SENIOR, BAESSLER, AND MONZO
`
`Esmolol, the first ultra-short-acting intravenous beta
`blocker for use in critically ill patients
`
`Lori Blanski, RN, MA, Joan Lutz, RN, BSN, and Atul Laddu, MD,
`Waukegan, Ill.
`
`,6-Adrenergic blockade is well recognized as a
`therapeutic tool in acute care settings for the
`
`From Du Pont Critical Care.
`Reprint requests: Lori Bianski, RN, MA, Du Pont Critical Care,
`1600 Waukegan Rd., Waukegan, Ill. 60085.
`
`treatment of supraventricular tachyarrhythmias
`(SVT), ischemic heart disease, and hypertension.
`,6-Blockers compete with adrenergic mediators for
`,6-adrenergic receptors: ,61 receptors of heart mus(cid:173)
`cle and ,62rreceptors of bronchial and vascular
`smooth muscle. With these ~eceptor sites blocked,
`
`80
`
`JANUARY 1988, VOL. 17, No.1
`
`MYLAN ET AL. - EXHIBIT 1010
`
`

`
`ESMOLOL, A TITRATABLE SHORT-ACTING BETA BLOCKER
`
`the chemical mediators of the sympathetic nervous
`system, norepinephrine and epinephrine, are un(cid:173)
`able to activate the receptor site and therefore
`cannot initiate the responses (such as chronotrop(cid:173)
`ic, inotropic, electrophysiologic, vasodilator, and
`bronchodilator responses) to J3-adrenergic stimu(cid:173)
`lation.1.2
`J3-Blockers may possess the properties of 13,(cid:173)
`and J32-selectivity,
`intrinsic sympathomimetic
`activity (ISA) and membrane-stabilizing activity
`(MSA).1.2 Cardioselective J3-blockers (e.g., meto(cid:173)
`prolol, atenolol) predominantly block the 131-
`receptors and are preferred in patients with
`peripheral vascular disease, chronic lung disease,
`and insulin-dependent diabetes mellitus. Noncar(cid:173)
`dioselective J3-blockers (e.g., propranolol, nadolol)
`block the effects of epinephrine and norepineph(cid:173)
`rine on both 13,- and J32-receptors.
`13-Blockers with ISA possess both partial ago(cid:173)
`nist activity and J3-blocking activity. ISA thus
`provides some degree of adrenergic stimulation in
`addition to blockade of J3-receptor sites. Conse(cid:173)
`quently, agents with this property reduce resting
`heart rate and myocardial contractility to a lesser
`degree than do agents without this property." 2
`The
`local anesthetic membrane-stabilizing
`effect on cardiac action potential possessed by
`some J3-blockers is similar to that exerted by
`quinidine. This property, known as MSA, is
`exhibited when very high doses of a J3-blocker are
`administered. Generally, MSA is present clinical(cid:173)
`ly only during incidents of J3-blocker intoxication
`and is not responsible for the antiarrhythmic
`action of these agents." 2
`Propranolol and metoprolol, the only other
`currently available intravenous J3-blockers, have
`relatively long elimination half-lives. Esmolol
`(Brevibloc), a new short-acting intravenous car(cid:173)
`dioselective J3-blocker with no significant ISA or
`MSA-, has recently been approved by the U.S.
`Food and Drug Administration and is available
`for clinical use. Structurally, esmolol is similar to
`other J3-blockers except for the ester linkage
`responsible for its short elimination half-life (9
`minutes).3 This short half-life allows for titration
`to desired effect and rapid reversal of J3-blockade
`after discontinuation of esmolol, thus providing an
`element of safety and control in treating critically
`ill patients. The purpose of this review is to
`discuss the pharmacokinetics, pharmacodynamics,
`and clinical use of esmolol.
`
`PHARMACOKINETICS
`Unlike most J3-blockers, which are metabolized
`by the liver, esmolol is metabolized by esterases
`located in red blood cells. Metabolism of esmolol
`
`results in the formation of an acid metabolite
`(ASL-8123) and methano1. 4 The acid metabolite
`exhibits only Y1soo of the activity of esmolol, with no
`noticeable J3-blocking effects observed at the time
`of peak concentration of the metabolite (30
`minutes after infusi011V Methanol blood levels
`have been found to be within endogenous levels
`and are less than 2% of those levels associated with
`methanol toxicity. 5
`Esmolol has a rapid distribution half-life of
`appreximately 2 minutes, and blood levels in(cid:173)
`crease linearly with dose. Total body clearance is
`approximately 20 L/kg/hr, consistent with the
`nonhepatic route of metabolism. In accordance
`with the high rate of metabolism in the blood, less
`than 2% of the drug is excreted unchanged in the
`urine. Esmolol has been shown to be 56% bound
`to human plasma protein, whereas the acid
`metabolite is only 7% bound,6 indicating that there
`would not be a significant change in the kinetics of
`esmolol and other drugs.
