Cardiac Intensive Care
`
`Dexmedetomidine use in a pediatric cardiac intensive care unit:
`Can we use it in infants after cardiac surgery?
`
`Constantinos Chrysostomou, MD; Joan Sanchez De Toledo, MD; Tracy Avolio, CCRN; Maria V. Motoa, MD;
`Donald Berry, BS, RPh; Victor O. Morell, MD; Richard Orr, MD; Ricardo Munoz, MD
`
`Objective: To assess clinical response of dexmedetomidine
`alone or in combination with conventional sedatives/analgesics
`after cardiac surgery.
`Design: Retrospective study.
`Setting: Pediatric cardiac intensive care unit.
`Patients: Infants and neonates after cardiac surgery.
`Measurements and Main Results: We identified 80 patients
`including 14 neonates, at mean age and weight of 4.1 ⴞ 3.1
`months and 5.5 ⴞ 2 kg, respectively, who received dexmedeto-
`midine for 25 ⴞ 13 hours at an average dose of 0.66 ⴞ 0.26
`␮g䡠kgⴚ1䡠hrⴚ1. Overall normal sleep to moderate sedation was
`documented 94% of the time and no pain to mild pain for 90%.
`Systolic blood pressure (SBP) decreased from 89 ⴞ 15 mm Hg to
`85 ⴞ 11 mm Hg (p ⴝ .05), heart rate (HR) from 149 ⴞ 22 bpm to
`129 ⴞ 16 bpm (p < .001), and respiratory rate (RR) remained
`unchanged. When baseline arterial blood gases were compared
`with the most abnormal values, pH decreased from 7.4 ⴞ 0.07 to
`7.37 ⴞ 0.05 (p ⴝ .006), PO2 from 91 ⴞ 67 mm Hg to 66 ⴞ 29
`mm Hg (p ⴝ .005), and CO2 increased from 45 ⴞ 8 mm Hg to 50ⴞ
`12 mm Hg (p ⴝ .001). At the beginning of the study, 37 patients
`(46%) were mechanically ventilated; and at 48 hours, 13 patients
`
`intubated and five patients failed extubation.
`(16%) were still
`Three groups of patients were identified: A, dexmedetomidine
`only (n ⴝ 20); B, dexmedetomidine with sedatives/analgesics
`(n ⴝ 38); and C, dexmedetomidine with both sedatives/analgesics
`and fentanyl infusion (n ⴝ 22). The doses of dexmedetomidine
`and rescue sedatives/analgesics were not significantly different
`among the three groups but duration of dexmedetomidine was
`longer in group C vs. A (p ⴝ .03) and C vs. B (p ⴝ .002). Pain,
`sedation, SBP, RR, and arterial blood gases were similar. HR was
`higher in group C vs. B (p ⴝ .01). Comparison between neonates
`and infants showed that infants required higher dexmedetomidine
`doses, 0.69 ⴞ 25 ␮g䡠kgⴚ1䡠hrⴚ1, and vs. 0.47 ⴞ 21 ␮g䡠kgⴚ1䡠hrⴚ1
`(p ⴝ .003) and had lower HR (p ⴝ .01), and RR (p ⴝ .009), and
`higher SBP (p < .001).
`Conclusions: Dexmedetomidine use in infants and neonates
`after cardiac surgery was well tolerated in both intubated and
`nonintubated patients. It provides an adequate level of sedation/
`analgesia either alone or in combination with low-dose conven-
`tional agents. (Pediatr Crit Care Med 2009; 10:654 – 660)
`KEY WORDS: sedation; analgesia; infants; dexmedetomidine; car-
`diac surgery; intensive care unit; neonates
`
`P roviding sedation and analge-
`
`sia in children after cardiac
`surgery can be challenging. Al-
`though our knowledge about
`sedative agents and their cardiorespira-
`tory interactions has improved during
`the last two decades, delivering optimal
`sedation in the postoperative period re-
`
`From the Department of Pediatrics and Critical
`Care Medicine, Division of Cardiac Intensive Care (CC,
`JSDT, TA, RM, DO, MVM, DB) and Department of
`Cardiothoracic Surgery (VOM), Children’s Hospital of
`Pittsburgh of the University of Pittsburgh Medical Cen-
`ter, Pittsburgh, PA.
`Supported, partially, by Hospira, Inc. Lake Forest, IL.
