Cardiac Preconditioning Effect of Ketamine-Dexmedetomidine versus Fentanyl-Propofol during Arrested Heart Revascularization.

BACKGROUND: Myocardial damage due to ischemia and reperfusion is still unavoidable during coronary surgery. Anesthetic agents have myocardial preconditioning effect. Ketamine has sympathomimetic effect, while dexmedetomidine has a sympatholytic effect in addition to anesthetic, analgesic, and anti-inflammatory properties of both the drugs. This study was carried out to compare ketamine-dexmedetomidine (KD) combination with fentanyl-propofol (FP) combination on the release of cardiac troponin T (cTnT) and outcome after coronary artery bypass graft. PATIENTS AND METHODS: Ninety adult patients who underwent coronary artery bypass grafting (CABG) were assigned to receive either KD base anesthesia (KD group) or FP anesthesia (FP group). Trends of high-sensitive cTnT, CK-MB, and serum cortisol were followed in the first postoperative 24 h. Other outcomes were vital signs, weaning from cardiopulmonary bypass, tracheal extubation time, and echocardiographic findings.
RESULTS: There was a significant lower release of cTnT in KD group than FP group during its peak values at 6 h after aortic unclamping (92.01 ± 7.332 in KD versus 96.73 ± 12.532 ng.L-1 P = 0.032). significant lower levels of serum cortisol levels were noted KD group than in FP group at 6 and 12 h after aortic unclamping P < 0.001. As regard tracheal extubation time, patients assigned to KD group extubated earlier than whom in FP group 202.22 ± 28.674 versus 304.67 ± 40.598 min respectively P < 0.001.
CONCLUSION: The use of KD during on-pump CABG confers better myocardial protective and anti-inflammatory effect than fentanyl propofol. Copyright:

INTRODUCTION

Although there are lots of progress in the surgical field of coronary artery disease (CAD) due to the newer techniques and anesthetic protocols held in coronary artery bypass grafting (CABG), perioperative myocardial damage still remains as a remarkable obstacle that might affect postoperative outcome.[1]

The protective effects of anesthetic agents on the myocardium gained popular attention either by the cardiac surgeons or by the anesthetists.[2] Contemporary myocardial ischemia could potentially protect cardiac muscle from further damage: a process which was later called preconditioning.[3]

One of the advantages of inhalational anesthetics is cardioprotective effects against myocardial ischemia–reperfusion (IR) injury which was proven in a number of animal experiments.[4] The first clinical trial that described the myocardial preconditioning effect with isoflurane in CABG was evidenced with decreased postoperative levels of cardiac troponin I (cTnI) and Creatine kinase-MB (CK-MB).[5]

Ketamine is a dissociative sedative and anesthetic drug with potent analgesic properties and marked sympathomimetic effects on the cardiovascular system.[6] The use of ketamine has been encouraged for anesthesia in hemodynamically unstable patients because of its sympathomimetic actions, but there are concerns about its use in patients with CAD.[7]

The use of dexmedetomidine has been increased as a component of general anesthesia, including cardiac surgical applications due to its sedative/hypnotic and analgesic effects, in addition to its cardioprotective properties.[8]

Improvement in ventricular contractility after ischemic episodes was noticed with the use of fentanyl and other opioids. Besides participating in the triggering of the cascade of ischemic preconditioning, opioids might mediate their effects by activation of cardiac receptors, independent of the action of these drugs on the central nervous system.[9]

There are many markers which reflect the magnitude of cardiac damage. Cardiac troponin T (cTnT) has been found to be the most sensitive (99%) and specific (78%).[10]

A retrospective observational study by Riha et al.[11] observed lower cardiac enzymes values with the use of ketamine–dexmedetomidine (KD) during CABG when compared with sevoflurane-sufentanil-based anesthesia.

The objective of this study is to compare the combined effect of KD with fentanyl–propofol (FP) as a cardiac preconditioning tool against ischemia and reperfusion injury during on-pump CABG.

PATIENTS AND METHODS

This prospective randomized comparative study was designed to include 90 adult patients (the American Society of Anesthesiologists II and III) who were scheduled for elective coronary artery bypass surgery using cardiopulmonary bypass at Cardiothoracic Surgery Department at Mansoura University Hospital in the interval between January 2018 and March 2019. Approval of Institutional Board Review was obtained with number R/16.05.110, ×. Written informed consent was obtained from all patients.

