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REVIEW ARTICLE
Year : 2013  |  Volume : 6  |  Issue : 1  |  Page : 5-13  

Dexmedetomidine: Expanding role in anesthesia


Department of Anaesthesia, BVU Medical College and Hospital, Sangli, Maharashtra, India

Date of Web Publication14-Mar-2013

Correspondence Address:
Jyotsna S Paranjpe
'Dhanvantari' 36, Ekata Colony, Market Yard, Sangli - 416 416, Maharashtra
India
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DOI: 10.4103/0975-2870.108625

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  Abstract 

The potential uses of dexmedetomidine (DEX), a highly selective α2 - adrenoceptor agonist are very diverse. DEX appears to mimic many of the actions of mythical 'ideal' sedative/analgesic agent. Although not orally active, DEX shows good bioavailability when administered via various other routes like intranasal, buccal, IM than intra-venous. DEX has similar pharmacokinetics in all age groups. Its side effects are predictable and easily treatable, hence it has found place as a part of fast-tracking anesthesia regimens in children. DEX is the sedative of choice for peri-operative use in high risk patients, since it is cardioprotective, neuroprotective and renoprotective. Premedication with DEX obtunds the autonomic pressor responses due to laryngoscopy and endotracheal intubation when used as an adjuvant to general anesthesia. DEX in high doses offers another approach to managing morbidly obese patients and patients with a compromised airway; without causing any cardio-respiratory depression. It is near ideal hypotensive agent used for controlled hypotension. Its value as a primary sedative and analgesic is becoming more accepted and evident in critically ill patients; in adult and paediatric intensive care units. Besides use in locoregional anesthesia, it is also used as an opioid substitute, for treatment of substance withdrawal, as an anti-shivering agent, for treatment of delirium and as an end of life medication. Availability of an antidote (Atipamezole) with similar elimination half life is taking the drug into new frontiers. However, use of DEX is contraindicated in patients with hepatic failure, hypovolemic shock, advanced heart block or ventricular dysfunction.

Keywords: Adjuvant, α2 -adrenoceptor agonists, analgesia, dexmedetomidine, premedication


How to cite this article:
Paranjpe JS. Dexmedetomidine: Expanding role in anesthesia. Med J DY Patil Univ 2013;6:5-13

How to cite this URL:
Paranjpe JS. Dexmedetomidine: Expanding role in anesthesia. Med J DY Patil Univ [serial online] 2013 [cited 2014 Oct 23];6:5-13. Available from: http://www.mjdrdypu.org/text.asp?2013/6/1/5/108625


  Introduction Top


Dexmedetomidine a second generation a 2 adrenergic receptor specific, pharmacologically active d- isomer of medetomidine was first synthesized in late 1980's. DEX appears to mimic many of the actions of mythical 'ideal' sedative/analgesic agent with its wide spectrum of actions encompassing the entire peri-operative period and then beyond that, into the critical care services. The food and drug administration (FDA) approved the use of DEX as an ICU sedative in 1999 and its use for nonintubated patients adult and pediatric, requiring sedation prior to and/or during surgical and other procedures in 2008. [1] DEX has been growing in popularity and expanding its role in anesthesia since then.

DEX became α2 agonist of choice, due to its greatest α2:α1 affinity (8 times greater than clonidine). [2],[3] This increased selectivity results in more predictable and effective sedation and analgesia and fewer side effects. [4] DEX has evolved as a panacea for various applications / procedures with multiple promising delivery routes. [2],[5],[6],[7],[8]

Chemical Structure: [Figure 1]
Figure 1: Chemical structure of Dexmeditomidine

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Chemical formula-C13H16N2 IUPAC name: 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. DEX is a small molecule containing imidazole ring.

