The Effect of Dexmedetomidine on the Acute Pain After Cardiothoracic Surgeries: A Systematic Review

Habibi, Valiollah; Kiabi, Farshad Hasanzadeh; Sharifi, Hassan

doi:10.21470/1678-9741-2017-0253

Valiollah Habibi

MD

Department of Cardiac Surgery, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Farshad Hasanzadeh Kiabi Correspondence Address: Farshad Hasanzadeh Kiabi, Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Email: hasanzadehkiabi@gmail.com

MD

Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Hassan Sharifi

PhD

Department of Medical Surgical Nursing, Faculty of Nursing, Iranshahr University of Medical Sciences, Iranshahr, Iran.

Correspondence Address: Farshad Hasanzadeh Kiabi, Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Email: hasanzadehkiabi@gmail.com

No conflict of interest.

Abbreviations, acronyms & symbols
CABG	= Coronary artery bypass graft
CTS	= Cardiothoracic surgeries
DEX	= Dexmedetomidine
FDA	= Food and Drug Administration
ICU	= Intensive care unit
NRS	= Numerical rating scales
PCIA	= Patient controlled intravenous analgesia
POP	= Postoperative pain
RCTs	= Randomized controlled trials
SUF	= Sufentanil
VAS	= Visual analogue scale
VRS	= Verbal rating scales

Study	Random sequence generation	Allocation concealment	Blinding of		Incomplete outcome data (attrition)	Selective reporting	Other bias
Study	Random sequence generation	Allocation concealment	Participants and personnel	Outcome assessment	Incomplete outcome data (attrition)	Selective reporting	Other bias
Dong et al.^[¹⁴14 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.^], 2017	Unclear	Unclear	Low	Unclear	Low	Low	Unclear
Dutta et al.^[¹⁵15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.^], 2017	Low	Low	Low	Low	Low	Low	Unclear
Jabbary Moghaddam et al.^[¹⁶16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.^], 2016	Low	Unclear	High	Low	High	Low	Unclear
Cai et al.^[¹⁷17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.^], 2016	Low	Low	Low	High	Low	Unclear	Unclear
Priye et al.^[¹⁸18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.^], 2015	Low	Unclear	Unclear	Unclear	Low	Low	Unclear
Ren et al.^[¹⁹19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.^], 2015	Low	Low	Low	Low	Low	Low	Low
Ramsay et al.^[²⁰20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.^], 2014	Low	Low	Unclear	Unclear	Low	Low	Unclear
Abdel-Meguid^[²¹21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.^], 2013	High	High	Unclear	Unclear	Low	Unclear	Unclear
Elhakim et al.^[²²22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.^], 2010	Unclear	Unclear	Low	Unclear	Low	Unclear	Unclear
Ghandi et al.^[²³23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.^], 2005	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Wahlander et al.^[²⁴24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.^], 2005	Low	Low	Low	Low	Low	Low	Low
Venn et al.^[²⁵25 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.^], 1999	Unclear	Unclear	Unclear	Unclear	Low	Low	Unclear