`With the use of an appropriate 1-minute load(cid:173)
`ing dose (500 J,Lg/kg/min), steady state blood
`concentration (1.59 J,Lg/ml) of esmolol is achieved
`within 5 minutes, is well maintained during
`infusion, and decreases rapidly after termination
`of the infusion. Esmolol blood levels of 0.3 and 1
`J,Lg/ml have been shown to produce reductions in
`heart rate (HR) of 50% and 80% and reductions
`in blood pressure (BP) of 30% and 50%, respec(cid:173)
`tively. Blood levels of esmolol are quickly altered
`by, a change in infusion rate or rapidly eliminated
`by discontinuing the infusion. 4
`Since the liver is not involved in the disposition
`of esmolol and clearance is almost entirely by
`nonrenal routes, the pharmacokinetic profile of
`esmolol in patients with hepatic disease (cirrhosis)
`and end-stage renal disease does not differ from
`•s On the other hand, the
`that of normal subjects. 7
`acid metabolite of esmolol is cleared by the kidney,
`and hence severe renal impairment increases the
`maximum blood concentration of this metabolite
`and its elimination half-life is prolonged tenfold.
`Severe hepatic disease has also been shown to
`increase maximum blood concentration of the acid
`metabolite. Consequently, care should be taken
`when esmolol is administered to patients with
`decreased renal or hepatic function.
`The pharmacokinetic profile of esmolol was
`evaluated at steady state levels in the presence of
`digoxin, morphine, and warfarin. Concurrent
`administration of intravenous digoxin and esmolol
`to normal volunteers resulted in a 10% to 20%
`increase in digoxin blood levels at some time
`points. Digoxin had no effect on esmolol pharma(cid:173)
`cokinetics. 9 When
`intravenous morphine and
`
`HEART & LUNG
`
`81
`
`

`
`110
`
`1011
`
`100
`
`911
`
`90
`
`E .. 85
`
`.c
`
`80
`
`75
`
`70
`
`811
`
`80
`
`BASELINE 2
`
`4
`
`8
`
`12
`
`18 FOLLOW-UP
`
`ESMOLOL (mg/mln)
`
`Fig. 1. Individual changes in HR with esmolol infusion in
`10 patients. Follow-up took place 10 to 30 minutes after
`cessation of infusion. Vertical bars indicate mean ± SEM.
`
`esmolol were administered concurrently, no effect
`on morphine blood levels was seen; however,
`esmolol blood levels increased by 46%. Similarly,
`concomitant administration of esmolol and warfa(cid:173)
`rin did not influence warfarin plasma levels, and
`esmolol concentrations were modestly increased.
`Succinylcholine, a short-acting muscle relaxant
`dependent on plasma cholinesterases for its rapid
`hydrolysis and inactivation, is commonly used
`during induction of anesthesia to facilitate rapid
`endotracheal intubation. Since the effects of succi(cid:173)
`nylcholine may be altered by inhibition of plasma
`cholinesterases by esmolol, an interaction study
`was undertaken in surgical patients. Esmolol was
`shown to have no significant effect on the develop(cid:173)
`ment of neuromuscular blockade, although the
`duration of blockade was prolonged by a period of
`3 minutes (from 5 to 8 minutes), which is still
`considered to be within the clinically accepted
`normal range. The digoxin, morphine, warfarin,
`and succinylcholine interactions with esmolol
`were considered clinically insignificant; neverthe(cid:173)
`less, caution is advised when esmolol is adminis(cid:173)
`tered to patients who are being treated with these
`agents. The short half-life of esmolol does, how(cid:173)
`ever, allow for rapid alteration in esmolol blood
`concentration by a simple decrease in the infusion
`rate or discontinuation of the infusion if an
`adverse effect appears.
