Review Article
Role of Dexmedetomidine on Outcomes after Elective Cardiac Surgery
Merve Yazici Kara1, Steve Leung1, Huseyin Oguz Yilmaz2 and Alparslan Tura3*
1Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, USA
2Department of Anesthesiology and Reanimation, Etimesgut Military Hospital, Ankara, Turkey
3Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, USA
*Corresponding author: Alparslan Turan, Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic 9500 Euclid Ave. P 77, Cleveland OH, 44195, USA
Published: 22 May, 2017
Cite this article as: Kara MY, Leung S, Yilmaz HO, Tura A.
Role of Dexmedetomidine on Outcomes
after Elective Cardiac Surgery. Clin
Surg. 2017; 2: 1489.
Abstract
Open heart surgery is commonly performed for coronary artery disease and valvular diseases
worldwide. Certain postoperative complications, such as atrial arrhythmias, delirium, renal
injury and persistent incisional pain remain common and hinder recovery and have enormous
cost implications. The etiologies of these complications are linked with the inflammatory
response associated with surgery and cardiopulmonary bypass. There is increasing evidence that,
dexmedetomidine, an alpha-2 adrenergic agonist used for conscious sedation, may reduce the
risk of these events due to its favorable pharmacologic effects on the heart and anti-inflammatory
properties. This paper addresses the pertinent pharmacologic effects of dexmedetomidine on
cardiac physiology and the current evidence for use of perioperative dexmedetomidine to prevent
postoperative complications after cardiac surgery.
Keywords: Dexmedetomidine; Alpha-2 adrenergic agonist; Cardiac surgery; Atrial arrhythmias;
Delirium; Renal function; Chronic postsurgical pain (CPSP)
Abbreviations
AF: Atrial Fibrillation; AV: Atrioventricular; AKI: Acute Kidney Injury; CPB: Cardiopulmonary Bypass; CABG: Coronary Artery Bypass Grafting; CKD: Chronic Kidney Disease; CPSP: Chronic Postsurgical Pain; HR: Heart Rate; ICU: Intensive Care Unit; IL-6: Interleukin-6; IL-8: Interleukin-8; IL-10: Interleukin-10; IRI: Ischemia/Reperfusion Injury; JET: Junctional Ectopic Tachycardia; MAP: Mean Arterial Pressure; OAA/S: Observer’s Assessment of Alertness Score of Sedation; POD: Postoperative Delirium; PTPS: Post-Thoracotomy Pain Syndrome; RBC: Red Blood Cell; TNFalpha: Tumor Necrosis Factor-Alpha; VAS: Visual Analogue Scales
Introduction
Dexmedetomidine, an alpha-2 adrenergic agonist with known sedative and analgesic properties
[1-3]. U.S. Food and Drug Administration suggested it for procedural and critical care sedation.
It is widely used for this purpose and has an excellent efficacy and safety record. Like any drug,
dexmedetomidine presumably has ancillary side effects and benefits. Likely consequences are
reduced risk of atrial fibrillation (AF) and flutter, delirium, renal injury and reduced persistent
incisional pain. It also causes reduction in blood pressure, bradycardia, and inhibition of platelet
aggregation, renin release and insulin secretion [3]. Dexmedetomidine has been used successfully
in anesthesia for neurosurgery, cardiac surgery, and bariatric surgery, as well as for sedation in the
intensive care unit (ICU) [4-8].
Open heart surgery is the mainstay treatment for heart diseases like coronary artery disease,
congenital or valvular heart diseases, which requires the use of cardiopulmonary bypass (CPB).
A combination of CPB, surgical trauma, and ischemia-reperfusion elicit a systemic inflammation,
which is characterized by surge in inflammatory cytokines and activation of immune cells. This
response is associated with many postoperative organ injuries. Recovery period after cardiac surgery
is frequently affected with different complications [9]. Postoperative atrial arrhythmia and delirium
are the most common complications encountered after coronary artery bypass grafting (CABG)
surgery. Postoperative atrial arrhythmias affect morbidity, mortality, prolong ICU and hospital
stay, and increase costs related to surgery [10]. Furthermore delirium is an important prognostic
determinant of hospital outcomes [11].