Study	Anesthesia
	Premedication	Induction	Maintenance	Neuromuscular relaxation	Rescue analgesic use
Dong et al.^[¹⁴14 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.^], 2017	MID 0.05 mg/kg/IV 2h preop	0.4 mcg/kg SUF, PROP, SEVO	SUF 1 mcg/kg/h and PROP, SEVO, oxygen, and CIS	CIS	IV injection of meperidine 50 mg
Dutta et al.^[¹⁵15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.^], 2017	Alprazolam on the night before and the morning of surgery	FEN and PROP	ISO and air/oxygen mixture	VECO	MO 3 mg IV
Jabbary Moghaddam et al.^[¹⁶16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.^], 2016	___	FEN 2 µg/kg, MID 0.05 mg/kg, LIDO, and ETO 1 - 2 mg/kg	Oxygen and ISO with 1% - 1.2% end-tidal concentration and FEN	CIS 1 - 2 µg/kg/min	DEX: 0.5 µg/kg/hour Con: MID 0.05 mg/kg
Cai et al.^[¹⁷17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.^], 2016	___	PROP 2 mg/kg, SUF 0.3 mcg/kg	SEVO with a minimal alveolar concentration of 1.0 to 1.3
	CIS 0.2 mg/kg	Ketorolac 30 mg or tramadol (100 mg)
Priye et al.^[¹⁸18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.^], 2015	Oral gabapentin 600 mg 45 min before surgery	MID 0.1 mg/kg, FEN 10 meg/kg, PROP 100 mcg/kg/min	___	VECO 0.2 mg/kg	FEN 25 mcg intermittent bolus
Ren et al.^[¹⁹19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.^], 2015	MID 0.5-2 mg	PROP 1.5-2 mg/kg, SUF (TCI 0.2 ng/mL), and CIS 0.2 mg/kg	PROP (TCI 2.4-3.0 mcg/mL), DEX 0.4-0.6 mcg/kg/h) and SUF (TCI 0.2-0.24 ng/mL)	CIS 0.04 mg/kg every hour	30 mg intravenous ketorolac and tramadol (100 mg)
Ramsay et al.^[²⁰20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.^], 2014	___	PROP, FEN, and SEVO	___	VECO	___
Abdel-Meguid^[²¹21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.^], 2013	LOR 2 mg orally one night before surgery and MO 0.1 mg/kg IM 2h Preop	SUF 1-1.5 µg/kg, MID 0.05-0.1 mg/kg	SEVO plus SUF 0.2 mcg/kg/hour, MID 1.5 mcg/kg/hour, and ROCU 0.5 mg/kg/hour	ROCU 0.9 mg/kg	___
Elhakim et al.^[²²22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.^], 2010	MID 0.07 mg/kg IM half an hour before surgery	FEN 3 mg/kg, thiopental 3-5 mg/kg and	End-tidal concentration of 0.3-0.5 vol% ISO	Pancuronium 0.1 mg/kg	Paracetamol
Ghandi et al.^[²³23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.^], 2005	MO 0.1 mg/kg/IM with oral LOR 1 mg	REM 1 µ/kg, MID 0.1 mg/kg and CIS 0.15 mg/kg	REM 0.1 - 0.05 µ/kg/minute, propofol 50 - 75 µg/kg/minute, MID 0.02 - 0.05 µ/kg/minute, CIS and low dose of SEVO	Not reported by authors	Not reported by authors
Wahlander et al.^[²⁴24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.^], 2005	___	PROP 2 to 3 mg/kg, FEN 2 mcg/kg	Oxygen, nitrous oxide, ISO, FEN, and VECO	VECO 0.1 mg/kg	3 mL 0.125% (3.75 mg) bupivacaine
Venn et al.^[²⁵25 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.^], 1999	___	Remifentanil	MO	___	MID 0.01-0.2 mg/kg/h and MO 2 mg

