Remifentanil versus  Morphine Analgesia and Sedation for Mechanically Ventilated Critically Ill Patients: A Randomized Double Blind Study

After Graz University ethics committee approval, all patients who agreed to participate in the study, or their legal representatives, gave a written informed consent. Forty postsurgical, 19 yr of age or older, American Society of Anesthesiologists physical status I-IV, orthopedic and general surgery subjects admitted intubated to the ICU and expected to require short-term or medium-term mechanical ventilation were enrolled in the study. Subjects with a modified ICU admission Simplified Acute Physiology Score II5of >52, with renal impairment (creatinine clearance of <50 ml/min), with medical conditions that may affect the ability to assess their level of sedation (e.g. , stroke, stupor, coma, dementia), or with an estimated 20% deviation from ideal body weight were excluded from the study.

A consecutive controlled randomized, double blind, parallel group study was conducted in conformity with the guidelines of the Consolidated Standards of Reporting Trials Statement6and editorial recommendations.7Patients were randomly allocated to the remifentanil or morphine groups according to a computer generated randomization list. To ensure equality in the severity of illness and a balanced subject case mix in the two treatment groups, randomization was stratified according to the subjects Simplified Acute Physiology Score II5in three subgroups: 6–29, 30–37, and 38–52. An assigned pain clinic nurse, the only one with access to the randomization code, prepared remifentanil 1.5 μg·kg⁻¹·ml⁻¹or morphine 7.5 μg·kg⁻¹·ml⁻¹infusion syringes according to individual patient body weights. All treating physicians and ICU personnel were blinded to the type of opioid used.

Baseline assessments of SAS score, Pain Intensity scale score ( Appendix 2), mean arterial pressure, and heart rate were recorded immediately before starting the study drug infusion and then once every 20 min for the first 6 h, after which assessments were made hourly.

The dosing algorithm is outlined in the flow chart (fig. 1). The blinded study drug was started at an initial infusion rate of 6 ml/h (remifentanil 0.15 μg·kg⁻¹·min⁻¹or morphine 0.75 μg·kg⁻¹·min⁻¹). The opioid infusion was adjusted, in the first intent, to achieve and maintain each subject at a target of an optimal sedation of SAS score 4 (a subject who is calm, cooperative, and easily arousable) without clinically significant pain, defined as Pain Intensity scale score ≤2. According to the dosing algorithm, provided that the subject had no clinically significant pain, if the SAS score was 4 then the current dose was maintained. If the SAS score was >4 then the opioid infusion rate was increased in 1 ml/h increments (0.025 μg·kg⁻¹·min⁻¹remifentanil or 0.125 μg·kg⁻¹·min⁻¹morphine). In subjects randomized to receive morphine a 5-ml (25 μg/kg) morphine bolus dose over 60 s was administered with each increase of the opioid infusion rate. However, to preserve the blind, subjects randomized to receive remifentanil received a 5-ml placebo bolus. If the subject had clinically significant pain, the opioid infusion rate was increased by 1 ml/h and a 5-ml bolus over 60 s was given by first intent irrespective of the SAS score at the time.

Only when the study drug infusion rate reached the midazolam trigger dose of 8 ml/h (remifentanil 0.2 μg·kg⁻¹·min⁻¹or morphine 1 μg·kg⁻¹·min⁻¹), was the requirement for supplementary sedation provided by the initiation of the open-label midazolam infusion (0.5 μg·kg⁻¹·min⁻¹) and a 30 μg/kg midazolam bolus. With each increase of the opioid infusion, the midazolam infusion rate was then increased by 0.125 μg·kg⁻¹·min⁻¹, accompanied with a midazolam bolus of 15 μg/kg. If the Pain Intensity scale score was ≤2 and SAS score was <4 the midazolam infusion rate was decreased by 0.125 μg·kg⁻¹·min⁻¹, and then the opioid infusion rate was decreased by 1 ml/h.