`
`PHARMACODYNAMICS
`The relative cardioselectivity of esmolol in com(cid:173)
`parison with propranolol was demonstrated in
`patients with asthma and chronic obstructive
`
`BLANSKI, LUTZ, ANDLADDU
`
`180
`
`11111
`
`1110
`
`1411
`
`140
`
`.. 1311
`
`:I:
`E
`E
`
`130
`
`125
`
`120
`
`1111
`
`110
`
`1011
`
`100
`
`BASELINE 2
`
`12
`8
`ESMOLOL (mg/mln)
`
`18 FOLLOW-UP
`
`Fig. 2. Individual changes in arterial SBP with esmolol
`infusion in 10 patients. Follow-up took place 10 to 30
`minutes after cessation of infusion. Vertical bars indicate
`mean ± SEM.
`
`pulmonary disease (COPD).!O In mildly asthmatic
`patients, therapeutically effective esmolol infu(cid:173)
`sions ranging from 100 to 300 ,ug/kg/min pro(cid:173)
`duced no significant increase in specific airway
`resistance in comparison with placebo. The bron(cid:173)
`chospastic potential of propranolol, however, was
`demonstrated when two of six patients receiving 1
`mg of propranolol experienced significant, symp(cid:173)
`tomatic bronchospasm requiring bronchodilator
`treatment. Furthermore, no adverse pulmonary
`effects were reported in patients with mild COPD
`(N = 51) who received esmolol for the treatment
`of SVT or during
`the perioperative period
`(N = 32).
`Because of the cardioselectivity of esmolol, there
`are important clinical indications for the treat(cid:173)
`ment of critically ill patients who frequently have
`a history of mild COPD or asthma. Rapid rever(cid:173)
`sal of action, in conjunction with the relative
`cardioselectivity of esmolol, allows safe initiation
`of ,B-blockade, if indicated, in these high-risk
`patients. Since ,B-selectivity is not absolute, esmo-
`101 should be carefully titrated to obtain the lowest
`If airway resistance
`possible effective dose.
`increases significantly during esmolol infusion)
`the infusion should be reduced or discontinued
`and an appropriate ,B2-stimulating agent adminis(cid:173)
`tered.
`The pharmacodynamics of esmolol in patients
`with acute myocardial
`ischemia
`(myocardial
`infarction, postmyocardial infarction angina, or
`acute unstable angina) has also been evaluated. ll
`
`82
`
`JANUARY 1988, VOL. 17, No.1
`
`

`
`ESMOLOL, A TITRATABLE SHORT-ACTING BETA BLOCKER
`
`A clinically significant reduction in mean HR
`(pretreatment, 92 ± 11 beats/min;
`treatment,
`83 ± 11 beats/min) occurred within the first 5
`minutes of esmolol titration (50 ,ug/kg/min), with
`maximum reduction in HR observed at a mainte(cid:173)
`nance dose of 150 ,ug/kg/min. Similar reductions
`in systolic blood pressure (SBP) and diastolic
`blood pressure (15% and 13%, respectively)
`occurred at the end of titration. Maximum reduc(cid:173)
`tion in HR occurred at doses below those causing
`maximal reduction in BP. Consistent with the
`decrease in HR and BP, there was a significant
`decrease in rate-pressure product. No effect on left
`ventricular filling pressure or systemic vascular
`resistance was noted, but cardiac index decreased
`significantly by the end of titration (2.8 ± 0.6 to
`2.2 ± 0.6 L/min/m2). Because of the short elimi(cid:173)
`nation half-life of esmolol, all hemodynamic
`parameters returned to near baseline levels within
`30 minutes after the infusion was terminated.
`In the same study, six of eight patients receiving
`concurrent administration of intravenous nitro(cid:173)
`glycerin and esmolol required discontinuation of
`nitroglycerin therapy to maintain SBP at 90 mm
`Hg or greater. Although SBP rapidly increased in
`response to the termination of nitroglycerin infu(cid:173)
`sion, close monitoring of a patient's hemodynamic
`state is recommended during concomitant admin(cid:173)
`istration of these two agents. If required, the
`dosage of either esmolol or nitroglycerin may be
`adjusted to maintain SBP.
`Patients admitted to critical care areas with
`varying degrees of left ventricular dysfunction
`may be candidates for the use of {3-blocking
`agents. Depression of the myocardium as a result
`of prolonged {3-blockade can, however, lead to
`cardiac failure. Thus the short half-life of esmolol
`also makes it useful in the therapeutic armamen(cid:173)
`tarium for these patients when the drug is proper(cid:173)
`ly administered.