Any patient with ongoing ischemia or unstable angina, acute myocardial infarction of <1-month duration, prior cardiac surgery, left ventricular ejection fraction <0.5, left bundle branch block, implantable pacemaker, preoperative administration of inotropic agents, serum creatinine higher than 1.5 mg.dL − 1, chronic liver disease, and valvular diseases and patients receiving sulfonylurea, theophylline, or allopurinol were excluded from the study.

All patients were subjected to preoperative clinical examination for the assessment of the cardiovascular function clinically; electrocardiogram (ECG), echocardiographic investigation, and coronary angiography and routine laboratory investigations were also conducted.

All preoperative cardiac medications except β-blockers were omitted on the day of surgery. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were discontinued at least 24 h before the surgery. Antiplatelet drugs were withheld at least a week prior to the surgery.

On arrival to the preanesthetic area, intravenous (i.v.) line was inserted, and 0.05 mg.kg − 1 midazolam was administered as a premedication and 10 mg morphine was injected intramuscularly to all patients. A radial artery catheter (20–22 G) was inserted under local anesthesia after doing modified Allen's test to monitor the arterial blood pressure and blood sampling during the entire procedure. Baseline high-sensitive cardiac troponin T (hs-cTnT) (Elecsys ® Troponin T assay, Hoffman-Roche), CK-MB by photometric method (Bayer, Leverkusen, Germany), and serum cortisol level (Elecsys ® serum cortisol assay, Hoffman-Roche) were measured.

Intraoperative monitoring included five-lead ECG, pulse oximetry, sidestream capnography, Foley's catheter, and core temperature.

Patients were randomly allocated using computer-generated program into one of two equal groups.

Ketamine–dexmedetomidine group: (n = 45)

Induction of anesthesia was given by i.v. 0.05 mg midazolam, 1 μg.kg−1 dexmedetomidine over 10 min, then 1–2 mg.kg−1 ketamine, and 0.15 mg.kg− 1 cisatracurium. Anesthesia was maintained by 0.2–1 μg.kg− 1.h−1 dexmedetomidine, 1–4 mg.k−1.h−1 ketamine, and cisatracurium 1–2 μg.kg−1.min−1 infusion to keep mean arterial blood pressure changes within 25% of the baseline. After completion of the surgery, the patient was transferred to the intensive care unit (ICU), fully monitored, and sedated with ketamine 0.25 mg.kg−1.h−1 and dexmedetomidine 0.2 μg.kg−1.h−1.

Fentanyl–propofol group: (n = 45)

The induction of anesthesia was by i.v. 0.05 mg midazolam, 5 μg.kg−1 fentanyl, 1–2 mg.kg− 1 propofol, and 0.15 mg.kg−1 cisatracurium. Anesthesia was maintained by 3–6 mg.kg−1.h−1 propofol, 1–4 μg.kg−1.h−1 fentanyl, and cisatracurium 1–2 μg.kg−1.min− 1 infusion to keep mean arterial blood pressure changes within 25% of the baseline. After completion of the surgery, the patient was transferred to the ICU, fully monitored, and sedated with fentanyl 0.5 μg.kg−1.h−1 and propofol 0.5 mg.kg−1.h−1.

Patients were mechanically ventilated with an oxygen-air mixture (1:1 ratio) aiming to maintain end-tidal CO2 around 35 mmHg.

A central venous catheter was inserted using Seldinger technique through the right internal jugular vein to monitor the filling pressure of the right side of the heart and infusion of vasoactive medications.

The surgical steps were standardized and performed by consultant level surgeon. Midline sternotomy was performed in all patients. The left internal mammary artery was harvested in all the patients and heparin 300 IU.kg− 1 was administered intravenously to achieve activated clotting time (ACT) of more than 450 s, ACT was repeated every 30 min. The cardiopulmonary bypass (CPB) circuit was primed with 1000 mL of Ringer's solution, with 250 mL of 20% mannitol. A nonpulsatile blood flow was adjusted at 2.4 L.min− 1.m 2 using a membrane oxygenator, with perfusion pressure maintained at between 45 and 70 mm Hg. Heparin was added as required. Cold crystalloid cardioplegic solution was used to arrest the heart and protect the myocardium. The patient temperature's was adjusted at 34°C, applying α-stat acid–base management.

