This work represents a meta-analysis of the largest number of RCTs about the use of dexmedetomidine versus propofol in the sedation following heart valve surgery and CABG currently available, involving 11 RCTs, totaling 1184 patients.
Three main reasons prompted this investigation. First, we wanted to perform a further and more recent meta-analysis comparing dexmedetomidine and propofol, after similar previous publications [1, 30-34], to provide the reader with a more comprehensive statistical analysis of such a comparison. To be more accurate, the comparison was limited RCTs and to those comparing dexmedetomidine and propofol only, in contrast with previous meta-analyses including comparisons between sedatives and placebo [32-35]. Second, studies conducted on an international level, rather than those limited to the United States, were included to provide the reader with a wider perspective, a higher external validity, and conclusions applicable to different healthcare systems. Third, we performed a critical analysis of the endpoints used so far in the literature to emphasize the importance of confounding factors affecting the outcomes on which previous meta-analyses [1, 30-35] were based. In fact, despite the apparent time advantages afforded by dexmedetomidine over propofol, the former does not show particular overall improvements in postoperative care of heart valve surgery and CABG patients.
Time-dependent outcomes assessed in the included studies (TTE, MVT, LOS-ICU, and LOS-H) showed great limitations for two reasons. First, many factors, such as patients’ comorbidities, surgical complications, and postoperative bleeding, are well known to influence the postoperative care of cardiac surgery patients [36]. In particular, the Society of Thoracic Surgeons (STS) listed in its database 6 acute postoperative complications of cardiac surgery (re-operation; deep sternal wound infection / mediastinitis; permanent stroke; renal failure; prolonged ventilation [> 24 hours]; and new-onset atrial fibrillation) [37], which can happen singularly or, in 4% of cases, in combination [38]. Each of those is therefore capable of altering the time-dependent endpoints used in the included studies. Second, local protocols and physician’s evaluations can affect the decision to extubate the patient, thus changing both TTE and MVT and, accordingly, LOS in ICU and in the hospital.
Regarding TTE, our results are consistent with those of Liu X et al., [1] showing a reduction in TTE in the dexmedetomidine group [Figure 2-A]. On the other hand, MVT seems to be unaffected by the type of sedation in our analysis [Figure 2-B], as previously found by Chang et al. [30]. However, any postoperative complication can delay the timing of extubation directly (e.g., prolonged ventilation) or indirectly (e.g., re-operation) and alter the value of these endpoints. Moreover, there is no consensus about the time of extubation after cardiac surgery, and the actual ventilation time that leads to complications is not known [32].
As shown in Figure 3-A and B, dexmedetomidine seems to reduce LOS-ICU but not LOS-H. A prolonged LOS-ICU or LOS-H has several implications, ranging from the increased risk of infections to adverse outcomes and growing financial issues [36]. Anyway, LOS-ICU and LOS-H are affected by the same factors that undermine the reliability of TTE and MVT, and indirectly by all the remaining postoperative complications of cardiac surgery [35]. Since the debate on the best “fast-track cardiac recovery” modality is still ongoing, the possible interference of this lack of consensus with results cannot be ruled out.
Therefore, we think that these time-dependent outcomes are inaccurate in the evaluation of postoperative sedation. In future investigations, it might be possible to stratify patients in classes of postoperative risk of complications and risk of prolonged LOS, and then assess other endpoints, such as the time elapsed between the decision to extubate and the actual extubation time.
Delirium incidence in adult ICU is related to several factors, such as age, mechanical ventilation or pain. Furthermore, delirium is strongly associated with increased ICU mortality and post – ICU cognitive impairment, also establishing a vicious circle with LOS-ICU [7]. Surprisingly, our analysis did not found a difference in the incidence of delirium between the two groups of patients [Figure 4-A]. This is in contrast with previous meta-analyses that found a reduction in delirium incidence with the perioperative use of dexmedetomidine [1, 32-33]. A possible explanation for this result is that our analysis included a more recent trial that favored propofol over dexmedetomidine [29] and could have influenced the results.
Despite decades of experience with propofol in cardiac anesthesia, bradycardia and hypotension are serious concerns that can potentially cause organ hypoperfusion and dysfunction, such as brain damage [9]. Our analysis suggests a significantly diminished incidence of bradycardia and hypotension in dexmedetomidine sedated patients following heart valve surgery and CABG. However, such adverse effects have also been reported with the use of dexmedetomidine, even if promptly resolved with fluid boluses. This suggests the need for close advanced monitoring with at least heart rhythm and non-invasive blood pressure regardless of the agent used for sedation.
Apart from the critic about time-dependent endpoints, several limitations were noted during our analysis. Firstly, analgesic therapy used to reduce pain during post – surgery (mainly opioids) showed high variability in dosage and different starting and ending points of administration that were not clearly stated. This variability was noted also with regard to other sedatives (e.g., benzodiazepines) used during the surgeries, without a standardized protocol for general anesthesia. Such variability could have affected both time-dependent outcomes and especially delirium, which has a number of influencing factors precipitating this clinical condition. Future trials should take into account these aspects and try to follow a standardized protocol for the administration of intraoperative general anesthesia and of postoperative analgesics.
Although our study intended to include all types of cardiac surgery, the search did not return any paper regarding cardiac transplants in the adult population. The post-cardiac transplant sedation has been covered only on the pediatric population, in which dexmedetomidine showed better prevention of opioid withdrawal syndrome [39]. However, more efforts are needed to evaluate sedation after this important subset of cardiac surgeries, with particular attention to the sympatholytic effects of dexmedetomidine on a denervated transplanted heart.
Additionally, the sedation scales used in these studies (RASS and Ramsey scores) are often affected by incorrect evaluation by healthcare professionals [40], and are validated on sedatives in general but not specifically on dexmedetomidine (that has a specific alpha – 2 receptor agonism related sedation mechanism). Since the sedation of dexmedetomidine resembles natural sleep [42], future studies should closely assess this particular aspect of sedation level evaluation.
Finally, the medical authorities globally, except for 2 countries, recommend limiting the use of dexmedetomidine to 24 hours. This may limit the benefits seen from using such a sedative in the postoperative setting of cardiac surgery patients [41].