Sedation on the ICU can be either analgesia or sedative based. With a sedative-based regimen, hypnotic agents are titrated to maintain patient comfort despite them having almost no analgesic effect, and the opioid dose is usually minimised. Patients are therefore kept asleep but are not necessarily pain free. When interviewed about their ICU stay, many patients recall significant unrelieved pain [24
]. Pain may evoke a stress response leading to adverse effects such as tachycardia, increased myocardial oxygen consumption, hypercoagulability, immunosuppression and persistent catabolism [14
]. Moreover, a sedative-based regimen may facilitate oversedation, which may lead to prolonged mechanical ventilation and longer stays in both the ICU and hospital [4
]. The increased duration of mechanical ventilation may translate into nosocomial complications, such as ventilator-associated pneumonia [28
]. Over-sedation may impede a recommended [29
] daily interruption or lightening of sedation, increase the incidence of complications [5
], hinder neurological assessment and increase costs through the need for a greater number of expensive tests such as CT scans of the brain [30
The aim of analgesia-based sedation is to focus in the first instance on achieving effective analgesia, with a sedative agent being given subsequently if required. Effective analgesia may diminish the stress response, provide comfort, and facilitate treatment of critically ill septic patients. Guidelines recommend that sedation of critically ill patients should be started only after providing adequate analgesia [14
The ideal sedative agent should be effective and easily titratable, with a rapid onset and offset of action, no accumulation, and it should be cost-effective by improving the quality of care, reducing the time spent on mechanical ventilation or reducing the length of stay in the ICU [4
]. Except for higher acquisition costs, remifentanil fulfils these attributes.
We have shown that after cardiac surgery, analgesia-based sedation with remifentanil and propofol allows a facilitated turnover of patients, achieved by significantly earlier extubation and discharge from the ICU, and can be administered at equal total costs, compared with a conventional sedation regimen with midazolam and fentanyl. Although both remifentanil and propofol are considerably more expensive than midazolam and fentanyl, the cost savings achieved by a shorter weaning time, leading to earlier extubation and an earlier discharge from the ICU, outweigh the higher acquisition costs. No difference between the two groups in the level of sedation or in safety was observed.
The shorter weaning time with remifentanil/propofol is a direct consequence of the pharmacokinetic profile of these two drugs. Remifentanil has a rapid onset (1 minute) and offset (half time <10 minutes) of action [33
]. Its organ-independent metabolism by non-specific blood and tissue esterases results in a pharmacokinetic profile unaffected by impaired kidney [9
] or liver [35
] function, which differentiates remifentanil from all other opioids. Remifentanil does not accumulate, even after prolonged infusion [36
Although both midazolam and fentanyl have a rapid onset and a short clinical duration with single doses, accumulation and prolonged sedative effects may be observed after continuous administration [38
], which is also indicated by a significantly longer context-sensitive half time of these drugs [36
Time from extubation (after discontinuation of the study medication) until discharge from the ICU was also significantly longer in the midazolam/fentanyl group. This recovery period after a long and difficult operation, such as open heart surgery with cardiopulmonary bypass in elderly patients with multiple co-morbidities, certainly is a multi-factorial event. Although patients in the remifentanil/propofol group were more severely ill, as shown by a higher SAPS II, a difference in vigilance, orientation and compliance after extubation was obvious. Patients in the midazolam/fentanyl group reached the predefined discharge criteria later. An accumulation of sedatives most likely can be presumed to be the reason.
With respect to adverse and serious adverse events and the duration of adequate sedation, no statistically significant differences could be determined. These findings correspond well with the published literature [12
]. The higher incidence of drug-related adverse events in the remifentanil/propofol group, mainly consisting of shivering, might be due to the unusually high remifentanil dose in our study and is not consistent with the findings of other studies [8
As pointed out, the mean infusion rate for remifentanil was very high (41.2 μg kg-1
), leading to very high drug costs. The summary of product characteristics of remifentanil recommends a starting dose of 6 to 9 μg kg-1
and the addition of a sedative drug already at a rate of 12 μg kg-1
. In our study, in spite of a very high remifentanil infusion rate of 60 μg kg-1
, more than half of the patients still needed the addition of propofol. Presumably, the earlier addition of propofol, following the recommendations in the summary of product characteristics of remifentanil, would have considerably reduced the drug costs of remifentanil, with only a smaller increase in the costs for propofol. As demonstrated in our scenario analysis, this real world scenario might even render cost savings to the hospital. This assumption is further supported by a recently published study in which the mean remifentanil infusion rate was 7.8 μg kg-1
, with a remifentanil 'trigger' dose for the addition of midazolam of 12 μg kg-1
]. In this study, extubation could be performed within 17 minutes after a duration of mechanical ventilation of more than 14 hours.
In addition to this cost-reducing consideration, according to the study protocol, a high concentration of 250 μg/ml remifentanil in the infusion syringes (10 mg remifentanil in 40 ml infusion solution) led to high wastage costs of remifentanil, which are included in the drug costs. A lower concentration certainly would reduce wastage costs and should be recommended in short term sedation.
Our study shows several limitations: as in any open study, there is the risk of biased patient assessment and treatment. On the other hand, an open study design offers the opportunity to investigate the drugs under real world conditions, that is, it measures the effectiveness instead of the efficacy.
When the protocol was being designed, we felt that it might be more feasible to use a three point scale instead of a validated sedation scale like the Sedation-Agitation Scale (SAS) or the Richmond Agitation Sedation Scale (RASS) for evaluating sedation, or the Visual Analogue Scale (VAS) or the Behavioural Pain Scale (BPS) for evaluating pain. To date, we would also prefer to use these validated scales.
Concomitant medications were not limited and not recorded, and data on tolerance and withdrawal were not collected in our trial.
According to standardised processes of the hospital, weaning was started on the morning after the operation at 0700. This was fixed due to an established one-shift system for physicians in the study centre and ensured close assessments in regard to extubation and discharge criteria during the daytime. This procedure led to longer postoperative mechanical ventilation and sedation than a fast track regimen, resulting in a mean time to weaning of more than 18 hours in both groups. A three-shift system would likely have enabled an earlier weaning, which might have had impact on time to extubation and discharge in both groups. However, the applied procedure resulted in the positive side effect of similar mechanical ventilation times in both groups and thus high comparability of the investigated regimens.
Finally, as our study was conducted in one German hospital, its results might not be directly transferable to other countries and settings. Instead, a case-by-case check of the transferability is advised.