Fluid administration strategy was maintained by Ringer's lactate to maintain CVP around 8 mmHg. Blood transfusion triggered when hemoglobin was 8 g.dL− 1 ± 1.

Hemodynamic measurements of heart rate (HR) and mean arterial pressure (MBP) were recorded (Nihon-Kohden BSM 3000 series) at baseline before anesthesia induction, immediate after intubation, at skin incision, at sternotomy, and every 15 min in the 1st h then every 30 min till the end of surgery.

Number of grafts, duration of CPB and aortic cross-clamping, number of patients required inotropic support, nitroglycerine and intra-aortic balloon pump (IABP), and defibrillation use were also recorded.

Hypotension was managed by norepinephrine perfusion and increasing i.v. fluid administration. Bradycardia (HR <40 b.p.m.) was managed by atropine sulfate 0.5 mg increment. Hypertension (MBP > 25% of basal value) was managed through a bolus dose of anesthetics (e.g., 1 μg.kg−1 dexmedetomidine in KD group and 1 μg.kg−1 fentanyl in FP group) and if persist, nitroglycerine was infused. Tachycardia (HR >100 b.p.m.) without hypertension was managed by i.v. propranolol 0.2 mg increment till effect. Blood glucose was maintained between 110 and 180 mg.dl−1 using insulin infusion as required. Weaning from CPB was completed after ensuring optimal filling pressure and hemodynamics using volume, vasoactive and inotropic medications.

The trachea was extubated after ensuring normothermia, absence of significant bleeding, normal metabolic and electrolyte milieu, and hemodynamic stability (PaO2 > 70 mmhg, PaCO2 <45 mmHg, pH 7.3–7.5, FiO2 <0.4, adrenaline <50 ng/kg/min, and adequate cough and swallowing).

cTnT (hs-cTnT), CK-MB, and serum cortisol levels at 1, 6, 12 and 24 h were measured after aortic unclamping to detect evidence of myocardial injury. Echocardiography was done on arrival to the ICU and on the 1st postoperative day. All samples were immediately centrifuged for 10 min at 3000 revolutions per minute and analyzed.

Sample size calculation

The power of this clinical trial was prospectively calculated using the G power analysis program. Sample size of the study calculation was based on cTnT concentration 6 h after aortic unclamping as the primary outcome variable; a difference of 20% between treatment groups was considered clinically significant. type 1 error was assumed to be 0.05 and power of 80%, 82 patients (41 patients in each group). We added 4 cases to each group to compensate for drop outs. Total number was 90 oatients (45 patients was included in each group).

Statistical data

Statistical analysis was done using the SPSS program version 22 for Windows (IBM Corporation, Armonk, NY, USA). Data were expressed as mean ± standard deviation (SD). The changes in quantitative data were done by Shapiro–Wilk's W test. Changes in values between the two groups were compared using unpaired t-test. Fisher's exact test and Chi-square test were used for qualitative data.

RESULTS

A total number of 108 patients underwent coronary artery bypass graft using CPB were screened for eligibility and 90 patients were enrolled in this study, 45 patients in each group as shown in flowchart [Figure 1].

Figure 1

Study flow diagram

There was no significant difference between both groups as regard age, sex, body mass index, NYHA class, and incidence of comorbid diseases (hypertension, diabetes mellitus, and previous myocardial infarction). Preoperative medications were comparable in both the groups [Table 1].

Table 1

Demographic data and preoperative medications of the studied groups: Data are expressed in number percentage, mean±standard deviation, and median (range)

	KD group (n=45), n (%)	FP group (n=45), n (%)	95% CI	P
Age (years)	58.07±7.225	56.71±8.844	−2.03-4.7
Gender
Male	64% (29)	−0.1, 0.28	0.362
Female	36% (16)	27% (12)
BMI	28.93±2.723	29.14±2.934	−1.4-0.97	0.719
NYHA class	3 (2-3)	3 (2-3)	−0.14-0.27	0.520
Hypertension	14 (31)	11 (24)	−0.25-0.12	0.480
Diabetes mellitus	17 (38)	15 (33)	−0.24-0.15	0.660
Previous MI	15 (33)	14 (31)	−0.22-0.17	0.822
Beta blockers	35 (78)	38 (84)	−0.09-0.23	0.419
Diuretics	16 (36)	13 (29)	−0.26-0.13	0.499
Nitrates	31 (69 )	29 (64)	−0.24-0.15	0.655
ACE inhibitors	30 (67)	28 (62)	−0.24-0.15	0.660
Antiplatelet therapy	30 (67)	26 (58)	−0.29-0.11	0.384