Effect of Dexmedetomidine on Cardiac Function and Coronary Blood Flow
Dexmedetomidine has several complex physiological effects on
the heart. Firstly, there is a direct dose-dependent cardio-protective
effect of dexmedetomidine on reperfusion injury. Additionally
when given at high doses it has favorable subendocardial-tosubepicardial
blood flow ratio providing better functional recovery
from myocardial stunning [12,13]. With its sympatholytic effect, it
reduces heart rate and consequently myocardial oxygen demand, so
that dexmedetomidine is a preferable sedative agent particularly in
cardiac patients [14].
Dexmedetomidine may cause coronary vasoconstriction
attributed to its alpha-agonist effects. Kundra et al. [15] assessed
the effect of dexmedetomidine on coronary diameter in patients
undergoing percutaneous coronary intervention. Dexmedetomidine
was shown to reduce coronary diameter by around 14% but
simultaneously reduces heart rate by 13% (myocardial oxygen
demand), therefore maintaining myocardial oxygen demand-supply
ratio. Also attributed to the alpha agonist effects is mild hypotension
and frequently associated with younger patients with high vagal tone.
Similarly in a recently published study by Chi et al. [16]
dexmedetomidine reduces myocardial damage in patients undergoing
off-pump CABG. Versus placebo, dexmedetomidine significantly
decreased levels of serum cardiac troponin I and creatinine kinase
MB. The attenuation of cardiac enzymes suggested the cardioprotective
role of dexmedetomidine, although the exact mechanism
has yet to be identified [16].
In a pharmacodynamics study of healthy males, low
concentrations of dexmedetomidine reduced myocardial perfusion
by 27% from baseline and a 23% reduction in myocardial oxygen
demand [17]. High dexmedetomidine plasma concentration had no
effect on either myocardial perfusion or rate–pressure product. In
this study it has been shown that during the low infusion rate systolic
myocardial function was attenuated by sympatholysis, and during the
high infusion rate after load was increased. This study showed that
levels that exceed the therapeutic level appear to be well tolerated,
while maintaining myocardial perfusion and do not provoke
myocardial ischemia.
Dexmedetomidine shows an anti-ischemic effect also related to
sympatholysis and improves myocardial oxygen balance with preferred
blood flow distribution to the endocardium [16]. Dexmedetomidine
inhibits the increase in cTnI and CK-MB, and attenuates the proinflammatory
cytokines production such as tumor necrosis factoralpha
(TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8),
and increases anti-inflammatory cytokine interleukin-10 (IL-10)
production. These findings show that dexmedetomdine attenuates
inflammation in addition to myocardial protection potential in CABG
with bypass. Increased concentrations of dexmedetomidine caused to
decreases in both cardiac output and heart rate (HR), and memory as
well as progressive increases in sedation and analgesia [18]. Moreover
biphasic dose–response relation for mean arterial pressure (MAP),
pulmonary arterial pressure, and vascular resistances, and a reduction
of the cold presser response also were observed.
After the administration of dexmedetomidine the respiratory
rate, end-tidal carbon dioxide, and systolic-diastolic-mean arterial
pressure did not change, however significant bradycardia was seen
[19]. As two markers of sinus nodal function, baseline sinus cycle
length, and corrected sinus node recovery time were both lengthened
with the administration of dexmedetomidine. Atrioventricular (AV)
nodal function was lengthened significantly. Dexmedetomidine
increased the atrial refractory period and reduced atrial excitability.
Dexmedetomidine depressed sinus and AV nodal function in
pediatric patients significantly without electrocardiogram interval
changes, showed a trend toward lower heart rates. While neither
spontaneous AV nodal block nor significant bradycardia were
not reported in this study. In an animal study dexmedetomidine
inhibited electrophysiological effects on pacemaker cells in sinoatrial
nodes which may not be facilitated by alpha 2-adrenoreceptor [20]. In
a recent study the incidence of AF was significantly lower in patients
given dexmedetomidine compared those who received propofol
(13.6% vs. 36.4%). Similarly in another study the median onset of AF
watched to be delayed in patients who had received dexmedetomidine
compared with control patients [21]. After repair of tetralogy of Fallot
the incidence of junctional ectopic tachycardia (JET) is 5.6%-14%
[22], and dexmedetomidine has shown to be beneficial for preventing
perioperative JET in this kind of patients.