`This study was performed at Cardiac Intensive
`Care Unit, Children’s Hospital of Pittsburgh of
`the
`University of Pittsburgh Medical Center.
`The authors have not disclosed any potential con-
`flicts of interest.
`For information regarding this article, E-mail:
`chrycx@chp.edu
`Copyright © 2009 by the Society of Critical Care
`Medicine and the World Federation of Pediatric Inten-
`sive and Critical Care Societies
`DOI: 10.1097/PCC.0b013e3181a00b7a
`
`654
`
`mains complex. Some of the factors that
`add to this complexity are the presence of
`an unpredictable and potentially labile
`physiology after cardiopulmonary bypass
`and the inability to accurately assess an
`infant’s level of sedation.
`In our institution, a successful effort
`for fast track and early extubation has
`been in place for the last 5 yrs. Nonethe-
`less, a significant proportion of patients
`remain, who could further benefit from
`newer sedative agents with a better safety
`profile and less respiratory depression.
`This is important for infants with both
`univentricular and biventricular physiol-
`ogy and particularly the ones which are
`extubated or near extubation. Dexme-
`detomidine is a highly specific alpha-2
`adrenergic receptor agonist with seda-
`tive, analgesic, and anxiolytic properties
`(1). It does not appear to significantly
`depress respiratory drive, thus interfer-
`ence with weaning from mechanical ven-
`tilation is less likely. In fact, it has been
`used both as a bridge to extubation as
`
`well as in nonintubated patients (2, 3). In
`our previous study, which was mainly
`focused on older children after cardiotho-
`racic surgery, dexmedetomidine was
`found to be well tolerated and provided
`targeted sedation and analgesia for 93%
`and 83% of the time, respectively (2). We
`describe our experience with the use of
`dexmedetomidine in a much younger and
`rather more difficult population: Infants,
`and neonates after congenital cardiac
`surgery.
`
`MATERIALS AND METHODS
`
`This retrospective case series study was
`approved by the Institutional Review Board of
`the University of Pittsburgh Medical Center/
`Children’s Hospital of Pittsburgh. To follow
`our institution’s policy, parental
`informed
`consent for investigational use of a drug was
`obtained for all patients younger than 1 year.
`Infants and neonates who were admitted to
`the cardiac intensive care unit (CICU) from
`January 2004 to May 2007 and had received
`dexmedetomidine were included.
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
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`Amneal Pharmaceuticals LLC – Exhibit 1045 – Page 654
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`

`
`Dexmedetomidine was started as a con-
`tinuous infusion, at a dose of 0.1–1.25
`␮g䡠kg⫺1䡠hr⫺1. If it was considered necessary, a
`1 ␮g/kg bolus at a rate of 0.1 ␮g䡠kg⫺1䡠min⫺1
`was given. According to the clinical practice in
`our CICU, the decision to give a bolus and the
`exact initial infusion dose was based on the
`physician’s judgment and the level of sedation
`that the patient had before the initiation of the
`infusion, i.e., the degree of residual intraoper-
`ative anesthesia. Twenty minutes after the on-
`set of the infusion, if sedation/analgesia were
`considered inadequate by the bedside nurse
`and by the physician on duty, dexmedetomi-
`dine infusion was increased by 0.1– 0.3
`␮g䡠kg⫺1䡠hr⫺1. If sedation/analgesia was still
`inadequate 20 minutes after the change of the
`infusion dose, a rescue agent was adminis-
`tered if necessary, and dexmedetomidine infu-
`sion was further increased to a maximum of
`1.5 ␮g䡠kg⫺1䡠hr⫺1. The maximum infusion
`dose of 1.5 ␮g䡠kg⫺1䡠hr⫺1 was a consensus de-
`cision among the intensivists and pharmacists
`involved with the care of CICU patients. Given
`the lack of an established sedation protocol
`and the diversity of our patient population, the
`rescue agents were multiple and included fen-
`tanyl, morphine, midazolam, lorazepam, ket-
`amine, and chloral hydrate.