BMI=Body mass index, NYHA=New york heart association, MI=Myocardial infarction, KD=Ketamine–dexmedetomidine, FP=Fentanyl propofol, CI=Confidence interval of the mean difference

In KD group, anesthesia was induced with 0.05 (0.04–0.09) mg.kg− 1 (median [range]) of midazolam and 1.7 (0.4–2.91) mg.kg− 1 of ketamine and 1.9 (1.6–2.5) μg.kg− 1 of dexmedetomidine. In FP group, induction of anesthesia was given by 0.05 (0.031–0.086) mg.kg− 1 of midazolam, 3 (1.5–5.4) μg.kg− 1 of fentanyl, and 1.7 (1.1–2.3) mg.kg− 1 of propofol. The trachea was intubated using of 0.9 mg of rocuronium in both the groups.

For maintenance of anesthesia, total doses of 10.12 (5.79–14.96) μg.kg− 1 of fentanyl and 12.6 (4.4–24.73) mg.kg−1 of propofol were used in the FP group, while 10.9 (2.7–18.1) mg.kg−1 of ketamine, 2.13 (1.7–2.9) μg.kg−1 of dexmedetomidine were used in the KD group.

HR and MBP readings were higher in the KP group than the FP group, but this rise had no statistical significance, but MBP at intubation was 109.42 ± 8.609 and 99.76 ± 8.345 mmHg in KD and FP groups, respectively, with P < 0.001, as shown in Figures 2 and 3.

Figure 2

Heart rate (beats per minute) of the studied groups

Figure 3

Mean blood pressures (mmHg) of the studied groups

Eleven patients in the KD group needed nitroglycerine infusion (more than 30 min.) in the face of 9 patients in the FP group (P = 0.714). The number of patients required inotropic support was comparable between both the groups, 5 patients in KD group had vasoactive inotropic score (VIS) >15 in face of 13 patients in FP group P < 0.001 as shown in Table 2.

Table 2

Surgical and cardiopulmonary bypass weaning data in the studied groups

	KD group (n=45)	FP group (n=45)	P
Number of grafts	2 (2-3)	2 (2-3)	0.635
Duration of surgery (min)	260.62±24.07	261.20±21.843	0.905
CPB time (min)	85.09±14.666	79.60±16.040	0.094
Aortic cross clamp time (min)	62.16±16.494	56.24±17.680	0.105
Volume of transfused crystalloids (mL)	3105.56±428.027	3272.22±634.747	0.148
Number of patients required inotropic support, n (%)	16 (36)	19 (42)	0.517
Use of nitroglycerin, n (%)	11 (24.4)	9 (20)	0.714
Number of patients required high-dose inotropic medications (VIS >15)	5	13	0.035
Number of patients required packed RBCs transfusion, n (%)	6 (13.3)	9 (20.0)	0.396
Number of patients required IABP (n)	1	2	1
Number of patients required defibrillation (n)	5	8	0.368
Time to tracheal extubation (min)	202.22±28.674	304.67±40.598	>0.001

CPB=Cardiopulmonary bypass, KD=Ketamine–dexmedetomidine, FP=Fentanyl propofol, IABP=Intra-aortic balloon pump, RBC=Red blood cell, VIS=Vasoactive inotropic score

In KD group, two patients developed bradycardia that required intervention in the face of no one in the FP group (P = 0.438).

As regards tracheal extubation time, patients assigned to KD group extubated earlier than whom in FP group 202.22 ± 28.674 versus 304.67 ± 40.598 min, respectively, P < 0.001. Surgical and CPB weaning data are shown in Table 2.

Hs-cTnT showed an insignificant difference between both the groups either preoperatively or 1, 12, and 24 h after aortic unclamping but significantly lower in the KD group at 6 h postunclamping 92.01 ± 7.332 in KD versus 96.73 ± 12.532 ng.L− 1 P = 0.032 [Table 3 and Figure 4]. CK-MB levels were comparable in both the groups [Table 4].