`Ten patients with a diagnosis of coronary
`artery disease and left ventricular dysfunction
`assessed by means of radionuclide angiography or
`contrast angiography were infused with incre(cid:173)
`mental doses of 2 to 16 mg/min of esmolol
`(equivalent to 25 to 200 ,ug/kg/min in an 80 kg
`patient).12 Nine of ten patients had a history of
`recent (range, 2 to 27 days) myocardial infarction
`with postinfarction angina. Baseline left ventricu(cid:173)
`lar ejection fraction (L VEF) was less than 25% in
`five patients and between 25% and 36% in the
`remaining five patients. Significant decreases in
`HR and BP occurred at the lowest doses (2 and 4
`mg/min, respectively), as shown in Figs. 1 and 2.
`At the maximum dose titrated (16 mg/min),
`
`!z
`w o
`
`II:
`W
`0..
`
`40
`
`36
`
`30
`
`26
`
`20
`
`15
`
`10~----~------~----'-----~-------
`16
`FOLLOW-UP
`BASELINE
`8
`
`ESMOLOL (mg/mln)
`
`Fig. 3. Individual changes in L VEF with esmolol infusion
`in 10 patients. In some patients the ejection fraction was also
`measured at a dose of 8 mg/min. Follow-up took place 10 to
`30 minutes after cessation of infusion. Vertical bars indicate
`mean ± SEM.
`
`esmolol produced a significant increase from base(cid:173)
`line in pulmonary artery wedge pressure (11 ± 1
`to 15 ± 2 mm Hg), mean pulmonary artery
`pressure (17 ± 2 to 22 ± 2 mm Hg), and mean
`right atrial pressure (8 ± 1 to 10 ± 1 mm Hg), as
`well as a significant decrease from baseline in
`cardiac output (4.9 ± 0.3 to 4.3 ± 0.3 L/min),
`accompanied by an increase in systemic vascular
`(15 ± 1.7
`to 16.9 ± 1.2 dynes.
`rooistance
`sec. cm-S
`).
`Ejection fraction measurements obtained dur(cid:173)
`ing infusion of the 8 and 16 mg/min doses
`revealed that esmolol produced a significant
`decrease in LVEF, with more marked changes at
`the 16 mg/min dose than at the 8 mg/min dose
`(Fig. 3). Despite
`this
`finding, all patients
`remained asymptomatic. As evidenced by signifi(cid:173)
`cant HR reduction (91 ± 4 beats/min at baseline;
`85 ± 4 beats/min at 2 mg/min), {3-blockade was
`achieved in these ischemic patients at do~es well
`below those which produced peak hemodynamic
`deterioration (i.e., 16 mg/min). Thus the titrata(cid:173)
`bility of esmolol allows for control of {3-blockade
`without the danger of further reduction of L VEF
`in patients with low LVEF. The esmolol dose
`increment should be very gradual in such patients.
`Bedside hemodynamic monitoring is suggested if
`higher doses are used. Furthermore, caution is
`advised during the administration of esmolol ip.
`patients who have more severe left ventricular
`dysfunction than those evaluated in this study.
`When SVT patients were divided into two age
`
`HEART & LUNG
`
`83
`
`

`
`BLANSKI, LUTZ, AND LADDU
`
`w 80
`(J) z o
`3; 60
`w
`a:
`o
`i=
`:::l
`W a.
`<C a: w
`
`::I:
`0
`I-
`DOSE
`(meg/kg/min)
`
`50
`
`100
`
`150
`
`250
`
`300·
`
`Fig. 4. Percentage of efficacy-study patients with therapeutic response during initial and
`crossover esmolol titration periods by esmolol dosage.
`
`groups «65 or >65 years of age), no difference in
`response to esmolol or incidence of hypotension
`with esmolol treatment was found. Moreover,
`recovery of HR after discontinuation of the esmo-
`101 infusion was similar for both groups.
`
`CLINICAL INDICATIONS
`Supraventricular tachycardia. The efficacy
`and safety of esmolol infusions has been investi(cid:173)
`gated in patients with SVT (atrial flutter, atrial
`fibrillation, and sinus tachycardia) in several
`wall-controlled
`(placebo
`and
`propranolol)
`studies. 13
`16 Maintenance doses administered in
`-
`the·se studies ranged from 25 to 300 ,ug/kg/min,
`each preceded by a i-minute 500,ug/kg/min
`loading dose. Criteria for desired therapeutic
`effect included 20% reduction in HR, decrease in
`HR to less than 100 beats/min, or conversion to
`normal sinus rhythm. Esmolol was found to be
`superior to placebo in the treatment of SVTY
`Sixty-two percent of patients (38/61) achieved a
`therapeutic response at an esmolol dose <200
`,ug/kg/min. As shown in Fig. 4, the increase in
`percentage of responders beyond the 200 ,ug/
`kg/min dose was minimal.
