU discharge.

Addendum For drug cost comparisons,

please see Table 5.

Acknowledgments The authors gratefully acknowledge the contributions and Beth Sherrill for statistical analyses and review.

of Amy Peng

pg/kg/min.

Although more patients who received remifentanil in our study required naloxone than was reported in the were study by Dershwitz et al. r5 the times to extubation similar between the two studies. Our results indicate that the incidence of naloxone use was not related to the dose of remifentanil used which is consistent with the known pharmacokinetic properties of remifentanil. The protocol mandated that naloxone be given if adequate respiration did not occur within 10 minutes after discontinuing the study drug. Because the times to adequate respiration following remifentanil were in the range of 1 to 16 minutes, it is, therefore, not unexpected for some patients to receive naloxone given the strict protocol requirements specified in our study. In clinical practice, the incidence of naloxone use may be lower than what we report because recovery procedures would not be constrained by the guidelines of a research protocol. Consistent with the rapid offset of remifentanil, more patients who received remifentanil (40%) experienced moderate to severe postoperative pain within 10 minutes after response to verbal command than did those who received alfentanil (10%). However, the incidence of postoperative

medication

use for pain

was similar

among

groups. Although no statistically significant differences in the incidence of nausea among groups were noted at any measurement time, the higher prevalence of nausea and emesis reported in the remifentanil groups may be related to the earlier onset In clinical practice, likely be diminished

540

of postoperative pain in these patients. the earlier occurrence of pain would by continuing the remifentanil infu-

J. Clin. Anesth., vol. 9, November

1997

References 1. Bovill JG, Sebel PS, Stanley TH: Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology 1984;61:731-55. 2. Monk TG, Mueller M, White PF: Treatment of stress responses during balanced anesthesia. Comparative effects of isoflurane, alfentanil, and trimethaphan. Anesthesiology 1992;76:39-45. pharmacodynamics, and 3. Shafer SL, Varvel JR: Pharmacokinetics, rational opioid selection. Anesthesiology 1991;74:53-63. 4. James MK: Remifentanil and anaesthesia for the future. Eq5 Opin Inwst Dmgs 1994;3:331-400. 5. Feldman PL, James MK, Brackeen MF, et al: Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgesics. 11%&d Chem 1991;34:2202-8. 6. James MK, Feldman PL, Schuster SV, Bilotta JM, Brackeen MF, Leighton HJ: Opioid receptor activity of GI87084B, a novel ultra-short acting analgesic, in isolated tissues. J Phamacol Exp Ther 1991;259:712-8. of 7. Egan TD, Lemmens HJ, Fiset P, et al: The pharmacokinetics the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993;79:881-92. pharma8. Glass PS, Hardman D, Kamiyama Y, et al: Preliminary cokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (G187084B). Anesth Analg 1993;77:103140. 9. Westmoreland

CL, Hoke JF, Sebel PS, Hug CC Jr, Muir KT: Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993;79:893-903. 10. Landis RJ, Heyman ER, Koch GG: Average partial association in three-way contingency tables: a review and discussion of alternative tests. Int Stat Rev 1978;46:237-54.

Remifentanil vs. aljentanil balanced anesthesia for TAH: Kovac et al. 11. Breslow NE: Covariance analysis of censored survival data. Biomet-

ncs 1974;30:89-99. 12. Philbin DM, ROSOTV CE, Schneider RC, Koski G, D’Ambra Mr\r: Fentanyl and sufentanil anesthesia revisited: how much is enough? AnwthesioZog)l 1990;‘73:5-11. 13. Cullen DJ, Eger EI 2d, Stevens WC, et al: Clinical signs of anesthesia. Anesthesiology 1972;36:21-36.

14. Ausems ME, Hug CC Jr, Stanski DR, Burm AG: Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. Anesthesiology 1986;65: 362-73.

15. Dershwitz M, Randel GI, Resow CE, et al: Initial clinical experience MTithremifentanil, a new opioid metabolized by esterases. Anesth ilnalg 1995;81:619-23.

Initial Clinical Experience with Remifentanil, A New Opioid Metabolized by Esterases M. Dershwitz, G.I. Randel, C.E. Rosow, R.J Fragen, P.M. Connors, E.S. Librojo, D.L. Shaw, A. W. Peng, B.D. Jamerson

Abstract Remifentanil is a new, esterase-metabolized opioid for anesthesia. Nonspecific esterases terminate the drug effect, with a context-sensitive half-time which plateaus a 3-4 min. This dose-ranging pilot study was designed to estimate the dose requirement of remifentanil for abolition of the responses to skin incision and intraoperative stimuli, and to determine the speed of recovery. Fifty-one unpremeditated patients took part at two centers. Anesthesia was induced with propofol, 6% nitrous oxide, and vecuronium. Remifentanil was then given (1 microgram/kg, plus an infusion of 0.0125-1.0 micrograms/kg/min). Responses were defined as: >15% increase in systolic blood pressure or >20% increase in heart rate, tearing, sweating, movement, or coughing. Responses to incision or surgery were treated with 0.5 micrograms/kg remifentanil boluses and a 50% increase in infusion rate, which could be done twice. Subsequent responses were treated with propofol or isoflurane. Remifentanil and nitrous oxide administration were terminated after the incision was closed. ED50 for response to skin incision varied between the two study sites (0.020 and 0.08’7 microgram/kg/min). ED50 for response to all surgical stimuli was 0.52 microgram/kg/min. At 0.3 microgram/kg/min or more, only 3 of 21 patients required isoflurane. Recovery was not longer in patients receiving larger doses to spontaneous ventilation (2.5-4.6 min), tracheal extubation (4.2-7.0 min), and response to verbal command (3.0-4.6 min). Postoperative pain was reported in most patients (92%) at a median time of 21 min. We conclude that remifentanil was effective and well tolerated as a component of nitrous oxide-opioid-relaxant anesthesia. Reprinted

from Anesthesia and Analgesia 1995;81:619-23.

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