Study	Design	Fixed TRT (drug) for all groups	Postoperative pain outcome assessment and time points	Authors conclusion / DEX reported complications
Dong et al.^[¹⁴14 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.^], 2017	Two parallel groups, N= 60 G1: PCIA (n=30) G2: DEX 4 mcg/kg added to PCIA (n=30) Surgery (n of CO, n of DEX): elective major open thoracotomy operations include esophageal neoplasia resection (16, 17), lobectomy (6, 7), pneumonectomy (1, 2), mediastinal mass (2, 2), and pneumothorax (5, 2) INT duration: the first 48h postop period Mean of age: G1=57.3 G2= 55.4, range=32-65 y M/F: 19/31	PCIA program: Drug: SUF 3.0 mcg/kg plus 8mg ondansetron Loading: 20 ml On demand: 2 ml Lock-out: 10 min Background: 4 ml	Outcomes: SUF consumption in the 48h postop period, the mean of pain intensity, the number of PCIA self-administer and meperidine injection Interval: 2, 6, 12, 24, 36 and 48h postop period Scales: VAS	The combination of DEX and SUF in PCIA reduces SUF consumption, the pain intensity, and supplemental analgesic requirements, while maintaining a good hemodynamic stability. DEX reported complications: bradycardia, hypotension, over sedation
Dutta et al.^[¹⁵15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.^], 2017	Two parallel groups, N= 30 G1: Standard drug (n=15) G2: a bolus of DEX 1 mcg/kg over 3 to 5 minutes followed by an infusion of 0.2 mcg/kg/hour added to standard drug (n=15) Surgery (n of CO, n of DEX): elective lung surgeries via anterolateral or posterolateral thoracotomy including lobectomy (2, 8), pneumonectomy (5, 5), cyst excision (5, 0), decortication (2, 2), and bullectomy (1, 0) INT duration: the first 24h postop period Mean of age: G1=34.4 G2= 42.1, range=18-70 M/F: 20/10	Standard drug: A bolus of 15 mL of 0.75% ROPI over 3 to 5 minutes, followed by an infusion of 0.2% ROPI at 0.1 mL/kg/h Thoracic paravertebral block by lignocaine 2% (3 mL) with adrenalin up to 72 hours after surgery	Outcomes: Intraoperative anesthetic drug requirement, pain scores, rescue analgesic use requirement, and incidence of pain syndrome in 2 months Intervals:1, 2, 3, 4, 8, 12, 16, 20, and 24h postop period Scales: VAS	Paravertebral DEX administration is associated with lower number of rescue analgesia, morphine required, total intraoperative fentanyl dose, propofol induction dose, and lower postop pain in 1, 2, 4, and 8 hours. DEX fails to lower the incidence of post-thoracotomy pain syndrome. DEX reported complications: bradycardia, hypotension, over sedation
Jabbary Moghaddam et al.^[¹⁶16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.^], 2016	Two parallel groups; N=104 G1: IV infusion of DEX 0.5 mcg/kg/h (n=50) G2: NS (n=54) Surgery (n of CO, n of DEX): elective CABG INT duration: from the initiation of anesthesia until extubation in the ICU Mean of age: G1=57.3, G2= 55.4 M/F: 71/33	None	Outcomes: the NRS score after surgery and the incidence of postop pain by telephone interview Intervals: two months scale: NRS and BPI	The incidence of postop was significantly lower in the DEX group than that of the control group. Pre-emptive intraoperative DEX may reduce pain DEX reported complications: not reported
Cai et al.^[¹⁷17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.^], 2016	Two parallel groups; N= 94 G1: DEX at a loading dose of 1 mcg/kg for 10 minutes, followed by continuous infusion at 0.5 mcg /kg/h (n=46) G2: NS (n=48) Surgery (n of CO, n of DEX): thoracic surgeries including thoracoscopic lobectomy (12, 10), open thoracic lobectomy (4, 6), incision of esophageal cancer (32, 30) INT duration: the first 48h postop period Mean of age: G1=54.6 G2= 55.4, range=18-65 M/F: 94/0	PCIA program: Drug: SUF 0.8 mg/mL Loading: 2 mL On demand: none Lock-out: 5 min Background: a 4-hour limit of 30 to 40 mL of SUF	Outcomes: The mean of pain at rest and with coughing and dosage of SUF during surgery Intervals: at arrival, 1, 4h, and every 4h thereafter until the 48h postop period Scales: NRS	Intraoperative DEX can reduce the opioid requirement and pain intensity, as well as reduce the cumulative dosage of SUF, NRS at rest, and NRS with coughing scores. DEX reported complications: bradycardia