`Esn;l.Olol administered by continuous infusion
`has also been found to be as effective as propran(cid:173)
`olol (3 to 6 mg intravenous bolus) in controlling
`HR, and it compared favorably with propranolol
`in co~version to- normal sinus rhythm in patients
`with SVT.14 Consistent with its brief duration of
`action, recovery from ,B-blockade during the post
`infusion period occurred within 10 minutes in
`esmolol-treated patients. In contrast, ,B-blockade
`persisted for 411z hours after the administration of
`propranolol. Therapeutic response was achieved
`in 70% of esmolol-treated patients (35/50) at
`
`doses of 200 ,ug/kg/min or less (Fig. 5). Further(cid:173)
`more, esmolol was well tolerated in patients with
`SVT during infusion for up to 24 hours. IS. 16
`Incremental doses of esmolol from 2 to 16
`mg/min for 10 minutes each, after 30-second
`loading doses of 10 or 20 mg boluses, have been
`shown to compare favorably with verapamil (5 or
`10 mg intravenous boluses) in the short-term
`treatment of patients with atrial fibrillation and
`flutterY Of 11 patients, nine (82%) achieved a
`ventricular rate of <100 beats/min in the esmo(cid:173)
`lol-treated group, in comparison with 5 of 10
`(50%) in the verapamil-treated group. Side effects
`(asymptomatic and symptomatic hypotension)
`were reported in 27% of the esmolol-treated and
`60% of the verapamH-treated patients.
`Potential risks have recently been reported with
`the use of intravenous verapamilfor treatment of
`atrial flutter and fibrillation when the underlying
`arrhythmia is incorrectly identified or the pres(cid:173)
`ence of a bypass tract is not identified. 18
`20 These
`-
`reports include patients with atrial fibrillation
`and unrecognized Wolff-Parkinson-White syn(cid:173)
`drome in whom verapamil therapy resulted in
`ventricular fibrillation or a marked increase in
`ventricular rate with consequent profound hypo(cid:173)
`tension. Furthermore, the onset of severe hypoten-
`. sion requiring emergency cardioversion after ver(cid:173)
`apamil therapy in patients with ventricular tachy(cid:173)
`cardia misdiagnosed as SVT with· aberrant
`ventricular conduction has also been reported.
`Consequently, if the hemodynamic status of the
`patient does not allow time for a thorough assess(cid:173)
`ment of the arrhythmia, cardioversion, rather than
`treatment with verapamil, is now indicated.
`Since esmolol has a rapid onset and offset of
`action, is easily titratable, and has compared
`
`84
`
`JANUARY 1988, VOL. 17, No.1
`
`

`
`ESMOLOL, A TITRATABLE SHORT-ACTING BETA BLOCKER
`
`100r---------------------------------------~
`
`lJ:J 80
`~
`0. fa 60
`
`II
`~ 40
`=:I
`W
`
`0. <
`ffi
`i=
`0
`ESMOLOl DOSE 50
`meg/kg/"*'
`PROPRANOlOL DOSE. 3
`mg
`
`.100
`
`150
`
`200
`
`250
`
`300
`
`6
`
`PL
`
`PL
`
`PL
`
`PL
`
`Fig. 5. Percentage of efficacy-study patients with therapeutic response during titration period
`by esmolol dosage. Key: solid bars, esmolol; open bars, propranolol.
`
`150
`
`130
`
`110
`
`E
`c.
`..c
`a: 90
`:I:
`
`70
`
`50
`
`++
`
`Fig. 6. HR changes during endotracheal intubation in pati~nts receiving esmolol (solid bars)
`or placebo (open bars) infusions. Key: *, significant change from baseline (p < 0.05) (maximal
`change from baseline not tested for significance); +, liignificant difference between esmolol and
`placebo with respect to change·from baseline (p < 0.05); ++, significant difference between
`esmolol and placebo with respect to change from baseline (p < 0.01).
`
`favorably with verapamil in controlling ventricu(cid:173)
`lar response in atrial fibrillation and flutter,
`esmolol holds promise as a therapeutic agent for
`such patients. Esmolol has been shown to be safe
`in patients with SVT (sinus tachycardia, atrial
`flutter, and atrial fibrillation)Y-16 Further, the
`safety of esmolol has been adequately documented
`in patients at risk of ,6-blockade.15
`If a desired therapeutic response is not obtained
`with esmolol, the infusion can be discontinued,
`and within 10 to 20 minutes, verapamil therapy
`may be started without concern for coricomitant
`effects of ,6-blockers on the atrioventricular node.