Mechanism of Action

[Figure 2] - α - Adrenergic synapse
Figure 2: A schematic diagram of alpha- adrenergic receptor

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DEX induces sedation resembling physiological sleep maintaining reusability without causing respiratory depression. It produces analgesia by central, spinal and peripheral mechanisms. Net result is neither the nerve/terminal are allowed to get stimulated, nor it can transmit/propagate the signal forwards. [5],[9]

The pre-synaptic type of α2 - receptors regulates the release of nor-adrenaline and adenosine tri phosphate (ATP), through negative feedback mechanism. [5] In CNS, the specific sites are locus coeruleus of upper brain stem and substantia gelatinosa in spinal cord. [10]

The supra-spinal level of analgesia and sedation may be due to modulation of descending noradrenergic pathway originating in the main noradrenergic nucleus/center locus coeruleus. This supraspinal action could explain the prolongation of spinal analgesia after intravenous administration of DEX.

The spinal level of antinociceptive action seems to be through the substantia gelatinosa (Lamina II of Rexed in grey matter of spinal cord). It closes the gate at the dorsal horn to stimuli coming from peripheral Aδ and C fibers and also inhibits release of nociceptive humoral transmitters like substance P. It produces hyper polarization of cell membrane. These mechanisms effectively suppress, both neuronal firing, as well as, release of neurotransmitter noradrenaline at the nerve terminals. [11] This antinociceptive effect may explain the prolongation of the sensory block when added to spinal anesthetics.

Activation of postsynaptic α2 - adrenoceptors is responsible for peripheral actions of the drug. [11],[12]

Activation of a 2 receptors leads to dose dependent reduction in level of plasma catecholamines (maximum 89%), bradycardia and hypotension secondary to sympathetic inhibition of medullary vasomotor center. [6],[13]

a 2 -adrenoceptors do not have an active role in the respiratory center, therefore, DEX throughout a broad range of plasma concentration (up to 8 ng/ml), has minimal effects on the respiratory system. [13],[14],[15]

[Figure 3] - Adrenergic receptors in CVS [Figure 4] - Subtypes: α-adrenergic receptors[2],[3],[16]
Figure 3: Adrenergic receptors in CVS

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Figure 4: Subtypes: Alpha -adrenergic receptors

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DEX does not have any direct effect on contractility of myocardium. [3],[16] After administering it rapidly or with a relatively large dose (>1000 μg/kg), biphasic response on BP is observed. [2],[4],[5] DEX evokes a biphasic blood pressure response: α -2B adrenergic receptors are responsible for the initial short hypertensive phase while subsequent hypotension is mediated by α 2A- adrenergic receptors.[2],[3],[9],[16] This direct effect on the peripheral vascular smooth muscle usually lasts for up to 10 min. [4],[5]

It is observed that DEX does not alter the sweating threshold; there is a dose dependent decrease in the vasoconstriction and shivering thresholds. [13],[17] Alpha-2 adrenergic agonists decrease the thermo sensitivity at spinal and supraspinal sites by suppressing the neuronal conductance.

Pharmacokinetics/Pharmacodynamics

Although not orally active, DEX shows good bioavailability when administered via various other routes (than conventional intra-venous route) such as intranasal, intramuscular, buccal, sublingual, intragastric, neuraxial, regional, intraarticular. [16],[18],[19]

Pharmacokinetics of the active DEX molecule does not change with age, sex or in patients with renal failure. [5]

DEX undergoes almost complete (> 95%) biotransformation in liver into all inactive metabolites. [12],[20] It is necessary to decrease the typical dose in patients with hepatic failure, since there is significant ­ t 1/2 in hepatic failure (7.5 h). The elimination half-life in healthy patients is approximately 2 h. [4],[5],[9]

In clinical doses, DEX also exhibits decongestant, antisialagogue, antishivering, antiemetic effects. [5],[6],[11],[17] Other claimed advantages include minimal respiratory depression with cardioprotection, neuroprotection and renoprotection, thus making it useful at various situations including offsite procedures.