The weaning from mechanical ventilation process began when patient heart rate was <100 beats/min, arterial partial pressure of oxygen was >60 mm Hg with fractional inspired oxygen concentration <0.5, arterial partial pressure of carbon dioxide (Paco²) was <45 mm Hg with minute volume <10 l, and patients required no further sedative medications. To preserve the blind of the study, at the point when the decision to commence the weaning process was made, the study drug infusion was replaced in a blinded “syringe swap,” so that subjects receiving remifentanil received a further infusion of remifentanil while subjects receiving morphine received a placebo infusion that marked the termination of the morphine infusion. At the beginning of the weaning process the midazolam infusion was stopped if it was running, and the study drug infusion was gradually reduced by 25% of the previous rate over a period of 1 h until it was stopped. The duration of mechanical ventilation was the time from the institution of the opioid infusion until its discontinuation. During the weaning process, the extubation criteria and the Pain Intensity scale scores were assessed once every 10 min. Patients were extubated when they were responsive to simple commands, their respiratory rate was 10–16 breaths/min with spontaneous tidal volume >5 ml/kg. With the start of the weaning process a nonopioid analgesic and a bolus dose of piritramide (0.05 mg/kg) were administered for longer acting pain relief. The piritramide dose was repeated if the Pain Intensity scale score was >2. The extubation time was the time from discontinuation of opioid infusion until extubation.

ICU discharge criteria were as follows: date of birth recollection, heart rate <90 beats/min, mean arterial pressure >80 mm Hg, Paco²<45 mmHg, respiratory rate of 10–16 breaths/min, and peripheral oxygen saturation >90%. Assessments for ICU discharge criteria were done every hour except during the sleeping hours between 22:00 and 06:00. ICU discharge time was the time from extubation until ICU discharge.

Based on the first 16 pilot patients, our a priori  power analysis for two-sided Student t  test (alpha = 0.05), assuming a 15% points difference between the two study groups in the mean percentage hours of optimal sedation during the study drug infusion, showed that a group size of 20 patients would be required to reveal a statistically significant difference between the two groups with >80% power.

Two-sample Student t  test was used for the analysis of the differences between the two groups. Data were expressed as mean ±SD. P  value of <0.05 was considered statistically significant.

Demographic characteristics, and baseline values were well matched, indicating a similar case mix of subjects in the two treatment groups (table 1). No deaths or serious adverse events leading to temporary or permanent discontinuation of study drug were reported during the study. There was no difference between remifentanil and morphine in terms of overall number of subjects with adverse events. There were three patients in each group who suffered from nausea and vomiting, whereas there were two patients in each group who suffered from hemodynamically related adverse events (table 1).

During the treatment period, the mean percentage hours of optimal sedation in the remifentanil group was significantly longer than that observed in the morphine group (table 2). Individual patient SAS scores are shown in figure 2. Subjects in the remifentanil group required less frequent infusion rate adjustments (0.34 ± 0.25 changes/h) than did those in the morphine group (0.42 ± 0.22 changes/h). The mean duration of mechanical ventilation, extubation time, and ICU discharge time were significantly longer in the morphine group than in the remifentanil group (table 2).

The weighted mean maintenance infusion rate of remifentanil was 0.13 ± 0.03 μg·kg⁻¹·min⁻¹and that of morphine was 0.68 ± 0.28 μg·kg⁻¹·min⁻¹. Individual patient opioid infusion rates are shown in figure 3. There were more subjects requiring midazolam in the morphine group (9 of 20) than in the remifentanil group (6 of 20). Furthermore, in those patients who required midazolam, the mean midazolam infusion rate was significantly higher in the morphine group (0.5 ± 0.3 μg·kg⁻¹·min⁻¹) than in the remifentanil group (0.2 ± 0.1 μg·kg⁻¹·min⁻¹).

During the study drug infusion, the mean arterial pressure was significantly lower in the remifentanil group (fig. 4A) than in the morphine group (fig. 4B). During the posttreatment period the respiratory rate was lower in the morphine group than in the remifentanil group (table 3).

The hypothesis of the primary end point of our study was accepted, as the mean percentage hours of optimal sedation was longer in the remifentanil group than in the morphine group. The lower mean percentage hours of optimal sedation in the morphine group probably reflects the nature of morphine’s long duration of action,1which demanded more frequent adjustments to maintain optimal sedation. On the other hand, the rapid onset and offset of action of remifentanil2enabled a stable level of sedation to be rapidly achieved with fewer infusion rate adjustments.

More subjects were optimally sedated without the addition of midazolam in the remifentanil group than in the morphine group. In those patients who required midazolam, patients in the morphine group required approximately 2.5 times more midazolam than did those in the remifentanil group. Because our study was not a clinical pharmacodynamic study comparing equipotent doses of two opioids but rather a clinical utility trial comparing two recommended opioid regimes,1,3this clearly indicates that patients in the remifentanil group experienced more pronounced opioid effect than those in the morphine group.