`On the other hand, if verapamil is initiated first
`and a desired therapeutic response is not obtained,
`the 3-
`to 6-hour electrophysiologic actions of
`verapamil would not safely allow ,6-blockade
`.
`therapy for several hours.
`Perioperative tachycardia and hyperten-
`
`sion. In patients with coronary artery disease,
`cardiac stress produced by increases in HR and
`BP during endotracheal intubation and surgical
`stimulation may contribute to perioperative ische(cid:173)
`mia.21 Esmolol has been shown to effectively
`control increases in intraoperative HR and BP. Its
`short duration of action is preferable over that of
`currently available long-acting intravenous ,6-
`blQckers, since the duration of intraoperative car(cid:173)
`diovascular stimulation is short and prolonged
`,6-blockade undesirable.
`In patients undergoing carotid endarterectomy,
`esmolol, given by continuous infusion begun
`befor·e
`induction of anesthesia,
`significantly
`blunted the maximum increases in HR and SBP
`(and hence the rate-pressure product) from base(cid:173)
`line values in comparison with placeho during the
`stimulus of endotracheal intubation (Figs. 6 to
`8).22 Average maximum HRincrease (not shown
`
`HEART 8!'- LUNG
`
`85
`
`

`
`BLANSKI, LUTZ, AND LADDU
`
`++
`
`300
`
`250
`
`CI
`:I:
`E 200
`E
`c..
`III
`f/) 150
`
`100
`
`Fig. 7. SBP changes during endotracheal intubation in patients receiving esmolol (solid bars)
`or placebo (open bars) infusions. Key: *, slgnificaI1t change from baseline (p < 0.05) (maximal
`change from baseline not tested for significance); ++, significant different between esmolol and
`placebo with respect to change from baseline (p < 0.01).
`
`in Fig. 6) in the placebo-treated patients was 24
`beats/min and only 9 beats/min in esmolol~
`treated patients. Average maximal SBP increase
`(not shown in Fig. 7) in the placebo group was 45
`mm Hg, whereas an average increase of 2 mm Hg
`was observed in esmolol-treated patients.
`In patients undergoing coronary artery bypass
`graft surgery, esmolol, given in the same manner
`as above, prevented significant increases in HR
`during induction, intubation, skin incision, sterno(cid:173)
`tomy, and mediastinal dissection in comparison
`with placebo-treated patients and those treated
`with standard therapy (oral calcium-channel
`blockers or oral (3-blockers).
`EsIllolol has also been studied for control of
`postoperative systolic hypertension in cardiac sur(cid:173)
`gery patients.24 Since these patients are commonly
`at risk for such serious complications as bleeding
`from fresh vascular sutures, cerebrovascular hem(cid:173)
`orrhage, and myocardial ischemia or infarction,
`rapid control of arterial hypertension is essential.
`By randomized sequence, patients received either
`a controlled infusion of esmolol (average dose,
`142 ± 100 p,g/kg/min) or nitroprusside (average
`dose, 1.6 ± 1.3 p,g/kg/min). Esmolol rapidly
`achieved a therapeutic response (average 20%
`decrease in SBP) in 11 of 12 hypertensive postsur(cid:173)
`gical patients (pretreatment SBP, 170 ± 12 mm
`Hg; treatment SBP, 136 ± 14 mm Hg) without
`complications. With nitroprusside, systolic pres(cid:173)
`sure decreased from 173 ± 11 mm Hg to 141 ±
`15 mm Hg (average 18% decrease) in 12 of 12
`patients.
`In addition, esmolol was shown to have hemo(cid:173)
`dynamic properties that are considerably different
`from those of nitroprusside. Cardiac index was
`decreased by esmolol (pretreatment, 2.9 ± 0.4
`
`L/min/m2; treatment, 2.2 ± 0.3 L/min/m2) and
`increased by nitroprusside (pretreatment, 3.0 ±
`0.5 L/min/m2; treatment, 3.2 ± 0.5 L/min/m2);
`neither drug significantly changed stroke volume.
`HR was significantly decreased by esmolol (pre(cid:173)
`treatment, 95 ± 9 beats/min; treatment, 82 ± 11
`beats/min). In contrast, HR increased with nitro(cid:173)
`prusside treatment from 97 ± 14 to 104 ± 15
`beats/min. Oxygen saturation and Pao2 were
`unchanged with esmolol, whereas nitroprusside
`treatment resulted
`in undesirable significant
`decreases in Pao2 from 118 ± 25 to 72 ± 15 mm
`Hg and in arterial oxygen saturation from 98 ±
`1 % to 94 ± 3%.