Priye et al.^[¹⁸18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.^], 2015	Two parallel groups; N= 64 G1: IV infusion of DEX 0.4 mcg/kg/h for 12h without a loading dose, (n=32) G2: NS (n=32) Surgery: elective cardiac surgery using cardiopulmonary bypass (CPB) including coronary artery bypass graft, valve surgery, and atrial septal defect closure. (Note: the number of subjects in each category was not identified by authors) INT duration: Intraoperative until the first 24h postop period Mean of age: G1=41.4 G2= 45.1, range= over 18 M/F: 33/31	None	Outcomes: Postop pain and total fentanyl consumption Intervals: 6, 12, 18, and 24h Scales: VAS	DEX is associated with lower pain score at 0, 6, 12, 18 and 24h postop period and fewer fentanyl consumption than normal saline. Also, DEX could reduce the incidence of delirium. DEX reported complications: without significant complications
Ren et al.^[¹⁹19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.^], 2015	Three parallel groups; N= 125 G1: SUF 0.02 mcg/kg/h, (n=41) G2: SUF 0.02 mcg/kg/h plus DEX 0.02 mcg/kg/h each (n=41) G3: SUF 0.02 mcg/kg/h plus IV infusion of DEX 0.04 mcg/kg/h (n=43) Surgery (n of CO, n of DEX1, 2): thoracic surgeries including thoracotomy in esophageal (one incision) (35, 34, 36) and thoracotomy in cardiac cancer (6, 7, 7) INT duration: the first 72h postop period Mean of age: G1=59.8, G2= 59.9, G3=60.5, range=35-65 M/F: 125/0	PCIA program: Drug: SUF 0.8 mg/mL Loading: 2 mL On demand: none Lock-out: 5 min Background: 2 ml/h, 4h limit of 40 ml Intraoperative DEX: a small bolus of 0.5 mcg/kg then reduced to 0.5 mg/kg/h	Outcomes: cumulative amount of self-administered SUF and the postop pain intensity scores both at rest and with coughing Intervals: 1, 4, 8, 16, 24, 48, and 72h Scales: NRS	Addition of DEX 0.04 mcg/kg/h to SUF improves the analgesic effect of SUF and is associated with greater patient satisfaction without side effects. This combination could decrease the total dosage of SUF during the first 72h after surgery. DEX reported complications: without significant complications
Ramsay et al.^[²⁰20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.^], 2014	Two parallel groups; N= 38 G1: IV infusion of DEX 0.1 to 0.5 mcg/kg/h, (n=19) G2: NS (n=19) Surgery: major open lateral thoracotomy (Note: sub-categories of thoracotomy has not been identified by authors) INT duration: 18 to 24h postop period Up to 24h after that (42-48h postop) Mean of age: G1=61, G2= 56, range=18-85 M/F: 15/23	PCIA Drug: MO Protocol: not reported, but the two groups were similar in the types of PCA pumps and supplemental opioids used Intraoperative: DEX at 0.2 to 0.5 mcg/kg/h without bolus until 30 minutes prior to transfer to the telemetry unit	Outcomes: the amount of self-administered opioid medication and average pain scores Intervals: 24h after ICU discharge and 24 to 48h postop Scales: VAS	In comparison with normal saline, DEX is associated with lower morphine consumption, however, the mean pain scores between DEX and normal saline groups were similar. DEX reported complications: hypotension, bradycardia
Abdel-Meguid^[²¹21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.^], 2013	Two parallel groups; N= 30 G1: DEX at 0.5 mcg/kg/h after the induction of anesthesia, that reduced to 0.3 mcg/kg/h on admission in the ICU and continued for 12h post extubation (n=15) G2: NS (n=15) Surgery: elective coronary artery surgery using OPCAB technique INT duration: The first 12h post extubation Mean of age: G1=55, G2= 52 M/F: 23/7	MO for postop pain management	Outcomes: The median of postop pain and total dose of MO Intervals: 2, 4, 6, 8, 10, 12h postop Scales: VAS	DEX showed a better pain control, a lower consumption of narcotics and earlier extubation time. DEX reported complications: not reported