When DEX is infused with doses more than 1.5 μg/kg, bradycardia and hypotension have been reported in almost 40% healthy surgical patients. [21] Usually, these temporary effects are predictable and can be successfully treated with vagolytics, vasopressors and volume infusions. [9],[14]

DEX has a rapid and predictable offset of action after stoppage of administration. Although not orally active, atipamezole (antisedan) is found to be an effective antagonist for reversing psychomotor impairment and vigilance caused by DEX. Antagonism is dose dependent; [9],[21] ratios in the range of 40:1 to 100:1 for atipamezole: dexmedetomidine were found to be effective. [22] Linear pharmacokinetics and similar elimination half-lives of these two drugs (app. 2 h) are a clear advantage considering the possible clinical applications for long term use in ICU. [23]

Clinical actions

Central

  1. Sedation, hypnosis, anxiolysis
  2. Analgesia
  3. Bradycardia and hypotension
Peripheral- [5],[9]

  1. Decreased GI secretions, inclusive of saliva and decreased GI motility
  2. Constriction of vascular and other smooth muscles
  3. Inhibition of rennin-angiotensin (RA) system and decreased release of rennin
  4. Increased glomerular filtration rate (GFR), Increased excretion of Na, water and thus diuresis
  5. Decreased intra-ocular pressure
  6. Decreased insulin release from the pancreas [5]
  7. Decreased platelet aggregation
  8. Decreased shivering threshold (by app. 2°C). [9]
Dosage and administration

Intravenous infusion of DEX is commonly initiated with a 1 μg /kg loading dose, administered over 10 min, followed by a maintenance infusion of 0.2-1.0 μg /kg/h. Limiting its usefulness is the caution that the drug cannot be given as a bolus due to concerns about peripheral alpha-2B receptor stimulation with resulting hypertension.

Clinical Applications

Peri-operative uses of DEX:

DEX when used as adjunct to GA, attenuates stress response to tracheal intubation/extubation. [6],[24] Optimal dose for attenuating pressor response seems to be 1 μg /kg with lesser doses not being effective. The analgesic-sparing effect observed after a preoperative or an intraoperative administration of DEX usually lasts up to 24 h, [25] which can be used to advantage in situations where high anesthetic concentration is either undesirable or not tolerated.

  1. Premedication

    Indications to the use of DEX as premedication include patients susceptible to preoperative and peri-operative stress, drug addicts and alcoholics, chronic opioid users and hypertensive patients. DEX when given as a premedication, it decreases oxygen consumption intraoperatively by 8% and post-operatively by 17%. [9]
  2. Intraoperative uses of DEX

    Intraoperative uses of DEX include its use as adjunct to general anesthesia, as adjunct to regional anesthesia, in monitored anesthesia care (MAC), or as a sole agent for total intravenous anesthesia (TIVA). [14]
    1. As an adjuvant to GA- DEX potentiates the anesthetic effects of all intraoperative anesthetics regardless of method of administration (intravenous, volatile or regional block). [5],[26],[27],[28] As an adjuvant to general anesthesia it has minimum alveolar concentration (MAC) reducing [26] and opiate sparing [21],[26],[29] properties, which helps in decreasing the inhalational anesthetics, IV anesthetics and opioid requirements by up to 90%. [30] DEX has a strong synergistic effect with other sedatives as well.

      In patients receiving DEX, The reduction in rate pressure product and myocardial oxygen demand reduce subsequent myocardial ischemia and infarction. This is beneficial for cardiac patients. [1],[5],[14],[31]

      DEX in high doses offers another approach to managing the patient with a compromised airway in patients with obstructive sleep apnoea, in morbidly obese patients, without causing any cardio-respiratory depression and ensuring faster, neuromuscular recovery and smooth emergence. [32],[33]

      There are few case reports regarding intraoperative use of DEX as an anesthetic adjuvant in minimizing episodes of abrupt arterial hypertension expected during manipulation of the tumor in pheochromocytoma surgery. [34],[35]

      Hudcova et al have reported the successful anaesthetic management of an MH (malignant hyperthermia)-susceptible patient presenting with an undiagnosed catecholamine-secreting paraganglioma and a coexisting carcinoid. They used the combination of a trigger-free total intravenous anesthetic technique consisting of propofol and DEX with the use of thoracic epidural analgesia using bupivacaine. [36]

      Controlled hypotension- It is evident from the literature that DEX is equally effective to remifentanil [37],[38] and esmolol [38] in controlled hypotension application during tympanoplasty. The parameters assessed were intraoperative bleeding, preoperative hemodynamics, lactate levels, recovery and adverse effects.
    2. As adjuvant to regional anesthesia: Efforts to find a better adjuvant in regional anesthesia are underway since long. a2 adrenergic agonists have both analgesic and sedative properties when used as an adjuvant in regional anesthesia. [9],[39]