Table 3

High-sensitive cardiac troponin T-enzyme in the studied groups: Data are expressed in mean±standard deviation

Hs-CTnT (ng/L)	KD group (n=45)	FP group (n=45)	95% CI	P
Basal	1.70±0.461	1.75±0.203	−0.2-0.10	0.541
1 h after aortic unclamping	87.78±5.662	88.09±4.972	−2.55-1.91	0.778
6 h after aortic unclamping	92.01±7.332	96.73±12.532	−9-−0.42	0.032
12 h after aortic unclamping	61.65±4.434	62.55±8.376	−3.7-1.91	0.525
24 h after aortic unclamping	31.49±5.366	30.48±9.556	−2.2-4.25	0.540

Hs-cTnT=High-sensitive cardiac troponin T, KD=Ketamine–dexmedetomidine, FP=Fentanyl propofol, CI=Confidence interval

Figure 4

High-sensitive cardiac troponin T-enzyme in the studied groups

Table 4

Creatinine phosphokinase-myocardial bound (creatine kinase-myocardial band) in the studied groups: data are expressed in mean±standard deviation

CK-MB (IU/L)	KD group (n=45)	FP group (n=45)	95% CI	P
Basal	2.78±0.389	2.67±0.642	−0.11–0.33	0.323
1 h after aortic unclamping	28.06±9.926	31.09±11.288	−7.49–1.42	0.179
6 h after aortic unclamping	58.45±11.791	62.38±12.366	−9.00–1.12	0.126
12 h after aortic unclamping	48.84±8.894	51.42±7.116	−5.95–0.80	0.133
24 h after aortic unclamping	40.46±8.384	42.54±5.853	−5.10–0.96	0.177

*P<0.05 Significant when compared with the control group. CK-MB=Creatine kinase-myocardial band, KD=Ketamine–dexmedetomidine, FP=Fentanyl– propofol, CI=Confidence interval

Patients in the KD group expressed significantly lower levels of serum cortisol levels than patients in the FP group at 6 and 12 h after aortic unclamping P < 0.001 at both the times, as shown in [Figure 5].

Figure 5

Plasma cortisol levels (mg/mL) in the studied groups

As regards echocardiographic examination, the number of patients showed regional wall motion abnormality (RWMA) expressed in (Nu and %) and left ventricular ejection fraction (LVEF) expressed in mean ± SD showed no statistically significant difference between both the groups [Table 5].

Table 5

Echocardiographic findings in the studied groups: data are expressed in numbers percentage and mean±standard deviation

	KD group (n=45)	FP group (n=45)	P
Number of patients expressed RWMA, n (%)
Basal	5 (11.1)	9 (20)	0.245
Arrival to the ICU	17 (37.8)	9 (20)	0.063
After 24 h	3 (6.7)	2 (4.4)	1
LVEF (mean±SD)
Basal	61.69±4.972	62.87±4.581	0.246
Arrival to the ICU	62.40±4.580	63.04±8.076	0.643
After 24 h	62.56±5.786	63.47±5.155	0.432

LVEF=Left ventricular ejection fraction, KD=Ketamine– dexmedetomidine, FP=Fentanyl–propofol, RWMA=Regional wall motion abnormality, ICU=Intensive care unit

DISCUSSION

The current study showed that no statistically significant difference between both the groups as regard cTnT except at 6 h postaortic unclamping (92.01 ± 7.332, 96.73 ± 12.532 ng/L, respectively, P = 0.032 with 95% confidence interval − 9, −0.42, respectively). Patients assigned to KD group exhibited a significant decrease in serum cortisol level, so we can claim that a combination of ketamine and dexmedetomidine offers myocardial protection during peaked hs-cTnT and marked anti-inflammatory effect when compared with fentanyl propofol combination during on-pump CABG.

