This was the first study evaluating the use of dexmedetomidine CRI in the anesthesia of septic dogs and comparing its hemodynamics, ventilatory and microcirculation effects with fentanyl’s under the same conditions. According to the results found, the infusion of dexmedetomidine at a dose of 3 g/kg/h during isoflurane anesthesia provided hemodynamic stability and higher values of systolic, mean and diastolic blood pressure and delta temperature compared to fentanyl, without compromising the sublingual microcirculation.
The OPS imaging technique is a noninvasive method used to evaluate microcirculation in humans(8,9), as it can reveal significant alterations in blood flow and decreased vascular density associated with microcirculatory derangements (9). Microcirculation is the main site of oxygen exchange between blood and adjacent tissues, and its homeostasis is altered in sepsis (10). In this study, there were no significant differences between the groups DEX and FENTA regarding the microcirculation evaluation with OPS, except for the microcirculatory flow index (MFI) at a single time point (T30), which indicated better results in the fentanyl group. It’s important to remember that the total vascular density (TVD) and the De Backer score (DBS) provide vessel density information, while MFI is a flow quality index. These parameters correlate with the continuity and the speed of flow of red cells in the microcirculation. Despite the use of dexmedetomidine or fentanyl in septic patients, our results are in accordance with those presented by Silverstein (11), who analyzed the microcirculation in the oral mucosa of anesthetized dogs undergoing elective surgery. In the present study, mean values of TVD slightly fluctuated around 21.8 in all three evaluation time points under the CRI, while MFI mean values oscillated between 2.71 and 3.06.
Microvascular alterations are common in patients with sepsis, as several inflammatory mediators are involved, in addition to other coexisting physiological mechanisms that might impair microcirculation (9). Recent studies have shown that dexmedetomidine reduces the inflammatory response, decreases the interaction between leukocyte and endothelium and produces mild hypocoagulation, which contributes to microcirculation recruitment and, from a certain point of view, to minimizing the microvascular changes caused by sepsis (12,13). These changes include endothelial cell dysfunction associated with molecular adhesion, increased leukocyte adhesion, glycocalyx degradation, vascular extravasation, microthrombi formation and local perfusion pressure alteration (2). The importance of the present study’s findings is that the OPS imaging technique demonstrated that dexmedetomidine, in comparison with fentanyl, does not compromise microcirculation or tissue perfusion, which was also evidenced by serum lactate concentration and blood gas results.
In a similar research, sublingual microscopy was used in human patients randomly divided into two groups receiving either a propofol or dexmedetomidine CRI for postoperative sedation after cardiac surgery. The dexmedetomidine group showed higher values of DBS and vascular density, which demonstrated that dexmedetomidine, in comparison to propofol, possibly has a property of preserving the microcirculation in these patients (14).
As it is a potent selective alpha 2 agonist, dexmedetomidine has a dual alpha 2 adrenoceptor activation characteristic, since its effect in vascular smooth muscle cells results in vasoconstriction while the activation of receptors in endothelial cells and the inhibition of the sympathetic nervous system causes vasodilation (3,13). The results presented here are consistent with the expected pharmacodynamics of dexmedetomidine, as a decrease in heart rate associated with an increase in blood pressure was observed, which was also shown in other experiments (15–17). This characteristic was also observed in critically ill dogs who received dexmedetomidine constant rate infusion in postoperative analgesia (18). Interestingly, in the present study mean heart rate values were higher than expected in the dexmedetomidine group: 87, 74 and 71 bpm in T0, T30 and T60, respectively. This finding is perhaps related to the fact that a dexmedetomidine loading dose was not used in this study. CRIs maintain lower plasma concentration levels than bolus injections and may therefore represent an option to avoid cardiovascular changes caused by the drugs (19). Dexmedetomidine’s alpha 2 selective properties can be observed with slow intravenous administration of low and medium doses (10–300 g/kg), whereas with higher doses (>1000 g/kg) or rapid intravenous infusion, both alpha 1 and alpha 2 activities can be observed in animals. Dexmedetomidine’s pharmacokinetic properties might also explain why its CRI produces great results without a loading dose, since it has rapid distribution (a six-minute distribution half-life) (4).