      As an adjuvant to neuraxial anesthesia: Intrathecal a2 receptor agonists are found to have antinociceptive action for both somatic and visceral pain. [7],[40]

      Recent experimental studies indicate that DEX produces a dose-dependent increase in the duration of the motor and sensory blocks induced by local anesthetics, [7],[41] regardless of the neuraxial route of administration (epidural, [39] caudal, [42] or spinal [5] ) without any evidence of neurotoxicity in human volunteers. [7],[25]

      Researchers have found that 3 μg DEX and 30 μg clonidine are equipotent intrathecally. [43] The addition of 5 μg of intrathecal DEX prolonged the post-operative analgesic effect of ropivacaine by 8 h. [7] Increasing the dose > 10 μg for prolonged surgeries like total hip or total knee needs further RCTs.

      The results of a study by Tekin et al are important since they support that intravenous DEX significantly prolongs the duration of sensory and motor block of spinal anesthesia and provides a significantly higher level of sedation compared to placebo in adult surgical patients. [44]

      The dose of clonidine is 1.5 to 2 times higher than DEX when used in epidural route. [10] Recommended dose of DEX as an adjunct for EA is 1.5-2 μg /kg.

      As an adjuvant in peripheral nerve block and intravenous regional anesthesia (IVRA): DEX when added to LAs or given IV prolongs the duration of sensory block of local anesthetics during peripheral nerve block. [25],[30]

      Dexmedetomidine (dose 0.5 μg/kg) has also been reported to improve block quality, prolong post-deflation analgesia, and decrease tourniquet pain when used as an additive to lignocaine in intravenous regional anesthesia. [12],[25],[30],[45]

      Al-Metwalli et al in their study reported that intra-articular administration of DEX decreases the need for post-operative analgesics after arthroscopic knee surgery. [46]

      Animal studies reported an interesting observation that perineural DEX alone provides a brief, partial sensory block indicating that a2 adrenergic receptors located at nerve endings may have a role in the analgesic effect of the drug. [45]
    3. Cardiovascular anesthesia- American College of Cardiology/American Heart Association (ACC/AHA) guideline has conferred the use of α2-adrenoceptor agonist as a grade IIb recommendation in the 2002 guideline update on peri-operative cardiovascular evaluation for non-cardiac surgery. Since, the use of β-blocker had been proven to significantly reduce peri-operative cardiac morbidity and mortality, α2-agonists were recommended in patients whom β -blockers are contraindicated. [47]

      Snapir A et al assessed myocardial blood flow (with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data collected before and during low (0.5 ng/ml) and high (5 ng/ml) mean plasma concentrations of DEX infusion. The results of this valuable study suggest that in healthy subjects, plasma concentrations of DEX that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia. [48]

      It is known that hemodynamic, sympathetic nervous system activity and renal function are tightly interrelated. DEX-induced sympatholysis might attenuate harmful hemodynamic events resulting in prevention of AKI in patients undergoing elective CABG with extracorporeal circulation during the first two post-operative days. In a cohort of relatively low-risk elective CABG patients, Kari Leino et al demonstrated that use of intravenous DEX did not alter renal function but was associated with an increase in urinary output. They were not able to demonstrate a significant DEX-related benefit in terms of renal function as evaluated with creatinine clearance. [49]
    4. Neuroanesthesia- Anesthesia for intracranial procedures requiring patient cooperation presents a challenge to the anesthesiologist. Common intraoperative complications associated with traditionally used neuroleptanalgesia include agitation, drowsiness, pain, respiratory depression and seizure. The pharmacology of DEX allowed achieving a level of sedation and analgesia sufficient to complete the neuropsychiatric testing required for the mapping of the cortical language area, electrocorticography, for bone flap removal, deep brain stimulation (DBS) as the final therapy for parkinson disease, [10] as well as to perform an awake tumor resection. The level of sedation was measured by using a bispectral electroencephalogram index (BIS). [50]