`.
`Because of the contrasting hemodynamic effects
`of these two agents, esmolol may broaden the
`treatment modalities available to the clinician as
`both monotherapy for moderate postoperative
`hypertension and as an adjunct to nitroprusside
`treatment in severe postoperative hypertension. In
`particular, esmolol appears to be an excellent
`agent for postoperative hypertension associated
`with hyperdynamic circulation, such as increased
`HR, cardiac output, and systolic arterial pres(cid:173)
`sure.
`
`SIDE EFFECTS
`Side effects associated with the administration
`of esmolol are, in general, mild and reversible.
`Known side effects are discussed below by body
`system.
`Cardiovascular effects. Symptomatic hypo(cid:173)
`tension (diaphoresis, dizziness) occurred in 12% of
`SVT patients treated with esmolol. Of these, only
`6% required discontinuation of esmolol therapy.
`Asymptomatic hypotension occurred in 25% of
`SVT patients. Hypotension resolved during the
`
`86
`
`JANUARY 1988, VOL. 17, No.1
`
`

`
`ESMOLOL, A TITRATABLE SHORT-ACTING BETA BLOCKER
`
`30
`
`Q.
`Q.
`0::
`
`++
`
`BASELINE
`
`PRE-
`PRE-
`INDUCTION INTUBATION
`
`MAXIMUM
`
`POST
`INF 2
`
`POST
`INF 5
`
`Fig. 8. Rate-pressure product changes during endotracheal intubation in patients receiving
`esmolol (solid bars) or placebo (open bars) infusions. Key: *, significant change from baseline
`(p < 0.05) (maximal change from baseline was not tested for significance); +, significant
`difference between esmolol and placebo with respect to change from baseline (p < 0.05); ++,
`significant different between esmolol and placebo with respect to change from baseline
`(p < 0.01).
`
`esmolol infusion in 63% of these patients and
`within 30 minutes after discontinuation of infu(cid:173)
`sion in 80% of the remaining patients.
`An increasing risk of developing hypotension
`has been observed with increasing esmolol dosage,
`particularly beyond the 200 p,g/kg/min dose.
`Thus the esmolol dose increment should be grad(cid:173)
`ual and BP carefully monitored. Care should be
`taken when esmolol therapy is initiated in patients
`with low pretreatment BPs.
`Central nervous system effects. Adverse
`effects on the central nervous system are infre(cid:173)
`quent and include somnolence, confusion, head(cid:173)
`ache, agitation, fatigue, paresthesia, asthenia,
`depression, abnormal thinking, anxiety, anorexia,
`and light-headedness. One brief (30-second) epi(cid:173)
`sode of grand mal seizure has been reported.
`Respiratory effects. Respiratory complications
`with- esmolol are rare and include bronchospasm,
`wheezing, dyspnea, nasal congestion, rhonchi, and
`rales.
`Gastrointestinal effects. Seven percent of
`patients studied experienced nausea. The occur(cid:173)
`rence of vomiting, dyspepsia, constipation, dry
`mouth, or abdominal discomfort is rare.
`Skin effects. Irritation (inflammation and
`induration) at the site of infusion has been report(cid:173)
`ed in approximately 8% of patients studied, but it
`can be managed by avoiding the administration of
`esmolol concentrations > 10 mg/ml (see the dis(cid:173)
`cussion of administration and dosage, below), or
`by changing the site of infusion. The use of
`butterfly needles should be avoided because they
`may cause injury to the vein.
`
`PATIENTS AT RISK WHEN TREATED WITH
`{j-BLOCKERS
`One hundred fifteen patients with disorders
`that are associated with a degree of risk by
`',B-blockade (i.e., congestive heart failure, COPD,
`asthma, diabetes mellitus, renal and hepatic dys(cid:173)
`function, and atrioventricular block greater than
`first degree) have received esmolol at the discre(cid:173)
`tion of their physician in clinical trials. These
`existing conditions were not exacerbated by esmo(cid:173)
`IQI in any patient.