Our study showed that a mean remifentanil infusion rate of 0.13 ± 0.03 μg·kg⁻¹·min⁻¹was required to maintain optimal sedation for the mechanically ventilated ICU patients. This dose was higher than the 0.086 μg·kg⁻¹·min⁻¹dose required for postoperative pain management in patients who were not mechanically ventilated8but still lower than remifentanil requirements during surgery.9 

None of the patients of the two groups of our study experienced any clinically significant pain during weaning from mechanical ventilation. This is consistent with the long duration of action of morphine, whereas the rapid offset of remifentanil analgesia was preempted by the piritramide and nonopioid analgesics administration that resulted in a smooth transition to alternative analgesia.

In our study, remifentanil mean infusion rate be-fore the start of the weaning process was 0.11 ± 0.02 μg·kg⁻¹·min⁻¹. This was not significantly different from the 0.14 ± 0.03 μg·kg⁻¹·min⁻¹mean infusion rate at the first hour of infusion, indicating absence of a clinically relevant acute tolerance. This is in accordance with the reported absence of acute tolerance in patients who self-controlled their analgesic requirements after orthopedic surgery using remifentanil target controlled infusions.10This is also in accordance with a second study that reported no significant decrease of pain threshold devolutions between 1 and 3 h of continuous remifentanil infusion in a randomized, placebo controlled double-blind crossover study.11 

Patients in the remifentanil group emerged from sedation faster than did those in the morphine group (Table 2). This is indicative of the short terminal half-life of remifentanil (less than 10 min),2which is independent of the duration of infusion12or the total dose given.13This is in accordance with previous reports of rapid emergence from sedation, within 10–20 min, after a 24 h continuous remifentanil infusion.14 

In our study the mean ICU discharge time was longer in the morphine group than in the remifentanil group. This was not solely attributable to the longer duration of action of morphine but also to the fact that more subjects were optimally sedated without the addition of midazolam in the remifentanil group than in the morphine group. In those patients who required midazolam, patients in the morphine group required approximately 2.5 times more midazolam than did those in the remifentanil group. In addition, one of our ICU discharge criteria, the date of birth recollection, was not assessed during the sleeping hours. This could have greatly contributed to the big difference in ICU discharge times, as this rendered patients who did not meet the ICU discharge criteria before 22:00 more likely to be discharged the next morning; this was the case with several patients in the morphine group.

Remifentanil was well tolerated in our ICU patients. The hemodynamic and adverse events safety profiles in the remifentanil group were similar to those in the morphine group (table 1). The incidence of remifentanil hemodynamic related adverse events was low (2 of 20) and in accordance with the results of a multicenter study that examined the frequency of remifentanil hemodynamic adverse effects in a large population of 1,229 patients in diverse clinical setting.15In our remifentanil group the incidence of nausea (2 of 20) and vomiting (1 of 20) was much lower than the 27% nausea incidence8,10and the 8% emesis8reported in other studies. One patient in our remifentanil group suffered from depression. Although it seemed to be a nondrug related complication, it could not be completely ruled out. Despite the notion that the pharmacodynamic effects of remifentanil are extremely short lived after the drug is stopped, a substantial and lingering impairment in the psychomotor effects has been reported and patients were still cognitively impaired after the infusion was discontinued.16 

Remifentanil provided clinically acceptable effectiveness in attenuating the cardiovascular responses induced by the endotracheal tube. However, the mean arterial pressure was lower in the remifentanil group than in the morphine group. Several studies explored the various possible mechanisms of remifentanil-related hypotension. Remifentanil in escalating doses was not associated with significant alterations in histamine concentrations.17Remifentanil infusion rates of more than 0.1 μg·kg⁻¹·min⁻¹significantly decreased epinephrine plasma concentrations.3A recent study demonstrated that microinfusions of remifentanil into the brachial artery resulted in a significant increase in the infused arm blood flow, providing evidence that direct vasodilatation of the peripheral circulatory beds might account for the hypotension noted with remifentanil.18 

With our study opioid infusions, the respiratory drive suppression was useful, as it allowed our study patients to tolerate the ventilatory support. However, during the postextubation period, the decreased respiratory rate in the morphine group reflected the longer half-life of morphine producing a more pronounced effect at the respiratory center. The rapid recovery of respiration after the termination of remifentanil infusion was in accordance with a previous report of a rapid recovery of respiration within 10 min from terminating a 24 h continuous remifentanil infusion.14 

In conclusion, a remifentanil-based regimen was more effective than a standard morphine-based regimen for the provision of optimal analgesia-sedation. The incidence of adverse events was low and comparable across the two treatment groups. The use of remifentanil by initiating and titrating the opioid infusion in the first intent resulted in lower midazolam requirements. The remifentanil-based regimen allowed a more rapid emergence from sedation and facilitated earlier extubation than the morphine-based regimen.