Elhakim et al.^[²²22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.^], 2010	Two parallel groups; N= 50 G1: DEX 1 mcg/kg plus bupivacaine 0.5% via epidural catheter (n=25) G2: bupivacaine 0.5% via epidural catheter (n=25) Surgery (n of CO, n of DEX): elective open thoracotomy for lung surgery with one-lung ventilation including right lobectomy (12, 11), right pleurectomy (7, 7), and right pneumectomy (6, 7) INT duration: after induction of general anesthesia until the first 24h postop period Mean of age: G1=52, G2=50, range=43-54 M/F: 50/0	Drug: IV crystalloids colloids and fentanyl bolus dose were added to the epidural medication	Outcomes: Postop pain scores, and postop analgesic use requirement Intervals: at 6, 12, 18, and 24h after surgery Scales: VRS	Epidural use of DEX decreases the anesthetic requirements and improves postoperative analgesia as well as shorter the ICU stay DEX reported complications: without significant complications
Ghandi et al.^[²³23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.^], 2005	Two parallel groups; N=100 G1: MO 0.2 mg via PCIA at 4 ml/h (n=50) G2: DEX 0.2 mcg/kg via PCIA (n=50) Surgery: candidates for open cardiac surgery INT duration: after surgery until the first 24h postop Mean of age: G1=66.7, G2= 65.4, range=54-81 M/F: not reported	PCIA, but the protocol not reported by authors	Outcomes: The mean of postop pain intensity and intravenous MO consumption Intervals: 2, 4, 6, 8,10,12, 14, 16 and 18h postop Scale: VAS	DEX is associated with lower pain score in the 2, 4, 6, 8, 10 and 12h postop periods. Male patients experienced lower pain than female in the DEX group. DEX reduced the IV MO consumption during ICU stay. DEX shortened the intubation time. DEX reported complications: without significant complications
Wahlander et al.^[²⁴24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.^], 2005	Two parallel groups; N= 28 G1: IV loading dose of DEX 0.5 mcg/kg over 20 minutes, followed by continuous IV infusion at 0.4 mcg/kg/h, (n=14) G2: NS (n=14) Surgery: elective thoracotomy for wedge resection, lobectomy, or pneumonectomy (Note: the number of subjects in each category was not identified by authors) INT duration: the first 24h post ICU Mean of age: G1=67.7, G2= 65.7, range= over 18 M/F: 12/16	In the operating room, a TEC loaded using 3 mL of 1.5% lidocaine-epinephrine mixture. PCEA program: Loading: 3 mL 0.125% (3.75 mg) bupivacaine, Lock-out: 20 min Background: 4-hour limit of 30 mL 0.125% (37.5 mg) bupivacaine	Outcomes: need for additional epidural bupivacaine administered by PCEA and the requirement for supplemental opioids (fentanyl) Intervals: at admission to SICU or PACU (zero time point) and then in 1, 2, 3, 4, 12, 16, and 24h postop periods Scales: VAS	IV DEX has beneficial analgesic effects on post-thoracotomy pain when using as an addition to a thoracic epidural infusion of 0.125% bupivacaine. It is unable to decrease the PCEA requirement, but is able to decrease the requirement for opioids and likelihood of respiratory depression DEX reported complications: hypotension and bradycardia
Venn et al.^[²⁵25 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.^], 1999	Two parallel groups; N= 98, cardiac (n=81) G1: IV DEX at a loading dose of 1 mcg/kg over 10 min followed by a maintenance infusion rate of 0.2-0.7 mcg/kg/h, maximum infusion rate of 0.7 mcg/kg/h (n=39) G2: NS (n=42) Surgery: cardiac surgery using cardiopulmonary bypass (n=81) and general surgery (n=17) INT duration: within 1h of arrival on the ICU until the first 24h after that Mean of age: G1=63.3, G2= 64.2, range= over 18 M/F: 54/27	MID 0.01-0.2 mg/kg/h and MO	Outcomes: postoperative analgesia (MO) Intervals: hourly up to first 24h postop period Scales: VAS	Intubated patients receiving DEX required 80% less MID and 50% less MO DEX could reduce the requirements for rescue sedation and analgesia in postop patients for up to 24h. MO requirement was reduced by half in the DEX group. DEX reported complications: bradycardia and hypotension

