|Ahead of print
Dexmedetomidine in cancer surgeries: Present status and consequences with its use
Abhijit S Nair, Mohammed Salman Saifuddin, Vibhavari Naik, Basanth Kumar Rayani
Department of Anaesthesiology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
|Date of Submission||29-Apr-2019|
|Date of Decision||02-Jan-2020|
|Date of Acceptance||07-Jan-2020|
|Date of Web Publication||20-Jul-2020|
Abhijit S Nair,
Department of Anaesthesiology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
Dexmedetomidine is a centrally acting α2 adrenoreceptor agonist used in perioperative medicine due to its sedative, analgesic and sympatholytic properties. Recently animal data has pointed towards potential role of dexmedetomidine in promoting cancer recurrence and metastasis when used perioperatively especially after breast surgeries. This is because of presence of α2 adrenoreceptors in breast cancer tissue. We reviewed existing literature in which dexmedetomidine was used in cancer surgeries and investigated its role in recurrence and metastasis.
Keywords: Dexmedetomidine, Cancer, recurrence, alpha-2 agonist, metastasis
| » Dexmedetomidine in Cancer Surgeries|| |
Alpha-2 adrenoreceptors are present in human mammary gland. The presence of these receptors in patients with breast cancer has been proven by reverse transcription polymerase chain reaction, immunocytochemistry and binding studies. Studies have shown that α2-adrenoceptors were associated with increased cell proliferation in vitro and with increased tumor growth in vivo.,
Dexmedetomidine is an essential component of multimodal analgesia (MMA) as it provides sedation, reduces intraoperative opioid consumption, and offers hemodynamic stability due to its sympatholytic effect. There is a growing body of evidence that supports that use of α2-adrenoceptors like dexmedetomidine and clonidine during cancer surgeries (especially breast surgeries) could lead to recurrence and promote metastasis due to its α2-adrenoceptors agonism effect. In this topical review, we have reviewed existing literature using keywords: Dexmedetomidine, cancer, recurrence, breast surgeries. The purpose of this review is to find correlation between perioperative use of dexmedetomidine in patients undergoing cancer surgeries and cancer recurrence/metastasis.
| » Perioperative Period After Oncosurgery|| |
Surgery is considered as the best curative option for several malignancies. However, this comes with a price as surgery involves tumor handling, uncontrolled systemic inflammatory process, immunosuppression, surgical pain, subjecting patients to anesthetics and psychological stress, all of which contribute to cancer recurrence due to various process. The catecholamine surge, inflammatory mediators, hormonal release, lowered natural killer cell activity due to immunosuppression and opioids, anesthetic agents especially inhalational anesthetics all provide a nidus for cancer cells that are left behind or metastasize during surgery. Poorly managed postoperative pain has also been implicated with having adverse outcomes after cancer surgeries. Other perioperative factors that are not desirable after onco-surgeries are hypothermia, blood transfusion, and prolonged surgeries.
Surgery and anesthetic agents stimulate hypothalamo-pituitary axis and sympathetic system which leads to release of several factors which eventually leads to immunosuppression. Anesthetic agents like propofol cause less immunosuppression when compared to inhalational anesthetics and opioids. Use of intraoperative lidocaine has shown to improve natural killer cell activity which is suppressed with opioids and inhalational anesthetics.
| » Role of Dexmedetomidine in Perioperative Medicine|| |
Dexmedetomidine is a centrally acting alpha-2 agonist approved by United States Food and Drug Administration for procedural sedation. It has several desirable properties like opioid and anesthetic sparing effect, central sympatholysis, arousable sedation mimicking natural sleep, and has cardiovascular stabilizing properties. There are several off-label indications for which dexmedetomidine is used in perioperative medicine. It is effective in reducing delirium and does not depress respiration., Based on above mentioned properties, dexmedetomidine has emerged as an important anesthetic agent in the armamentarium of anesthesiologists. Dexmedetomidine has a good profile for use as a sedative in mechanically ventilated patients in ICU. In a study involving 201 patients with sepsis who were randomized to receive dexmedetomidine and no dexmedetomidine for ICU sedation, it was found that the quality of sedation with dexmedetomidine was better. However, there was no statistically significant improvement in mortality or ventilator free days in dexmedetomidine group.
Major oncological surgeries involving extensive resection leads to an inflammatory cascade leading to systemic inflammatory response syndrome. This leads to pyrexia, hemodynamic instability, fluid shifts, and lowers immunity making patients susceptible to perioperative infections. Perioperative use of dexmedetomidine has shown to reduce or lower levels of inflammatory mediators like cytokines and interleukins, decrease the inhibition of immunity and reduce perioperative opioid consumption thereby facilitating early recovery. Dexmedetomidine had shown to decrease lung oedema, reduced neutrophil infiltration, reduced inflammatory factors production, and inhibited mitogen-activated protein kinase (MAPK) activation due to its anti-inflammatory effects when used in mice injected with lipopolysaccharide. Use of dexmedetomidine during breast surgeries have shown to effectively maintain the homeostasis of cell immune function of patients. However, this beneficial effect has not been extensively studied in all types of malignancies.