A study by Riha et al.[11] observed lower cardiac enzymes values with the use of KD during CABG when compared with sevoflurane-sufentanil-based anesthesia. Although our results agreed with them to some extent, their study has major limitations and differences with us. The nature of their study was a retrospective observational. It included a limited number of patients, also diabetic patients on sulfonylurea were not excluded, which is known to inhibit cardiac preconditioning. We excluded any patient on any medications which are known to inhibit any probable myocardial protection. They used opioids in both the groups and opioid receptors are known to play a role in cardiac preconditioning which pose a strong drawback. They used inhalational anesthetic (sevoflurane) in one group, while we used total i.v. anesthesia in both the groups and we offered a precise number about the doses of the used drugs. They followed biomarkers of myocardial injury on arrival to the ICU and then on the 1st postoperative day; these times are not constant to specific event as aortic unclamping. They could not follow-up the changes in cardiac enzymes during first postoperative 24 h which represent the peak of cardiac enzymes elevation. Riha et al. could not prove the anti-inflammatory effect of KD combination. They did not investigate the effect of the study drugs on hemodynamics during stress times as intubation, skin incision, and sternotomy. They did not investigate the impact of the study drugs on weaning from cardiopulmonary bypass in terms of vasoactive inotropic score. In our study, infusion of study drugs was continued in the ICU till extubation and time to tracheal extubation was recorded and analyzed. We used hs-cTnT which is very sensitive to small myocardial injury.

The development of high-sensitivity troponin assays enabled identification of small-scale myocardial injuries, allowing the detection of even small myocardial injuries.[12] Following myocardial injury, there are two peaks of cTnT release including early peak at 3–5 h and late one on the 5th day after cell necrosis.[13]

In a pragmatic, multicenter, randomized, single-blind trial involving patients undergoing elective, isolated CABG, when intraoperative anesthesia was compared with a volatile anesthetic. Moreover, a composite of perioperative nonfatal myocardial infarction at 30 days or death at 30 days and other major secondary outcomes did not differ significantly between the two groups.[14]

However, racemic ketamine reported to inhibit ischemic preconditioning in vivo by inhibiting sarcolemmal adenosine triphosphate-sensitive potassium ATP channels;[15] other experiments showed that a racemic mixture of ketamine and its S-(+)-enantiomer could trigger myocardial preconditioning in vitro. This effect is mediated by the activation of ATP potassium channels and stimulation of α- and ß-adrenergic receptors.[16]

When ketamine was used as the sole analgesic during cardiac surgery, it reduced the inflammatory cytokine response associated with extracorporeal circulation. Furthermore, ketamine might promote the production of anti-inflammatory cytokines after major surgery, as was suggested by the significantly higher plasma concentrations of interleukin-10 at the end of surgery compared with sufentanil-based analgesia.[17]

Induction and maintenance of anesthesia with ketamine might carry some risks. Due to its sympathomimetic effects, it may lead to hypertension and tachycardia which may increase myocardial oxygen demand, so dexmedetomidine is added as an adjunct in KD group.

Cardiovascular mortality and morbidity can be decreased with the sympatholytic effects of α2-receptor agonists in patients with CAD.[18] Perioperative dexmedetomidine use might also confer an early postoperative benefit for cardiac surgical patients with the well-proven benefits of sympatholytic, anti-inflammatory, and anti-delirium effects in the setting of cardiac surgery.[19]

Studies have shown that dexmedetomidine provides protective effects on the myocardium. α2-Adrenergic agonists have protective effects against myocardial ischemia by increasing the cAMP level which further induces coronary vasodilatation effect. Dexmedetomidine preconditioning has been shown to attenuate myocardial ischemia/reperfusion injury through activating prosurvival kinases.[20]

The meta-analysis included 18 studies included 1730 patients that compared dexmedetomidine to other treatments in the setting of cardiac surgery, most of the findings agreed with its myocardial protective results in the adult population.[21] Gong et al. included a total of 8 randomized controlled trials discussed the use of dexmedetomidine in cardiac surgery, their results revealed that a lower risk of delirium, a shorter length of intubation, but a higher incidence of bradycardia were found in dexmedetomidine group when compared with propofol. There were no statistically significant differences in the risks of hypotension or atrial fibrillation or the time of ICU stay between dexmedetomidine and propofol regimens. Unlike their ICU stay result, it was observed a significantly shorter stay in ICU with dexmedetomidine.[22]

Studies on human subjects have not reported cardioprotective effects for propofol.[23] Compared with isoflurane, the use of only high-dose propofol during CPB led to reduced levels of cardiac enzymes in patients undergoing CABG.[24] Conversely, compared with isoflurane, normal doses of propofol did not produce altered cTnI levels.[25]