Study, year	Time and route of injection	Protocol for DEX injection in DEX group
Dong et al.^[¹⁴14 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.^], 2017	Start: Postoperatively, after transfer to the general ward End: after 48h; Route: IV using PCIA	A PCIA protocol consists of sufentanil 3 mcg/kg and 8 mg ondansetron was started for all patients. The PCIA was programmed to deliver a 2ml bolus with a lockout interval of 10 min, and a background infusion rate of 4 ml/h. DEX 4 mcg/kg was added to the PCIA for DEX group.
Dutta et al.^[¹⁵15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.^], 2017	Start: Intraoperatively, before induction of anesthesia End: after 72h post-operative period; Route: epidural catheter	All patients received the study medications through paravertebral (multipored epidural) catheter. Patients in the DEX group received 15 mL of 0.75% ropivacaine plus DEX, 1 mg/kg bolus over 3-to-5 minutes followed by an infusion of 0.2% ropivacaine plus 0.2 mg/kg/h of dexmedetomidine at 0.1 mL/kg/h. Paravertebral infusion was stopped and the catheter was removed 72h after surgery.
Jabbary Moghaddam et al.^[¹⁶16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.^], 2016	Start: Intraoperatively, after induction; End: ?h after extubation in ICU; Route: IV infusion	0.5 mcg/kg/h of DEX was infused from the initiation of anesthesia until extubation in the ICU.
Cai et al.^[¹⁷17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.^], 2016	Start: Intraoperatively, before the start of anesthesia End: 30min before the end of surgery; Route: IV infusion	Before anesthesia, patients were administered a loading dose of 1 mg/kg DEX for 10min, followed by continuous infusion at 0.5 mg/kg/h until 30min before the end of surgery.
Priye et al.^[¹⁸18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.^], 2015	Start: Post-operative, after transfer to ICU; End: after 12h; Route: IV infusion	After surgery, patients were transferred intubated and ventilated to the ICU to receive 12h infusion of DEX 0.4 mcg/kg/h without a loading dose.
Ren et al.^[¹⁹19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.^], 2015	Start: Postoperatively, after patients were transferred to PACU; End: after 72h; Route: IV using PCIA	All patient received DEX intraoperatively. After surgery, 2 doses of DEX in addition of sufentanil were compared with sufentanil using same PCIA protocol. PCIA was programmed to deliver a bolus dose of 2 mL, with background infusion of 2 mL/h and a lockout of 5min, 4h limit of 40 mL.
Ramsay et al.^[²⁰20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.^], 2014	Start: Postoperatively, 18 to 24h after surgery when patients were admitted to the telemetry unit; End: After 24h; Route: IV infusion	An intraoperative infusion of DEX at 0.2 to 0.5 mcg/kg/h was started for all patients that continued during their ICU or PACU. 0.1-0.5 mcg/kg/h DEX was started about 18 to 24h after surgery when patients were admitted to the telemetry unit for up to 24h.
Abdel-Meguid^[²¹21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.^], 2013	Start: Intraoperatively, after induction; End: 12h after extubation; Route: IV infusion	DEX started by continuous infusion at 0.5 mcg/kg/h after induction of anesthesia; this was reduced to 0.3 mcg/kg/h on admission to the ICU and continued for 12h post extubation.
Elhakim et al.^[²²22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.^], 2010	Start: Intraoperatively, after induction of general anesthesia; End: after 24h; Route: epidural catheter	The DEX group received DEX 1 mcg/kg in combination with bupivacaine 0.5% 30-40 mg via the thoracic epidural catheter, which was inserted at the T6-7 interspace.
Ghandi et al.^[²³23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.^], 2005	Start: Postoperatively, after transfer to ICU; End: after 24h; Route: IV using PCIA	After transfer of patients to ICU, they received infusion of DEX 0.2 mcg via a PCIA pump in the first 24 hours after surgery.
Wahlander et al.^[²⁴24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.^], 2005	Start: Postoperatively, on ICU arrival; End: after 24h; Route: IV infusion	The DEX group received an IV loading dose of DEX of 0.5 mcg/kg over 20min, followed by continuous IV infusion at 0.4 mcg/kg/h.
Venn et al.^[²⁵25 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.^], 1999	Start: Postoperatively, after transfer to ICU; End: 6h-24h after extubation; Route: IV infusion	DEX started within 1h of arrival on the ICU with a loading dose of 1 mcg/kg over 10min followed by a maintenance infusion rate of 0.2-0.7 mcg/kg/h to total maximum duration of infusion was 24h.