Dogs in DEX group showed an increase in MAP that was not observed in the fentanyl group. Indeed, before the beginning of the CRIs the dogs in DEX group showed lower MAP values compared with FENTA group; however, after the start of the CRIs, MAP mean values improved in DEX group and remained higher than FENTA group’s values until the end of the infusion. Uilenreef (20) found that ASA I-II canine patients anesthetized with dexmedetomidine CRI (at 1 - 3 μg/kg/h) and isoflurane, following induction with propofol, showed stable blood pressure values, which were in fact considered to be relatively high for values usually observed with inhalation anesthesia protocols. Unlike humans, in dogs, alpha 2 agonists do not normally induce hypotension after an initial hypertension phase, probably on account of the fact that the vasoconstriction period is more sustained in this species, or because the loading doses intensify its effects (16,21).
There were no significant differences in body temperature, PaO2, SaO2, HCO3, AG, Cl, Na, K, BE between groups. Pascoe et al. (22) found similar results when testing three different dexmedetomidine CRI doses (0.1, 0.5 and 3 g/kg/h) in healthy dogs to evaluate its impact on isoflurane MAC. A study that assessed dexmedetomidine’s pharmacokinetics, cardiovascular and respiratory effects during a period of 24 hours of infusion concluded that although it caused hemodynamic changes, tissue oxygenation and acid-base balance parameters remained within acceptable limits (23), which corroborates with the blood gas results presented here. Despite the significant difference in pH between the groups, which suggested that the FENTA group (lower pH) had a worse microcirculatory performance, this finding is probably associated with respiratory acidosis.
Mean values of serum lactate concentration remained below 2 mmol / L by the end of surgery (T60) in both groups without significant differences between them, indicating that effective fluid replacement and oxygenation were performed during the anesthetic procedure. Similar data were found by studies that evaluated the use of dexmedetomidine infusions in healthy patients, where no significant alterations of serum lactate concentration were observed (22). This marker is associated with better hospital outcome in humans when its levels are lower than 2 mmol/L (24), and a retrospective study by Houwink (25) reported that lactate was the most important mortality predictor in critically ill human patients. In the present study, lactate clearance was statistically significant in the DEX group, however it was not in the FENTA group, which reinforces the fact that dexmedetomidine CRI at this dose does not impair tissue perfusion.
In addition, delta temperature has been shown to be an important predictor of mortality in human ICU, and may be related to microcirculation (25). The present study found higher delta temperature values in the DEX group, however this information is not sufficient to conclude microcirculatory blood flow and oxygenation were inferior in dexmedetomidine group. More studies about delta temperature and the use of dexmedetomidine are needed.
Aiming to minimize potential adverse effects during the administration of dexmedetomidine boluses, such as hypertension followed by hypotension (26,27), it was decided that the administration of a loading dose would not be performed, which however proved to be effective as evidenced by heart rate and blood pressure values, as well as microcirculatory parameters. The dexmedetomidine CRI dose was chosen based on studies that reported using doses between 1–5 g/kg/h in the anesthesia of healthy dogs (20,22,28).
Low CRI doses result in greater plasma concentration constancy, better hemodynamic stability and faster biotransformation. Even though loading doses produce sedation more rapidly, they tend to cause greater hemodynamic instability in critically ill patients when administered as an intravenous bolus, as demonstrated by Pypendop (19), who compared CRI with intravenous bolus administration of alpha 2 agonists.
Furthermore, as dexmedetomidine has a short half-life, gradual discontinuation of the infusion leads to a faster return of the patient’s level of consciousness (29,30).
This study had a few limitations. The microcirculation monitoring technology is under constant improvement, therefore new equipment and software are always being introduced in the market. For this reason, the equipment used in this study could not be the most up-to-date that is currently available. However, the results obtained in this study were consistent with other studies’, indicating that the technology used correlates well with more recent versions of the device. Furthermore, the surgical procedures were not performed by a single person, as there were two alternating surgeons that participated in the study.