There are many rationales to use dexmedetomidine in cardiac
surgery. In a study by Kabukçu et al. [23] HR and mean arterial pressure
were reported to be relatively decreased with dexmedetomidine
infusion when compared to baseline values. Authors did not
encounter severe bradycardia or hypotension requiring intervention.
They determined no response to sternotomy and bypass. During
the CABG, dexmedetomidine provides a stable hemodynamic
status and can be safely used. Furthermore, dexmedetomidine was
found to decrease the need of inhalational anesthetics required
for cardiac surgery and another recent study demonstrated that
dexmedetomidine combined with ketamine had significant cardioprotective
effects in cardiac surgery compared to inhalational agent
combined with opioids [24].
Cardiac surgery and CPB strongly triggers an inflammatory
response. Increased levels of pro-inflammatory cytokines can be
detected during and after cardiac surgery [25]. AF after cardiac
surgery seems to be in response to a pro-inflammatory state [26].
Sepsis and subsequently multi organ dysfunction remains as one of
the leading reasons of death after cardiac surgery and both states are
characterized by an uncontrolled inflammatory response. Clinical
studies suggest that dexmedetomidine has anti-inflammatory effects
[27]. IL-6, IL-8 and TNF-α levels were significantly decreased with
dexmedetomidine treatment. Moreover, in a model of septic shock it
has shown that the administration of dexmedetomidine is associated
with less impairment of exogenous lactate clearance, and lower
arterial and portal lactate levels [28].
Atrial Arrhythmias after Cardiac Surgery
The incidence of AF after cardiac surgery ranges from 15%-50%
depending on the cardiac surgical procedure, patient population,
and perioperative exposure to prophylactic interventions [29,30]. A
large single-center clinic trial (N = 999: University-affiliated medical
center) found a 30.5% incidence of AF after coronary and/or valve
surgery [29]. The risk of AF after cardiac surgery was excessive in
patients older than 65 years with left atrial enlargement and mitral
valve disease. In a recent registry analysis the overall incidence
of AF was 17.1% [31]. Independent risk factors for AF in this trial
included advanced age, smoking history, hypertension, congestive
heart failure, urgent surgery, and emergency coronary artery bypass
grafting. Although AF may occur at any time after cardiac surgery, it most commonly occurs within 4 days of surgery, with a peak
incidence on postoperative day 2 [32].|
Inflammation seems to play a significant role in pathogenesis
of AF after cardiac surgery [26]. Cardiac surgery causes local and
systemic inflammation, which has been shown to be related with
AF and facilitate re-entry. Previously defined effect on cardiac
electrophysiology and inflammation makes dexmedetomidine a
reasonable prophylactic drug for postoperative AF. Supporting these,
in a recent retrospective study, including 765 cardiac patients received
dexmedetomidine for postoperative sedation in ICU, and 17,011
cardiac patients who did not [33], the incidence of atrial arrhythmias
were reported lower for patients who received dexmedetomidine
postoperatively. In another study, the results suggest that in
cardiovascular surgery patients incidence of AF after extubation can
be reduced by adequate sedation with dexmedetomidine during the
nighttime [34].
Delirium after Cardiac Surgery
Delirium is an acute cognitive dysfunction defined by
confusion, pathological changes in consciousness, and fluctuating
inattention [35]. This is a symptom of acute illness and usually
occurs in patients after cardiac surgery [36] and prolongs ICU and
hospital stay. Particularly patients undergoing on-pump cardiac
surgery are considered at high risk [11]. In a review article, old
age, history of cerebrovascular disease, psychiatric impairment
and cognitive dysfunction, receiving peri-operative Red Blood Cell
(RBC) transfusions, and type of surgery and were preoperative and
intraoperative predictors for postoperative delirium development.
