Dexmedetomidine For The Treatment Of Acute Lung Injury: A Fact Or Fiction?

Abstract

Dexmedetomidine has been widely used in the intensive care unit (ICU), with the primary aim to keep patients on an appropriate level of sedation. Both observational and randomized controlled trials have observed that the use of dexmedetomidine is associated with improved outcomes for mechanically ventilated patients [1]. In ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to other sedatives in maintaining sedation level, but was associated with shortened MV duration and improved ability to communicate pain [2]. MV is an important factor for delirium and dexmedetomidine was found to be associated with lower risk of delirium [3, 4]. Prophylactic low-dose dexmedetomidine is able to reduce the occurrence of delirium during the first 7 days after surgery for patients aged over 65 years who are admitted to the ICU after surgery [4]. Thus, the beneficial effect of might be explained by the reduction of delirium in the treated group. In fact, delirium can be considered as a type of acute organ dysfunction mediated via inflammatory response. There has been evidence that inflammatory biomarkers such as C-reactive protein was positively correlated with the occurrence of delirium [5].

Keywords:

• Dexmedetomidine
• acute lung injury
• effectiveness

This article refers to:

Dexmedetomidine Ameliorates Post-CPB Lung Injury in Rats by Activating the PI3K/Akt Pathway

Along the same line of acute organ dysfunctions induced by systematic inflammatory response, acute lung injury (ALI) is an important one that contributes to patient-important outcomes. Thus, many studies begin to investigate the effectiveness of dexmedetomidine in reducing inflammatory response in the prevention and/or treatment of ALI. Numerous animal studies have confirmed the role of dexmedetomidine in ameliorating ALI. Potential inflammatory pathways via which dexmedetomidine enact its anti-inflammatory effects include PYD domains-containing protein 3 (NLRP3) [6], NF-κB pathway [7], and the α2AR/PI3K/Akt pathway [8]. ALI in essence is a clinical syndrome that encompasses an extremely heterogenous population. Subphenotypes of ALI can present large differences in clinical presentations and responses to treatment [9, 10]. The underlying causes of ALI plays an important role in the formation of these subphenotypes. Thus, the effect of dexmedetomidine may be different for ALI with different causes. In this issue of the Journal of Investigative Surgery, the authors investigated the role of dexmedetomidine in ameliorating post-cardiopulmonary bypass (CBP) lung injury and found that dexmedetomidine was able to reduce lung injury in rats via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway [11]. The study has several implications: 1) dexmedetomidine is able to modulate inflammatory response via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; this pathway has not yet been extensively investigated and it is novel to link dexmedetomidine to the pathway. 2) CBP-induced lung injury is different from other causes including pneumonia, massive transfusion and trauma. The study confirmed the role of dexmedetomidine in mediating inflammatory response, irrespective of the underlying causes. 3) the inflammatory modulating effect of dexmedetomidine is promising to be translated to clinical benefits since the lung function was observed to be improved in the rat model. Respiratory index and PaO2/FiO2 ratio are important indicators of the severity of lung injury [12, 13]. The Berlin definition also relies on the PaO2/FiO2 ratio to define the severity of lung injury [14]. Thus, the finding that dexmedetomidine is able to improve RI and PaO2/FiO2 ratio has direct link to clinical outcomes. 4) the finding is helpful to identify potential subphenotypes of patients who may benefit from dexmedetomidine treatment. There is a variety of reasons for the use of MV for critically ill patients including but not limited to impaired airway clearance, heart failure, chronic obstructive pulmonary disease and acute lung injury. Conditions such as heart failure may not benefit from dexmedetomidine treatment since this condition is less likely to involve inflammatory response. Thus, the concept of precise medicine can be practiced by categorizing patients into more subphenotypes by inflammatory biomarker profiles [15].

Although dexmedetomidine was able to reduce lung injury in a variety of conditions, the translation of basic research to clinical practice may have a gap. Many confounding factors may influence the effectiveness of dexmedetomidine in real clinical practice. That is why a recent large RCT failed to identify beneficial effect of the use of dexmedetomidine versus other sedatives. The Dexmedetomidine for Sepsis in Intensive Care Unit Randomized Evaluation (DESIRE) Trial investigated the effect of dexmedetomidine on mortality and the duration of MV. The results showed that dexmedetomidine did not result in improvement in mortality and ventilator-free days [16]. Most probably, the study included a heterogeneous population of patients requiring MV for at least 24 hours, while the reasons for intubation and MV were not explicitly addressed. With the widespread use of protective mechanical ventilation (e.g. low tidal volume, high positive end expiratory pressure and low driving pressure) [17, 18], the lung injury induced by inappropriate ventilator setting can be reduced in large magnitude. The potential target of dexmedetomidine is to reduce lung injury. Thus, the beneficial effect of dexmedetomidine can be minimal if lung injury has already been reduced to its minimum in nowadays. Reporting bias of basic studies is also another reason for why clinical findings usually cannot replicate the findings from animal models. The reporting quality of many experimental studies in critical care medicine is suboptimal [19]. Some of the limitations in reporting discussed by Merkow JS and colleagues are also applicable to the present study such as power estimation, randomization and blinding [19]. Furthermore, the study used rat as the animal model, which is largely different from human being. Thus, further bench and clinical studies should be implemented before the results can be translated to clinical practice.