| » Dexmedetomidine in Breast Surgeries|| |
Due to its sedative, analgesic and sympatholytic properties; dexmedetomidine has become an important agent for use in perioperative period in major surgeries, including oncosurgeries. Several studies have demonstrated the anti-inflammatory effects of dexmedetomidine owing to its properties of lowering inflammatory markers like serum IL-6, IL-8, and TNF-α levels.,
Xia et al. studied human breast cancer cell line MD Anderson-Metastatic Breast (MDA-MB)-231 and injected it with dexmedetomidine at various concentrations for 48 hours. The author found that in a dose-dependent manner, the cells treated with dexmedetomidine proliferated compared to control group. Dexmedetomidine was found to activate the a2-adrenoceptor/extracellular signal-regulated kinase pathway thereby leading to pro-tumorigenic effects. Bruzzone et al. also studied the effect of clonidine and dexmedetomidine in medroxyprogesterone acetate induced mammary ductal carcinomas of mice which were incubated for 48 hours. The authors found that α2-Adrenoceptor agonists enhanced tumor growth and rauwolscine, yohimbine which are a2-adrenoceptor antagonists reversed the effect of alpha-2 agonists. Lavon et al. used sub-hypnotic doses of dexmedetomidine infusion for 6–12 hr and studied it in the context of stress and surgery, its effects on metastasis in various cancer types (breast, lung, and colon) in naïve animals with cancer. Tumor-cell retention and growth of metastases was found to increase in animals with all 3 cancers. Metastatic load was found to be increased in liver, lungs, kidneys, and brain in both genders. The authors concluded that all effects were mediated via alpha-2 adrenoreceptors and therefore should not be used in cancer patients undergoing surgery. Szpunar et al. studied effect of dexmedetomidine on metastatic mammary adenocarcinoma. They found that dexmedetomidine use was associated with increased tumor growth and metastasis but was not associated with increased angiogenesis in mice. The tumor growth was also associated with an alteration in mammary tumor collagen microstructure. A clinical trial is currently ongoing which aims to investigate the impact of perioperative dexmedetomidine on breast cancer recurrence and its effects on the patients' immune system.
[Table 1] shows the studies involving use of dexmedetomidine in patients with cancer, cancer cell lines treated with dexmedetomidine and animals injected with cancer cells. The findings show variable results like proliferation of tumor, reduced survival, metastasis.
|Table 1: Studies involving use of dexmedetomidine in patients with cancer, cancer cell lines treated with dexmedetomidine and animals injected with cancer cells|
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| » Dexmedetomidine in Cancer Surgeries Other Than Breast Malignancies|| |
Cata et al. investigated the association between the use of intraoperative dexmedetomidine with no intraoperative dexmedetomidine in patients with non-small cell lung cancer (NSCLC) who underwent surgery. They studied this in 251 patients in each group in an attempt to find out increase in recurrence-free survival (RFS) and overall survival (OS) after lung surgery if dexmedetomidine is used intraoperatively. On analysis of their data, the authors concluded that intraoperative use of dexmedetomidine was associated with worsening of OS. Dose of dexmedetomidine was not at all associated with OS. Guo et al. investigated the protective effect of dexmedetomidine against perioperative inflammation and on pulmonary function in patients undergoing radical resection of lung cancer. They enrolled 124 patients (62 patients received dexmedetomidine and 62 patients did not). Anesthesia management was otherwise standardized in both groups. On analysis, authors concluded that patients in dexmedetomidine group had reduced the inflammatory response and preserved lung function when compared to control group.
In a similar study involving patients with carcinoma stomach undergoing surgery, Dong et al. observed that dexmedetomidine effectively reduced the release of inflammatory factors in these patients, perioperatively. This anti-inflammatory effect was possibly due to downregulation of nuclear factor kappa-B (NF-κB) which is a protein complex that controls transcription of DNA, cytokine production and cell survival. However, in above-mentioned studies (Guo et al. and Dong et al.), authors did not study the overall survival or recurrence-free survival in these patients. Su et al. enrolled 103 lung cancer patients (52 patients received perioperative dexmedetomidine and 51 patients were control) who were scheduled for surgery. The authors found that patients who received dexmedetomidine showed proliferation of monocytic myeloid-derived suppressor cells (M-MDSC) during postoperative period along with potent proangiogenic ability due to increased production of vascular endothelial growth factor. They also studied effect of dexmedetomidine in mice Lewis lung carcinoma cells and observed proliferation of M-MDSC and angiogenesis.
Dexmedetomidine has been shown to have opioid sparing effects, confers hemodynamic stability, intraoperatively. However, data comparing perioperative use of dexmedetomidine versus morphine is very limited. Well-designed studies could explore this possibility and if dexmedetomidine is found superior, it could be used more aggressively in cancer surgeries where there are no issues on tumor biology.
| » Conclusion|| |
Alpha-2 adrenoreceptors are expressed in breast cancer tissue. The existing studies involving mice and cell lines of human breast cancer cells points towards the potential role of dexmedetomidine in promoting cancer recurrence and metastasis owing to its role in facilitating angiogenesis thereby leading to metastasis. Randomized studies in human cancer patients are lacking although trials are ongoing. The role of dexmedetomidine in recurrence and metastasis in other cancers like lung, stomach is supported by inconclusive data. Ongoing studies might give direction to anesthesiologists involved in oncosurgeries to decide when to use dexmedetomidine and when to avoid in the perioperative period. Till then, it is advisable to use dexmedetomidine cautiously in patients undergoing breast cancer surgeries. However, in high risk patients with serious cardiac ailments (left ventricular dysfunction, pulmonary hypertension) where hemodynamic instability can have catastrophic consequences, use of dexmedetomidine is inevitable and thus is a necessary evil. In other patients, hemodynamic stability and better management of perioperative pain can be addressed by using a multimodal analgesic regimen in the form of IV lidocaine, gabapentinoids, acetaminophen, non-steroidal anti-inflammatory agents. Whenever possible and feasible, regional anesthesia techniques like a paravertebral block, pectoralis block, or an erector spinae plane block should be used.
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