Intra-operative variables, such as length of CPB or intra- operative
platelet transfusion were not investigated yet [36,37]. In a recent
study delirium occurred in 26 % of ICU patients who underwent
cardiac surgery [38]. Authors stated that CPB duration, low MAP,
low hemoglobin levels, low body temperature, high norepinephrine
requirements, and transfusions of blood products were significant
intra-operative risk factors in terms of intra-operative variables.
Platelet transfusions were only independent predictor in multivariate
logistic regression analysis. This suggests that during cardiac surgery
different events might promote post-operative delirium.
Dexmedetomidine has anti-inflammatory properties, decreases
use of opioids and benzodiazepines that contribute to delirium, and
provides sedation very similar to natural sleep that can attenuate
delirium seen after cardiac surgery. In a recent analysis of 194 patients
who underwent cardiac surgery, delirium occurred in 26 % of the ICU
patients [38]. In another study article in press postoperative delirium
and stroke also were decreased significantly in the dexmedetomidine
group [38]. This study found that perioperative use significantly
reduced in-hospital and operative mortality and was correlated with
improved early survival rates in elderly patients undergoing cardiac
surgery. The authors’ results further suggested that perioperative
intravenous dexmedetomidine was related with a reduced incidence
of postoperative stroke and delirium after cardiac surgery.
Studies estimating delirium after cardiac surgery with
dexmedetomidine have mixed results. In a prospective randomized
clinical study, results showed that dexmedetomidine based
postoperative sedation significantly reduced delirium when
compared with propofol in elderly patients after cardiac surgery [39].
Dexmedetomidine administration resulted in reduced incidence,
delayed beginning, and shortened interval of Postoperative Delirium
(POD). The study suggests that dexmedetomidine sedation prevents
one out of every eight delirium cases. Furthermore, due to reduced
incidence and shortened length of POD, this approach was cost
effective. Postoperative sedation practices have undergone an
evolution process by targeting a more balanced regimen of hypnoticand
analgesia-based sedation. Unlike other sedatives, which are
frequently used in the critically ill patients, dexmedetomidine has a
unique mechanism of exhibiting sedative, anxiolytic, and analgesic
effects without respiratory depression. Moreover, in critically ill
patients dexmedetomidine improves the quality of sleep, primarily
affecting the non REM sleep pattern [40,41]. Since it is a α2-adrenergic
receptor agonist, has also been shown to have notable opioid-sparing
effect. In addition, dexmedetomidine has poor anticholinergic effects
and has been shown to reduce the inflammatory response of CPB [42].
Dexmedetomidine may contribute to the decreased incidence and
duration of POD with a combination of all of these unique properties.
Renal Function after Cardiac Surgery
Adult cardiac surgery is significantly associated with the
occurrence of postoperative acute kidney injury (AKI). According to
its definition the incidence and outcomes of AKI may vary [43]. AKI
increases the morbidity and mortality substantially after operation.
In a prospective cohort study the overall incidence of AKI was
found 31.2% [44]. The overall hospital mortality was 1.9% and was
significantly higher in AKI group (5.4%). Especially CABG combined
valve surgery, aneurysm surgery, heart transplantation, is considered
as high-risk surgeries. Male gender, high age and BMI, incidence of
hypertension and chronic heart failure, preexisting chronic kidney
disease (CKD), long CPB time, intra-operative hypotension were
preoperative and intraoperative risk factors of AKI occurrence after
cardiac surgery.
The effect of dexmedetomidine on the renal function has
been extensively studied. There are multiple mechanisms that
dexmedetomidine can influence kidney functions. Cardiac surgery
activates sympathetic nervous system; dexmedetomidine-induced
sympatholysis might reduce risky hemodynamic events resulting in
prevention of AKI.