      The use of DEX infusion as an anesthetic adjuvant up to 0.6ng/ml plasma concentration did not change the ability to record the evoked potentials by any clinically significant amount. DEX has been found to provide neuro-protective effect by decreasing cerebral blood flow without interfering either with cerebral metabolic rate (CMRO2) or intra cranial pressure (ICP). [51],[52]
    5. Sedative for monitored anesthesia care (MAC): DEX is an almost ideal agent for MAC for a broad range of airway procedures including fiberoptic bronchoscopy, dental procedures, ophthalmological procedures, head and neck procedures, neurosurgery, vascular surgery, providing better patient satisfaction, less opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl. [1],[6],[53] However, it lacks amnesia and controllability because of its slow onset and offset. [9]

      Various studies on patients undergoing ophthalmologic surgeries have reported that IV DEX 0.6 μg /kg, effectively prevented the rise of intraocular pressure in response to suxamethonium and tracheal intubation. [53],[54] Intraocular pressure was reduced by 34% within 10 min after a single IV dose of DEX. [55]

      DEX has been used without any topicalization for AFOI in a patient with a critical airway who had a true documented allergy to local anesthetics. [30]

      Kaygusus et al compared DEX with propofol during extracorporeal shock-wave lithotripsy (ESWL) procedures and found use of both drugs safe and efficacious. [56]
  3. Post-operative analgesia

    Special properties of DEX flavor its use in recovery room. In addition to its sympatholytic effects, analgesic effects, decreased rate of shivering, wide safety margins and the preservation of respiratory function allows the continuation of the DEX infusion in the extubated, spontaneously breathing patient. [55]
Intravenous DEX infusion given post-operatively is associated with a reduction in nausea and vomiting, reducing post-operative morbidity. [30]

Self-administration of DEX by adding to intravenous patient-controlled analgesia morphine (5 μg DEX per 1 mg morphine dose) improves post-operative analgesia and decreases post-operative morphine consumption by 30%, as well as decreasing morphine-induced side effects like nausea, without additional sedation. [25]

Intensive care unit sedation:

Its unique sedative action mimics normal sleep, which translates into an advantage during weaning from mechanical ventilation. DEX need not be discontinued and the ongoing sedation can be maintained following tracheal extubation. [14],[30] DEX is an imidazole agent but unlike etomidate, it does not appear to inhibit steroidogenesis. [2] Moreover, it may prevent inflammatory effects in sepsis patients during sedation. [57]

Treatment of substance withdrawal:

DEX may have special value in alleviating opioid withdrawal symptoms besides helping to control pain. [25] DEX has a potential for treatment of agitation and alcohol withdrawal in alcoholic patients after brain trauma. [55]

As an opioid substitute:

DEX may offer an alternative in patients developing tolerance to opioids or in those forms of pain with poor response to opioid analgesics, like sympathetically maintained neuropathic pain. [58]

Treatment of delirium:

Riker et al have demonstrated that there is a 22.6% absolute reduction in incidence and 48% reduction in the duration of delirium achieved with DEX compared to midazolam in all patients, and in patients who were delirious at enrolment. [59] Others have reported that DEX was significantly better than midazolam for attenuating the cardiostimulatory and postanesthetic delirium effects of ketamine. [60]

As an anti-shivering agent:

Results of recent RCTs on post-operative patients who underwent general [61] and epidural [39] anesthesia showed lower incidence in post-operative shivering in DEX group.

As an end of life medication:

Recently, an investigator initiated IND was approved by the FDA to examine the use of DEX in treating cancer patients at the end of life who are suffering from intractable pain, agitation or delirium. DEX is evolving as an adjuvant analgesic, both as intravenous and as a component medication of the intrathecal polyanalgesia infusion via intrathecal drug delivery systems (IDDS), in cancer pain refractory to comprehensive medical management (CMM) or multiple treatment modalities. [62]

In pediatrics:

Use of DEX by noninvasive route like intranasal, buccal may substitute narcotics causing respiratory depression and other for fear of needle prick. The pharmacokinetics of DEX in infants and children are predictable and consistent with results similar to that reported in adults. [63] One of the earliest applications for DEX in pediatric patients was to prevent/treat emergence delirium. [1],[25],[33]