`
`ADMINISTRATION AND DOSAGE
`Administration
`Esmolol is a potent drug that must be diluted
`before infusion and is compatible with the following
`commonly used intravenous fluids at a final
`concentration of 10 mg/ml: dextrose (5 % ) injection,
`USP; dextrose (5%) in Ringer's injection; dextrose
`(5%) and sodium chloride (0.45%) injection, USP;
`dextrose (5%) and sodium chloride (0.9%) injection,
`USP; lactated Ringer's injection, USP; potassium
`chloride (40 mEq/L) in dextrose (5%) injection;
`sodium chloride (0.45%) injection, USP; sodium
`chloride (0.9%) injection, USP. Esmolol is not
`compatible with sodium bicarbonate (5%) injection
`(USP) and should not be admixed with other drugs
`before dilution.
`
`Dosage
`A loading dose of esmolol (500 p,g/kg/min for 1
`minute) is required to rapidly attain steady-state
`blood levels and the desired hemodynamic effect.
`tachycardia. The usual
`Supraventricular
`
`HEART & LUNG
`
`87
`
`

`
`effective dosage of esmolol for the treatment of
`SVT is 50 to 200 JLg/kg/min, although dosages as
`high as 300 JLg/kg/min have been used. In some
`patients a dosage of 25 JLg/kg/min has been
`adequate to control rapid ventricular response. To
`initiate the treatment of a patient with SVT, one
`should administer a loading infusion of 500 JLg/
`kg/min of esmolol for 1 minute, followed by a 50
`JLg/kg/min maintenance infusion for 4 minutes. If
`an adequate therapeutic effect is not observed
`within 4 minutes at the 50 JLg/kg/min dose, the
`same 1-minute loading dose of 500 JLg/kg/min
`should be repeated, followed with an increase in
`the maintenance infusion to 100 JLg/kg/min for 4
`minutes. The titration should be continued with
`the use of 50 JLg/kg/min maintenance infusion
`increments, each preceded by a 1-minute loading
`infusion of 500 JLg/kg/min. As the desired HR or
`a safety end point such as low BP is approached,
`the initial 1-minute loading infusion of 500 JLg/
`kg/min should not be given, and the next incre(cid:173)
`ment in dosage should be reduced from 50 to 25
`JLg/kg/min or lower. Alternatively or in addition,
`the interval between dose increments may be
`extended from 4 to 10 minutes. Maintenance
`dosages above 200 JLg/kg/min have shown little
`additional benefit and are not recommended. In
`the event of an adverse reaction, the dosage of
`esmolol may be reduced or discontinued. Safe
`infusion of esmolol for up to 24 hours has been
`well documented.
`In addition,
`limited data
`regarding infusions ranging from 24 to 48 hours
`in duration (48 patients) indicate that esmolol is
`well tolerated up to 48 hours.
`Abrupt cessation of esmolol has not been
`reported to produce the withdrawal effects com(cid:173)
`monly observed with abrupt withdrawal of {3-
`blockers after long-term use patients with coro(cid:173)
`nary artery disease. Caution must still be used
`when esmolol is discontinued under these circum(cid:173)
`stances.
`After adequate control of HR and a stable
`clinical status are achieved in patients with SVT,
`a transition to alternative antiarrhythmic agents
`such as propranolol, digoxin, and verapamil may
`be accomplicated.
`The dosage of esmolol before transfer should be
`reduced as follows:
`1. Within the first hour after the first dose of
`the alternative agent, the esmolol infusion
`rate should be reduced by one half.
`2. After the second dose of the alternative
`agent, the patient's response should be mon(cid:173)
`itored, and if satisfactory control is main(cid:173)
`tained for the first hour, the esmolol infusion
`should be discontinued.
`
`BLANSKI, LUTZ, AND LADDU
`
`A recommended guideline for transition to an
`alternative antiarrhythmic agent is given below,
`but labeling instructions for the agent selected
`should be carefully considered:
`
`Alternate agent
`Propranolol hydrochloride
`Digoxin (oral or IV)
`Verapamil
`
`Dosage
`10-20 mg every 4-6 hr
`0.125-0.5 mg every 6 hr
`80 mg every 6 hr
`
`Perioperative tachycardia and hyperten(cid:173)
`sion. In perioperative settings (such as induction,
`intratracheal intubation, and surgical manipula(cid:173)
`tions) where it is not possible to titrate esmolol to
`the desired therapeutic effect, esmolol has been
`infused in a loading dosage of 500 JLg/kg/min for
`4 minutes to achieve desired blood levels rapidly,
`followed by a maintenance dosage of 200 to 300
`JLg/kg/min. If necessary, the dosage may be
`subsequently reduced. The hypotensive effects of
`inhalation anesthetic agents m