Ischemia-reperfusion injury is one of the most important causes
of acute renal failure. In a recent animal model was studied to explore
whether dexmedetomidine has any protective effect against renal
ischemia/reperfusion injury (IRI) [45]. Renal IRI resulted more
CD3 T-cell infiltration and unregulated the expression of TNF-α,
ICAM-1, IL-1β, HMGB1 and TLR4. Additionally renal IRI resulted
in significant renal injury, as evidenced by inflammatory reaction and
renal parenchymal loss characterized by tubular atrophy, rarefaction
of peritubular capillaries, and podocyte depletion. While, all these
changes were reduced by the administration of dexmedetomidine.
In accordance with the above, several small clinical studies have
investigated the renal protective role of dexmedetomidine after
cardiac surgery. In a randomized trial by Cho et al. of 200 patients
(100 treatment vs. 100 placebo) undergoing valvular heart surgery.
Those who receive perioperative dexmedetomidine infusion had a
lower incidence of AKI versus placebo (21% vs. 38%) and shorter
length of ICU stay [46]. Furthermore, of those who developed AKI,
dexmedetomidine group had significantly lower severity versus
the control group. Similarly, a randomized placebo-controlled trial
by Balkanay et al. [47]. reported that dexmedetomidine use after
CABG showed a dose-dependent renal protective effect. Although conventional renal function tests such as creatinine were not
significantly different among control and treatment groups, serum
levels of neutrophil gelatinase-associated lipocalin, a sensitive
biomarker for renal injury, were significantly lower in the treatment
group.
In another study it has been showed that dexmedetomidine
infusion after CPB surgery reduced the incidence of AKI (26.1%
vs. 33.75%) [48]. In addition, dexmedetomidine use after surgery
was more likely to reduce the occurrence of AKI in those with
preoperative normal kidney function and mild CKD after cardiac
surgery. Administration of dexmedetomidine after surgery was
also associated with reduced incidence of any complication and
mortalities within 30-days.
Chronic Pain after Cardiac Surgery
Chronic postsurgical pain (CPSP) is frequently seen complication
after many surgical procedures, including cardiac surgery. After
cardiac surgeries the incidence of CPSP varies from 9.5% to 56%.
Pain following thoracotomy is of moderate to severe nature.
Treatment of thoracotomy pain is a critical task. Thoracotomy pain
has acute effects throughout postoperative period and affects the
respiratory mechanics, which has an important impact on morbidity.
Inadequately treated thoracotomy pain in the acute phase may
also cause to chronic pain syndrome. In their study on 948 cases
that had undergone thoracotomy, Maguire et al. [27] determined
the postoperative chronic pain as 57% between 7-12 months, 36%
between 4-5 years and 21% between 6-7 years [49]. In a recent study
authors reported the prevalence of CPSP at 5 years after cardiac
surgery of 3.8% is lower than previously reported [50]. The majority
of patients (89.8%) did not report postsurgical pain, neither 1 year for
5 years after surgery.
The present Italian survey is the largest one assessing the
prevalence of postsurgical pain after rehabilitation following cardiac
surgery, up to 3 years after the intervention. Their results show that
20% of patients were still suffering from pain 3 years after surgery,
mainly at the sternotomy site, which was severe in one-quarter of
the patients. Results from this large multicenter survey indicate that
the prevalence of pain at the 3-year time point after cardiac surgery
was significantly lower than that reported by the 3-month and 1-year
groups; however, one out of five patients still complained of pain at 3
years after the intervention, with the symptom scored as severe in one
quarter of the patients. Moreover, up to one-third of the patients aged
above 75 years in the 3-year group still reported pain [51].
Why some patients develop persistent incisional pain remains
unknown. But one theory is that severe acute pain, such as a scalpel
blade cutting through skin, provokes activation of high-threshold
peripheral sensory neurons which signal the presence, location,
and intensity of the injury. Normally, peripheral sensory neuron
activation fades once the stimulus is removed. Inflammatory pain is
the increased pain sensitivity that occurs in reaction to tissue injury
and inflammation and is termed peripheral sensitization. Peripheral
sensitization results from the local effect of inflammatory mediators,
including prostanoids released from injured and inflammatory cells,
on the peripheral terminals of high-threshold sensory neurons.
Inflammatory pain remains until the surgical wound has healthy.