Study, year	Time points in hour after surgery
Study, year	1	2	4	6	8	10	12	16	18	24	36	48	72
Dong et al.^[¹⁴14 Dong CS, Zhang J, Lu Q, Sun P, Yu JM, Wu C, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia:a randomized, controlled clinical study. BMC Anesthesiol. 2017;17(1):33.^], 2017				^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.						^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Dutta et al.^[¹⁵15 Dutta V, Kumar B, Jayant A, Mishra AK. Effect of continuous paravertebral dexmedetomidine administration on intraoperative anesthetic drug requirement and post-thoracotomy pain syndrome after thoracotomy: a randomized controlled trial. J Cardiothorac Vasc Anesth. 2017;31(1):159-165.^], 2017	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Jabbary Moghaddam et al.^[¹⁶16 Jabbary Moghaddam M, Barkhori A, Mirkheshti A, Hashemian M, Amir Mohajerani S. The effect of pre-emptive dexmedetomidine on the incidence of post-thoracotomy pain syndrome in patients undergoing coronary artery bypass grafting. Anesth Pain Med. 2016;6(3):e36344.^], 2016	The incidence of postoperative pain was reported
Cai et al.^[¹⁷17 Cai X, Zhang P, Lu S, Zhang Z, Yu A, Liu D, et al. Effects of intraoperative dexmedetomidine on postoperative pain in highly nicotine-dependent patients after thoracic surgery: a prospective, randomized, controlled trial. Medicine (Baltimore). 2016;95(22):e3814.^], 2016	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Priye et al.^[¹⁸18 Priye S, Jagannath S, Singh D, Shivaprakash S, Reddy DP. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: a randomized, double-blind study. Saudi J Anaesth. 2015;9(4):353-8.^], 2015	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.			^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.			^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Ren et al.^[¹⁹19 Ren C, Zhang X, Liu Z, Li C, Zhang Z, Qi F, et al. Effect of intraoperative and postoperative infusion of dexmedetomidine on the quality of postoperative analgesia in highly nicotine-dependent patients after thoracic surgery: a consort-prospective, randomized, controlled trial. Medicine (Baltimore). 2015;94(32):e1329.^], 2015	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.			^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Ramsay et al.^[²⁰20 Ramsay MA, Newman KB, Leeper B, Hamman BL, Hebeler RF Jr, Henry AC, et al. Dexmedetomidine infusion for analgesia up to 48 hours after lung surgery performed by lateral thoracotomy. Proc (Bayl Univ Med Cent). 2014;27(1):3-10.^], 2014	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.							^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Abdel-Meguid^[²¹21 Abdel-Meguid ME. Dexmedetomidine as anesthetic adjunct for fast tracking and pain control in off-pump coronary artery bypass. Saudi J Anaesth. 2013;7(1):6-8.^], 2013	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Elhakim et al.^[²²22 Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand. 2010;54(6):703-9.^], 2010				^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.			^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Ghandi et al.^[²³23 Ghandi I, Alavi SM, Babaee T, Ghadrdoost B, Bakhshandeh H, Ziyaeifard M, et al. The analgesic effect of morphine and dexmedetomidine intravenous patient-controlled analgesia method to control pain after open cardiac surgery: a randomized control trial. Arch Crit Care Med. 2015;1(3):e6453.^], 2005		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Wahlander et al.^[²⁴24 Wahlander S, Frumento RJ, Wagener G, Saldana-Ferretti B, Joshi RR, Playford HR, et al. A prospective, double-blind, randomized, placebo-controlled study of dexmedetomidine as an adjunct to epidural analgesia after thoracic surgery. J Cardiothorac Vasc Anesth. 2005;19(5):630-5.^], 2005		^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.	^* * Pain score was significantly lower in the DEX group at (the desired hour) after surgery in comparison with the control group.
Venn et al.^[²⁵25 Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999;54(12):1136-42.^], 1999	Pain was not reported

Adverse Events	In DEX (n)	In Control (n)	Odds ratio (CI 95%)
Atrial fibrillation	10 (53)	6 (56)	1.998 (0.272-14.660)
Bradycardia	7 (62)	4 (62)	1.448 (0.158-13.247)
Hypotension	16 (115)	6 (118)	3.453 (0.714-16.698)
Nausea/Vomiting	59 (208)	80 (213)	0.641 (0.209-1.962)
Pruritus	18 (153)	45 (153)	0.260 (0.068-1.000)
Hypertension	4 (30)	7 (30)	0.505 (0.131-1.951)
Respiratory depression	4 (30)	9 (30)	0.359 (0.096-1.331)
Atelectasis	23 (50)	34 (50)	0.400 (0.177-0.904)
Delirium	8 (41)	12 (41)	0.585 (0.210-1.631)

Authors' roles & responsibilities
VH	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published
FHK	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published
HS	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; final approval of the version to be published

[1] Correspondence Address: Farshad Hasanzadeh Kiabi, Department of Anesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Email: hasanzadehkiabi@gmail.com

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The Effect of Dexmedetomidine on the Acute Pain After Cardiothoracic Surgeries: A Systematic Review

Abstract

Introduction:

Objective:

Methods:

Results:

Conclusion: