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Postoperative Analgesia with Remifentanil in Patients Undergoing Cardiac Surgery

Section Editor(s): Tuman, Kenneth J.Steinlechner, Barbara MD; Koinig, Herbert MD; Grubhofer, Georg MD; Ponschab, Martin MD; Eislmeir, Silvia MD; Dworschak, Martin MD; Rajek, Angela MD

doi: 10.1213/01.ANE.0000147703.85557.09
Cardiovascular Anesthesia: Research Report
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Chinese Language Editions

Remifentanil, a short-acting opioid, is commonly used in cardiac anesthesia. In this study we sought to demonstrate the feasibility of pain treatment and to determine the remifentanil dose necessary for adequate analgesia in tracheally extubated patients after cardiac surgery. Thirty patients undergoing elective cardiac surgery were included in this study. After surgery, the intraoperatively administered remifentanil was initially continued at 0.05 μg · kg−1 · min−1. Before tracheal extubation, a nonsteroidal antiinflammatory drug was administered and remifentanil was reduced to 0.035 μg · kg−1 · min−1. Pain assessment using a visual analog scale (VAS) was performed after tracheal extubation, in 2-min intervals for 10 min, every 10 min until the end of the first hour and every 30 min during the ensuing 5 h. A VAS score ≥30 or a respiratory rate <10 breaths/min was followed by an increase or decrease in the remifentanil dose by 0.005 μg · kg−1 · min−1, respectively. For rapid dose adaptation during the first 10 min, remifentanil was increased twice by 0.005 μg · kg−1 · min−1 and then 3 times by 0.01 μg · kg−1 · min−1. With a mean remifentanil dose of 0.051 μg · kg−1 · min−1 VAS decreased to 26 ± 14 after 30 min. Sufficient analgesia was achieved with remifentanil doses ranging from 0.03 to 0.09 μg · kg−1 · min−1. A maximum mean remifentanil dose of 0.057 μg · kg−1 · min−1 was reached after 4 h. The combination of remifentanil with a nonsteroidal antiinflammatory drug provided adequate analgesia in 73% of patients 30 min after tracheal extubation. Rapid dose titration was necessary during the first 10 min in 50% of patients. Increasing the initial remifentanil dose could shorten the titration period but may be associated with respiratory complications.

IMPLICATIONS: Postoperative continuation of remifentanil infusion in combination with a nonsteroidal antiinflammatory drug provides sufficient analgesia to patients after cardiac surgery without major side effects.

Division of Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, University Hospital of Vienna, Austria

Presented, in part, at the Annual Meeting of the European Association of Cardiothoracic Anaesthesiologists, May 25–28, 2003, Prague, Czech Republic.

Accepted for publication September 27, 2004.

Address correspondence to Barbara Steinlechner, MD, Cardiothoracic and Vascular Anesthesia and Intensive Care Medicine, University Hospital Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Address e-mail to

Postoperative pain after cardiac surgery may provoke the release of neurohumoral agents (1) by activation of the autonomic nervous system, causing hemodynamic instability and myocardial ischemia (2). Pain of thoracic origin can lead to poor inspiratory efforts in the spontaneously breathing patient and may contribute to postoperative pulmonary dysfunction and hypoventilation. Therefore, adequate analgesia is of particular importance for the prevention of postoperative respiratory complications such as atelectasis and pneumonia (3).

Postoperative pain treatment is routinely started before admission to the intensive care unit with a long-acting opioid. In contrast, remifentanil is an analog of fentanyl and is rapidly hydrolyzed by esterases in plasma and tissues. It has a context-sensitive half-life of 3–4 min that is independent of the duration of infusion (4–6). These characteristics facilitate titration of dose to effect and also allow the use of very large doses without prolonging recovery from its effects (7). Rapid onset and metabolism enable prompt control of the perioperative stress response and allow rapid recovery (8). This makes remifentanil the most predictable opioid for precise pain treatment. However, rapid onset and potency require individual dose titration in spontaneously breathing patients. Remifentanil for postoperative pain treatment has been described by a number of authors using different remifentanil doses in combination with an opioid rescue therapy (9–12). None of these investigations was performed in patients after cardiac surgery and only in the study by Schraag et al. (13) was remifentanil administered continuously for more than 1 h after tracheal extubation. Nonsteroidal antiinflammatory drugs (NSAIDs) are frequently used in combination with opioids in the postoperative period and these drugs effectively reduce opioid consumption in noncardiac surgery patients (14,15).

The aim of this investigation was to demonstrate the feasibility of providing sufficient postoperative analgesia with a manually titrated continuous infusion of remifentanil after cardiac surgery. Another goal of our study was to define the effective remifentanil dose necessary for adequate pain relief when remifentanil is applied in combination with a single IV dose of lornoxicam, a non-opioid NSAID. Compared with previous investigations remifentanil in this study was administered for 6 h in tracheally extubated patients.

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With approval from our ethics committee and after written, informed consent, 30 patients of either gender, ASA physical status III–IV, undergoing elective cardiac surgery were included in our study. Patients were excluded if there was evidence of renal disease, hypersensitivity to opioids, allergy or sensitivity to NSAIDs, previous history of peptic ulcer disease, alcohol or drug abuse, neurological deficit, congestive heart failure (ejection fraction <40%), age <18 yr or >80 yr, a body mass index >35, pregnancy, participation in another clinical study, or language problems. Heart failure may preclude fast track anesthesia whereas old age and extreme obesity may delay weaning from mechanical ventilation, prompting exclusion of such patients from our study. The purpose and protocol of our study and the use of the visual analog scale (VAS) were explained to all patients preoperatively (16).

Patients were premedicated with 7.5 mg of midazolam PO 1 h before surgery. Intraoperative monitoring included electrocardiogram, arterial and central venous pressures, pulse oximetry, and capnometry (9000 XL; Siemens Medical Solutions Inc., Sweden). Anesthesia was induced with midazolam (0.05 mg/kg) followed by 2–3 mg · kg−1 · h−1 of propofol and a continuous IV infusion of remifentanil (ULTIVA®, Glaxo Smith Kline Pharma GmbH, Vienna, Austria) at 0.25–0.5 μg · kg−1 · min−1 until loss of consciousness (i.e., loss of response to verbal commands and loss of the eyelash reflex). Tracheal intubation was facilitated with 0.2 mg/kg of cisatracurium and patients were mechanically ventilated using a mixture of 50% oxygen in air. Anesthesia was maintained by continuous administration of remifentanil at 0.15–0.4 μg · kg−1 · min−1 and propofol 3–6 mg · kg−1 · h−1.

Postoperatively, monitoring included electrocardiogram, arterial blood pressure, central venous pressure, oximetry, and capnometry. Tracheal extubation time was defined as the period from the end of surgery until tracheal extubation. After tracheal extubation, respiratory rate was derived from the electrocardiogram and recorded continuously (Hewlett Packard, Agilent Technologies, Palo Alto, CA). After arrival in the intensive care unit, the rates of the propofol and remifentanil infusions were decreased to 1 mg · kg−1 · h−1 and 0.05 μg · kg−1 · min−1, respectively. Thirty minutes before tracheal extubation, a single IV dose of lornoxicam 8 mg (Xefo®, Nycomed GmbH, Linz, Austria) was administered.

In all patients forced-air warming (BairHugger; Augustine Medical Inc., Eden Prairie, MN) was performed from arrival in the intensive care unit until the perfusion index was >1.0, which is considered the beginning of vasodilation. Skin vasoconstriction during hypothermia reduces dermal blood flow. This can be estimated by the peripheral perfusion index derived from a fingertip pulse oximetry signal. The perfusion index has been implemented in monitoring systems (Hewlett Packard, Agilent Technologies, Palo Alto, CA) as an index of peripheral perfusion (17). The perfusion index is calculated using a patented algorithm using both red and infrared pulsations. It is generally accepted that tracheal extubation should not be performed during shivering or at a core temperature of <36.0°C. Pezawas et al. (18) used the perfusion index to guide safe tracheal extubation, as an increasing perfusion index reflects internal redistribution of body heat with peripheral vasodilation.

When the perfusion index was >1, warming and the continuous infusion of propofol were stopped and remifentanil was reduced from 0.05 μg · kg−1 · min−1 to 0.035 μg · kg−1 · min−1. This starting dose was chosen to avoid hypopnea resulting from a combined effect of residual sedation from propofol with concomitant remifentanil application. This value was also the smaller dose of the 95% confidence interval (CI) determined in a pilot study for an efficient analgesic dose of remifentanil after cardiac surgery. Tracheal extubation occurred when the following criteria were achieved: patient responsive and cooperative, negative inspiratory force > −20 mm Hg, core temperature >36.5°C, arterial pH >7.3, chest tube drainage <100 mL/h, and absence of uncontrolled dysrhythmia (19).

Patients then received oxygen via a face-mask at a rate of 6 L/min. Heart rate, mean arterial blood pressure, respiratory rate, and oxygen saturation were recorded continuously (Hewlett Packard, Agilent Technologies, Palo Alto, CA). Arterial blood gas analysis was performed every 2 h. Respiratory depression was defined as apnea or a respiratory rate < 8 breaths/min. Any degree of limited awareness (level of consciousness [LOC] score 3–5) or postoperative nausea and vomiting were recorded during the study period.

Pain assessment was begun after tracheal extubation. Baseline evaluation using a VAS color scale was performed and the LOC score was determined. Adequate pain relief was defined as VAS rating <30 (mm) on the 100 (mm) VAS scale. Pain assessment was completed 6 h thereafter.

The color spectrum of the ruler we used to assess VAS had been explained to the patient the day before surgery. Pain intensity could be graded by the patient using this ruler that he or she could move on a color scale from bright yellow on the far left of the scale (i.e., no pain) to dark red on the far right (i.e., worst pain imaginable). On the back of the 10-cm scale, the 10 cm were divided in mm and each color was assigned a specific VAS grade from 0 mm (bright yellow) to 100 mm (dark red). For pain assessment, patients were only shown the colored scale. However, the corresponding VAS grade in mm was the data recorded.

The LOC score was determined on a 5-degree LOC scale (20): 1 = alert, awake; 2 = lethargic, tends to drift off to sleep when not stimulated, spontaneous movements are decreased and awareness is limited; 3 = obtunded, difficult to arouse; is confused when aroused; 4 = stuporous, unresponsive, arousable only by vigorous and repeated stimuli; 5 = comatose, unarousable, and unresponsive.

During the first 10 min after tracheal extubation, pain assessment was done in 2-min intervals followed by 10-min intervals until the end of the first hour. During the ensuing 5 h, pain was evaluated every 30 min. The intensity of postoperative pain was not assessed by the study investigator but by the anesthesiologist on call.

In patients reporting a VAS ≥30 at the defined time points of pain assessment, the remifentanil infusion was increased in steps of 0.005 μg · kg−1 · min−1, whereas in patients with a respiratory rate less than 10 breaths/min the remifentanil dose was reduced in steps of 0.005 μg · kg−1 · min−1. For rapid dose adaptation during the first 10 min after tracheal extubation, the remifentanil dose was increased twice by 0.005 μg · kg−1 · min−1 if necessary. Thereafter, a VAS ≥30 prompted an increase of the remifentanil dose in steps of 0.01 μg · kg−1 · min−1 for the next 3 times.

Remifentanil infusion was continued beyond the study period to avoid wasting an expensive drug. Thirty minutes before scheduled completion of the infusion, a second dose of 8 mg lornoxicam was administered IV, which was then followed by an IV bolus of 3 mg piritramide, a synthetic opioid (Dipidolor®, Janssen-Cilag Pharma, Vienna, Austria). Concomitantly, the remifentanil infusion rate was decreased by 50% (i.e., remifentanil infusion still continued for an additional 60 min). In patients reporting moderate or severe pain (pain assessment using a verbal rating scale) (21,22) before termination of the remifentanil infusion, a second dose of piritramide (4.5 mg) was given IV. The transition from remifentanil to the long-acting piritramide was done according to standard practice at our institution.

In a pilot study performed in 11 patients, we found that a mean effective remifentanil infusion rate of 0.05 μg · kg−1 · min−1 (95% CI = 0.034 – 0.063) could reduce VAS to <30 within 30 min.

To increase precision and to narrow the CI of the mean effective infusion rate we performed a sample size calculation. Assuming that a difference in the mean effective infusion rate of 0.015 μg · kg−1 · min−1 is clinically relevant, a study group sample of 30 patients was used to detect this difference with a power of 80%.

Values in the following sections are either given as absolute numbers or means ± sd.

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Patient characteristics and data regarding surgical procedures are presented in Table 1.

Table 1

Table 1

The severity of pain as assessed by the VAS score continued to decrease over the duration of the study period and reached 8.0 ± 7 at 6 h (Fig. 1). With an initial dose of 0.035 μg · kg−1 · min−1 remifentanil, VAS immediately after tracheal extubation was 42 ± 22. Because of frequent dose adaptation within the first 10 min of the study period, the remifentanil dose was increased to 0.047 ± 0.011 μg · kg−1 · min−1. VAS decreased simultaneously to 30 ± 15. During the first 10 min 60% of our patients experienced sufficient pain relief with only minimal dose adaptations. The other patients required rapid dose titration to 0.056 ± 0.01 μg · kg−1 · min−1. Only one patient of this group received the maximum remifentanil rate achievable within these 10 min (i.e., 0.075 μg · kg−1 · min−1). The average remifentanil rate in all our patients after 20 and 30 min was further increased in steps of 0.003 μg · kg−1 · min−1 and 0.002 μg · kg−1 · min−1, respectively. Thereby, VAS reached 26 ± 14 at 30 min after tracheal extubation with a corresponding remifentanil dose of 0.051 ± 0.012 μg · kg−1 · min−1. Time to tracheal extubation did not affect the initial VAS score and was not associated with slower or faster remifentanil infusion rates after tracheal extubation. Sixty minutes after dose titration a 95% CI of 0.049–0.059 μg · kg−1 · min−1 was calculated. After 4 h of evaluation the maximum remifentanil dose had been reached (0.057 ± 0.015 μg · kg−1 · min−1) and no further changes were necessary. Sufficient analgesia was obtained with remifentanil doses ranging from 0.03 to 0.09 μg · kg−1 · min−1 (Fig. 2). Only one patient needed a remifentanil infusion rate of 0.09 μg · kg−1 · min−1. By the end of the study period, VAS had continuously decreased to 8 ± 7 (Fig. 1).

Figure 1

Figure 1

Figure 2

Figure 2

During the study period the mean respiratory rate was 17 ± 1 breaths/min. The slowest respiratory rate (i.e., 9 breaths/min) was recorded 9 times in 5 patients. These minor compromises of respiration without accompanying hypoxemia were not linked, as could be suspected, to an excessively rapid remifentanil infusion rate. However, according to our protocol the remifentanil rate applied at these time points (mean, 0.054 μg · kg−1 · min−1; median, 0.055 μg · kg−1 · min−1; range, 0.03–0.07 μg · kg−1 · min−1) was decreased, resulting in an increase of the respiratory rate. Respiratory rates less than 9 breaths/min were not detected in any patient at any point in time. The most rapid respiratory rate (28 breaths/min) was documented 6 times in 4 patients. Two incidents of VAS ≥30 in 2 patients occurred within the first 20 minutes. The corresponding remifentanil infusion rates were 0.045 and 0.035 μg · kg−1 · min−1, respectively. Mean Pco2 was 42 ± 1 mm Hg (range, 27–51 mm Hg) and mean Po2 was 123 ± 15 mm Hg (range, 56–192 mm Hg) during the first 6 h after tracheal extubation. Arterial saturation as determined by pulse oximetry with the patients breathing supplemental oxygen via face mask was always between 95% and 100%. Hemodynamic and respiratory variables, such as heart rate (3 of 30 patients were pacemaker-dependent), mean arterial blood pressure, and oxygen saturation were stable throughout the study period. A LOC >3 was not observed during the study period. In particular, there was no difference in the LOC between patients with early tracheal extubation compared with those extubated late. Postoperative nausea was documented in 4 patients (13%). Nausea, in this study, never occurred in connection with pain. Severe respiratory depression (i.e., apnea or respiratory rate ≤8 breaths/min) was not observed.

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Adequate pain relief after cardiac surgery reduces postoperative complications and is therefore of major interest. Although remifentanil, a short-acting opioid, is commonly used for cardiac anesthesia, postoperative pain management using remifentanil has not been described. In our study we demonstrated that manual titration of a continuous infusion of remifentanil was feasible and effective for pain management in tracheally extubated patients after cardiac surgery without resulting in respiratory compromise.

Previous studies using remifentanil infusion in tracheally extubated patients after noncardiac surgery reported average infusion rates of 0.05–0.26 μg · kg−1 · min−1 (9–12). However, adequate analgesia was documented with much larger doses in individual patients. Bowdle et al. (9) were the first who evaluated remifentanil for postoperative analgesia in tracheally extubated patients. They found that sufficient analgesia could be achieved in 67% of patients within 3 minutes after major noncardiac major surgery with remifentanil doses ranging from 0.05–0.15 μg · kg−1 · min−1. However, some patients required even larger doses because of inadequate analgesia. Additionally, a remifentanil bolus dose, as well as morphine, were administered before the end of a 30-minute remifentanil titration period. Severe complications, i.e., hypoxemia and respiratory depression (Sao2 <90% or respiratory rate <12 breaths/min), were reported in 29% and apnea in 6% of patients with this analgesic regimen. In another study conducted by Schuttler et al. (11) remifentanil was applied at similar doses. Bolus administration and/or an increase of the remifentanil infusion rate also resulted in frequent muscle rigidity, respiratory depression, and apnea.

The immediate postoperative remifentanil dose titration scheme was modified by the study group of Yarmush et al. (12) For dose adaptation, they used increments of 0.025 μg · kg−1 · min−1 every 5 minutes during the first 20 minutes. This titration period resulted in adequate analgesia in 58% of his patients 25 minutes after tracheal extubation and decreased the incidence of respiratory adverse events (transient respiratory depression = respiratory rate < 8 breaths/min, apnea, or both in 14% of patients). This study demonstrated that remifentanil can be used for pain management in tracheally extubated patients if conducted under appropriate supervision. With a similar postoperative analgesic regimen Sneyd et al. (10) reported adequate pain control in 81% of patients within 30 minutes after tracheal extubation. The average remifentanil infusion rate was 0.1 μg · kg−1 · min−1 until the first scheduled morphine bolus was administered. However, many patients experienced moderate pain when the infusion was titrated to effect, indicating that the initial infusion rate was either too low or the titration scheme too slow or inflexible. Compared with manual titration of remifentanil Schraag et al. (13) demonstrated excellent results using a target controlled remifentanil infusion with 2-minute intervals for dose titration. Adequate analgesia was achieved in nearly 90% of patients after a mean time of 18.9 minutes.

To provide sufficient analgesia during the immediate postoperative period, we tried to optimize this manual titration scheme by increasing the frequency of dose adaptation and reducing the increments of remifentanil. The option of administrating a remifentanil bolus or rescue opioid application was not included in our study protocol. Nevertheless, adequate analgesia could be achieved in the majority of our patients within the first 10 minutes. All patients received supplemental oxygen via face mask. Under these circumstances normal oxygen saturation may be maintained, despite significant respiratory depression. Therefore, the respiratory rate was recorded continuously, and a sedation score was determined at the defined time points. Additionally, arterial blood gas analysis was performed at regular intervals. According to our protocol, the remifentanil dose was reduced in 4 patients because of a respiratory rate of 9 breaths/min producing a spontaneous recovery of the respiratory rate. In the present study, this optimized manual titration scheme in combination with IV lornoxicam given twice, before tracheal extubation and before termination of remifentanil, resulted in significantly lower remifentanil infusion rates as compared with all other investigations using remifentanil for postoperative pain management.

Transition from remifentanil to a long-acting opioid was done according to standard practice guidelines of our institution. In our study, the mean duration of remifentanil infusion after tracheal extubation was 13.6 ± 4 hours at a mean rate of 0.054 ± 0.02 μg · kg−1 · min−1. Discontinuation of remifentanil was performed using a combination of a NSAID (lornoxicam) and a long-acting opioid (piritramide) administered 30 minutes before the anticipated termination of remifentanil. Our cardiac surgery patients, except those with renal insufficiency, normally receive NSAIDs in addition to an opioid for pain treatment. The first dose of lornoxicam is usually given 30 minutes before tracheal extubation. After noncardiac surgery with a frequent incidence of moderate to severe postoperative pain, the combination of NSAIDs and opioids provides satisfactory analgesia and reduces opioid consumption. Norholt et al. (14) found that IM administered lornoxicam at 8 mg was as effective as 20 mg IM morphine in patients with moderate or severe pain after dental surgery. Another study by Rosenow et al. (23) showed that lornoxicam is as effective as morphine but better tolerated when given IV by patient-controlled analgesia for treatment of postoperative pain after laminectomy or discectomy. Trampitsch et al. (15) demonstrated that lornoxicam improves the quality of postoperative analgesia and leads to reduced consumption of opioid analgesics postoperatively. Therefore, we conclude that combining remifentanil with lornoxicam might have been responsible for the low remifentanil infusion rates in our patients that were necessary for adequate pain control.

Our investigation shows that excellent analgesic conditions can be achieved immediately after cardiac surgery using remifentanil infusion in combination with a NSAID. We found that remifentanil was an effective opioid for the treatment of postoperative pain that provides adequate analgesia in 73% of patients at an average dose of 0.051 μg · kg−1 · min−1 within 30 minutes after tracheal extubation without administration of additional rescue opioids. Had we increased the starting dose of remifentanil to 0.05 μg · kg−1 · min−1 the titration period could have potentially been shortened. However, this might have been accompanied by more severe respiratory complications, as residual effects from previously applied sedatives may have still been active. The interventions described in the present study were associated with no incidence of major side effects. Nevertheless, the use of remifentanil as an analgesic in the immediate postoperative period requires careful monitoring and supervision by trained personnel to provide individual dose titration.

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