If a focus of ongoing inflammation persists, so will the pain. But
peripheral pain can also provoke central sensitization, which is an
increase in the excitability of spinal neurons because of persistent
nociceptive afferent input from peripheral neurons. It thus seems
likely that good control of acute postoperative pain and inflammation
by aggressive early pain management reduces the risk of persistent
incisional pain by blunting central sensitization [52,53].
Dexmedetomidine has anti-inflammatory and analgesic
properties. Anti-inflammatory properties of dexmedetomidine have
been previously described. Clonidine has been widely given as an
analgesic adjuvant treatment in perioperative conditions and chronic
pain therapy [54]. Dexmedetomidine comes from same family of
drugs with clonidine using the same receptors with different affinity.
The incidence of post-thoracotomy pain syndrome (PTPS) in
the dexmedetomidine group was 22% patients, however 52% patients
in the control group had PTPS [2]. In the progression neuropathic
syndromes the role of the sympathetic nervous system of has been
well known. Sympathetic overstimulation can provoke a sympathetic
pain. Additionally sympathetic stimulation may also be aggravating
the increased inflammatory processes in neuropathic pain syndromes.
Dexmedetomidine prevents sympathetic stimulation by exhibiting
sympatholytic activity, and could be an effective pre-emptive therapy
for neuropathic pain syndrome in PTPS.
It has been shown that when dexmedetomidine added to
intravenous patient-controlled analgesia, the efficacy of morphine had
improved. This combination decreased the postoperative analgesia
and postoperative morphine consumption by 30%, and decreased
the morphine-induced side effects [55]. Alpha 2-adrenerjic receptor
agonists and opioids act by different mechanisms and therefore their
combination makes a synergistic analgesic effect without increasing
the complications [54].
Dexmedetomidine can be effective on persistent postoperative
pain formation either by decreasing inflammation, which plays a
crucial role in maintaining of peripheral sensation, and/or providing
better acute pain control which is blamed as an important factor
in chronic pain formation. In a recent study authors aimed to
compare fentanyl, remifentanil and dexmedetomidine in terms of
hemodynamic stability, postoperative pain control and achievement
of sedation postoperatively. Results showed that showed that
compared with other groups, hypnosis, and the modified observer’s
assessment of alertness (OAA/S) score of sedation were significantly
lower in dexmedetomidine group after arrival at the PACU, whereas
the pain Visual analogue scales (VAS) scores and BIS were not
significantly different from other groups [27]. HR and blood pressure
in the dexmedetomidine-received group were significantly lower
than those of other groups. At sedative doses the patients received
dexmedetomidine showed better postoperative hemodynamic
stability than those received remifentanyl or fentanyl, and
demonstrated a similar effect of pain control as remifentanyl group
and fentanyl group with patient awareness during sedation.
Pharmaco-Economics
Using dexmedetomidine in the postoperative period is that it is relatively expensive compared to other sedative drugs? However, the complications including AF associated with other cheaper sedative drugs are extremely costly. The costs of using Dexmedetomidine for preventing atrial arrhythmias as compared to the cost of cheaper sedatives and the costs of treating the associated complications has not been addressed. Therefore, assessing the cost-effectiveness of Dexmedetomidine needs to be investigated as well.
Summary
Dexmedetomidine, an alpha-2 agonist, is a proven effective and safe sedative for use in the intensive care setting and for conscious sedation. Dexmedetomidine has gradually gained popularity in the perioperative period due to its ability to reduce anesthetics and opioid consumption. There is increasing clinical evidence that perioperative infusion of dexmedetomidine is protective against myocardial complications, delirium, renal injury and persistent incisional pain after cardiac surgery. Existing studies are limited by heterogeneous surgical population and infusion rates, but nonetheless it demonstrates dexmedetomidine is a useful adjunct in patients in elective cardiac surgery. However, large multi-center prospective studies are required to truly measure the benefits of routine use of perioperative dexmedetomidine in cardiac surgery, especially its economic impact.
Acknowledgment
Dr. Merve Yazici Kara was supported by a grant for life expenses from TARD: Turkish Society of Anesthesiology and Reanimation.
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