In babies, DEX is used for various applications including procedural-sedation, sedation during mechanical ventilation, prevention of emergence agitation, prevention of withdrawal symptoms following prolonged use of opioids and benzodiazepines. [63] However, the effect of DEX on the seizure threshold during withdrawal from benzodiazepines has yet to be determined. [64]

Dexmedetomidine by IV [65] or IM [66] route has been used solely to sedate children for procedures without stimulation and its use in MRI and CT scan are becoming popular. [10] Doses required for bolus and infusion are (2 to 3 μg/kg and 2 μg/kg/h, respectively). [1],[65] A processed electroencephalogram (Bispectral Index) can be used to guide the titration of DEX in neurologically impaired infants. [64]

Anecdotal experience suggests that a combination of DEX with ketamine may be effective for painful invasive procedures. The combination of DEX with ketamine makes pharmacologic sense as the two medications have the potential to balance the hemodynamic and adverse effects of the other. [1],[63]

In the patients with tracheomalacia, easy collapsibility of the trachea during coughing and recovery from anesthesia may make extubation of the trachea extremely difficult, leading to prolonged intubation and ventilation. Khaled Al Zaben et al have reported the successful use of dexmedetomidine (5-10 μg /kg/h) as the main anesthetic agent, supplemented by smaller propofol dose (100 μg/kg/min)for three pediatric patients with tracheomalacia presenting for different kinds of urgent operations. [67]

Obstetric analgesia:

Use of DEX in obstetric analgesia is being explored in view of the high lipophilicity. It is retained in the placental tissue, thereby resulting in less foetal transfer and a decreased incidence of fetal bradycardia. [25] Continuous intravenous DEX infusion has been successfully used as an adjuvant to systemic opioids in laboring parturients who could not benefit from epidural analgesia. [30],[68] DEX demonstrates an antinociceptive effect in visceral pain conditions. [7],[40] Furthermore, the researchers endorse that the drug also possesses attractive properties such as maternal hemodynamic stability, anxiolysis, and stimulation of uterine contractions. [25]

Current status of the use of dexmedetomidine in India:

A large body of recent work in India supports its favorable profile in improving peri-operative outcome in general and locoregional anaesthesia. [7],[24],[30],[40],[41],[42],[61] Few researchers have recommended it as the best choice as the primary sedative in adult and paediatric ICU, for short term, as well as long term use. [2],[8] The availability of low dose ampoules (50μg/ml) can be the step ahead towards affordability in developing countries like India.

A word of caution:

Most of the adverse events associated with use of DEX occur during or briefly after loading of the drug. Multiple studies have demonstrated that by omitting or reducing the loading dose, adverse effects can be reduced. [4],[5],[13],[20],[21] Although, avoiding the loading dose may prevent erratic hemodynamic effects, it may potentially prolong the onset of action and time to steady state for DEX. [4]

Sympatholytic or bradycardic actions of α2-adrenoceptor agonists may be deleterious in hypovolemic patients or patients with fixed stroke volume. Overdose of DEX may cause first-degree or second-degree atrioventricular block, atrial fibrillation. [14] Severe bradycardia leading to cardiac arrest has been reported in the literature, but the case reports have multiple confounding factors that might have contributed to the cardiac arrest. [4]

Patients with hepatic dysfunction may require a lower dose of DEX than healthy subjects to achieve a similar response, given the extensive hepatic metabolism of DEX. [14] As such, caution should be exercised when coadministering DEX with other sedatives, analgesics, vasodilators, or other negative chronotropic medications. [4] DEX is not recommended for microvascular free flap procedures, as α2 agonists may cause direct vasoconstriction and reduction in flap blood flow.[14] For the same reason, its use in neurovascular patients or those considered at high risk of vasospasm is not recommended. It is not indicated in recent acute epilepsy or uncontrolled seizure activity.

The teratogenic effects of DEX have not been adequately studied at this time, but the drug does cross the placenta and should be used during pregnancy or breast feeding only if the benefits justify the risk to the fetus. [5],[9]

In nutshell: [Figure 5] and [Figure 6]
Figure 5: Established indications

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Figure 6: Future role

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