Most studies have found δ- and κ-receptors, but not μ-receptors are expressed in cardiomyocytes. More specifically κ1 was reported in the crude membrane preparation of a rat heart homogenate, and both κ- and δ-, but not μ-receptors, have been identified in rat atrial and ventricular tissue.[26] Fentanyl is considered to be selective for μ-receptors; it can also interact with δ- and κ-receptors. Fentanyl protects the heart against myocardial IR injury via δ-receptor crosstalk with adenosine A1-receptors and mitochondrial K ATP-linked mechanisms.[27]

Although ketamine is known to increase HR and blood pressure, we observed no statistically significant difference in HR readings between both the groups. The mean blood pressure was significantly higher in the KD group than the FP group (109.42 ± 8.609 and 99.76 ± 8.345 mmHg, respectively, P < 0.001). The concomitant use of dexmedetomidine blunted the expected tachycardic effect of ketamine in the KD group during the induction of anesthesia.

An i.v. bolus administration of dexmedetomidine, which results in a high (peak) plasma concentration, results in an increase in blood pressure combined with a marked decrease in HR. During this phase, a marked rise in systemic vascular resistance is mediated by α2-receptor activation in the vascular smooth muscles. This is accompanied by a rapid decrease in HR, presumably caused by the baroceptor reflex.[28] Later on, when dexmedetomidine plasma concentrations decrease, the vasoconstriction attenuates, as dexmedetomidine also activates α2-receptors in the vascular endothelial cells causing vasodilatation. Together with presynaptic α2-adrenoreceptors inhibiting the sympathetic release of catecholamines and the increased vagal activity, this results in a hypotensive phase.[29]

Patel et al. found that the combination of clonidine and ketamine in anesthesia induction during CABG led to a smaller decrease in vital signs after induction agent being delivered, along with effective suppression of the pressure response to laryngoscopy and endotracheal intubation; the lowest rise in HR and blood pressure was in the group clonidine and ketamine when compared with baseline readings.[30]

Our results agreed with Patel results except MBP at intubation which was higher in the KD group. This may be owing to their use of fentanyl together with clonidine and ketamine during induction.

During anesthesia maintenance, HR and mean blood pressure were running with no statistically significant difference between both the groups. Clonidine with ketamine produced stable hemodynamics. This indicates effective clonidine-mediated central sympatholytic action.[30]

Our results revealed no statistically ;tatistical significance in the number of patients that required inotropic support, however, the number of patients that needed a high dose of vasoactive inotropic medications (VIS score > 15) was significantly lower in KD group (5 patients) than FP group (13 patients) P = 0.035.

The issue of cardiac output and ketamine showed some controversies. Some authors thought that ketamine has a direct myocardial depression, whereas others reported that ketamine augments cardiac output through an indirect way by catecholamines potentiation.[31] Other studies demonstrated direct positive ionotropic effects of ketamine on human myocytes.[32]

Tracheal extubation time was significantly shorter in the KD group than the FP group (202.22 ± 28.674 vs. 304.67 ± 598 min respectively P < 0.00). Elimination of infused medications depends on their context sensitive half-life which is the time required for drug concentration to decrease to half of its value after a given duration of drug infusion.[33] Each drug has its special characteristics. Fentanyl has a short 50% drug declining times if infused for 15 min. Thereafter, the time for fentanyl increases rapidly toward clinically unreasonable half-times which could reach more than 200 min if infused for 4 h.[34] Most hypnotic agents exhibit short context-sensitive half-times. The elimination half-life of dexmedetomidine is 2–3 h when infused in ICU.[29]

Dexmedetomidine decreases anesthetic requirements either volatile or i.v. agents by exerting an opioid-sparing effect.[35] A great advantage for dexmedetomidine is a minimal respiratory depression in contrast to fentanyl which has a marked effect. These factors predispose to early quiet tracheal extubation.

There are some limitations of this study; we did not follow-up on the cardiac enzyme till it reach back to baseline. We did not monitor the effect of combined drugs on more invasive and complex hemodynamics using a pulmonary artery catheter. This was because of relatively low-risk profile of the patients. This could be investigated in a further study using a Swan Ganz catheter or using transesophageal echocardiography. Another limitation is that we did not examine the impact of dexmedetomidine on the negative psychotropic experience of ketamine; however, this is out of scope of our study.

CONCLUSION

This study suggests that the use of KD during on-pump CABG confers better myocardial protective and anti-inflammatory effect than fentanyl propofol.

Financial support and sponsorship

Mansoura University, Mansoura, Egypt.

Conflicts of interest

There are no conflicts of interest.