`Heart rate (HR), systolic blood pressure
`(SBP), respiratory rate (RR), and sedation and
`analgesia scores were recorded by the nursing
`staff at baseline, i.e., measurement within 1
`hour before starting dexmedetomidine, and
`every hour thereafter. Arterial blood gas (ABG)
`results also were recorded every 1– 4 hrs as
`clinically indicated. A hypertensive or hypo-
`tensive episode was defined as a 30% change
`from baseline and/or if the SBP was below or
`
`Table 1. Cardiac diagnosis/procedures performed
`
`Tetralogy of Fallot
`Coarctation of the aorta
`VSD with or without ASD
`Atrioventricular septal defect
`Glenn
`Hypoplastic or interrupted aortic
`arch and VSD
`Norwood stage I (HLHS)
`Total anomalous pulmonary venous
`return
`Pulmonary valvotomy and VSD
`Blalock-Taussig shunt
`Transposition of the great arteries
`Aortopulmonary window
`Right ventricle to pulmonary artery
`conduit
`Left pulmonary artery augmentation
`Othera
`
`n (%)
`
`19 (24)
`14 (17.5)
`12 (15)
`9 (11)
`9 (11)
`3 (4)
`
`2 (2.5)
`2 (2.5)
`
`2 (2.5)
`2 (2.5)
`1
`1
`1
`
`1
`2
`
`ASD, atrial septal defect; HLHS, hypoplastic left
`heart syndrome; VSD, ventricular septal defect.
`aOne patient s/p cardiac catheterization and
`one with severe pulmonary hypertension.
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
`above the 5th to 95th percentile for age. A
`bradycardic episode was defined as a 30%
`change from baseline and/or if the HR was
`below the fifth percentile for age. Low RR rate
`was defined as a RR below the fifth percentile
`for age. Sedation was assessed using a pediat-
`ric intensive care unit sedation scale ranging
`from 0 to 3 (0, none, alert, or normal sleep,
`easy to arouse; 1, mild sedation, occasionally
`drowsy, easy to arouse; 2, moderate sedation,
`frequently drowsy but easy to arouse; 3, severe
`sedation, somnolent, difficult to arouse). An-
`algesia was assessed with two 0 –10 pain score
`scales: The FLACC (face, legs, activity, cry, and
`consolability) for patients older than 2 months
`old, and the CRIES (cries, requires oxygen for
`saturation less than 95%, increased vital signs,
`expression, sleepless) for patients 0 – 6 months
`old (4, 5). A pain score of 0 was considered
`pain free, 1–3 mild pain, 4 –7 moderate pain,
`and 8 –10 severe pain. The targeted level of
`sedation and analgesia was 0 –2 and 0 –3, re-
`spectively. Data were collected for as long as
`the dexmedetomidine infusion was being ad-
`ministered to a maximum of 48 hours.
`Absolute exclusion criteria for the use of
`dexmedetomidine included decompensated
`heart failure, acute hemodynamic instability,
`septic shock, and ventricular arrhythmias.
`Relative exclusion criteria included a high
`RACHS-1 (risk adjustment for congenital
`heart surgery) score, 5 and 6 (6).
`Patients were divided into three groups: A,
`dexmedetomidine only (n ⫽ 20); B, dexme-
`detomidine with sedatives/analgesics (n ⫽ 38);
`and C, dexmedetomidine with both sedatives/
`infusion (n ⫽ 22).
`analgesics and fentanyl
`Three major comparisons of data were per-
`formed: between baseline and while on dexme-
`detomidine infusion; among groups A, B, and
`C; and between neonates and infants. Baseline
`vital signs were compared with the lowest val-
`ues and baseline ABGs with the lowest pH,
`base excess, PO2, and the highest CO2 levels
`while receiving dexmedetomidine. Categorical
`
`Table 2. Baseline patient characteristics
`
`variables were reported as frequencies and
`percentages. Continuous variables were re-
`ported as mean ⫾ SD if the distribution was
`normal and as median with range if the dis-
`tribution was not normal. Paired Student’s t
`test or the Wilcoxon test, depending on the
`distribution of the data being analyzed, was
`used to compare continuous variables before
`and during dexmedetomidine infusion.
`Groups A, B, and C, were analyzed by the
`analysis of variance test or Kruskal-Wallis test,
`depending on the distribution, followed by the
`Bonferroni equation or the Dwass-Steel-
`Chritchlow-Fligner test, respectively, for be-
`tween-group differences. Pain and sedation
`scores were analyzed by analysis of variance
`based on Kruskal-Wallis. Data from neonates
`and infants were either analyzed by an unpaired
`Student’s t test or the Mann-Whitney test. Pear-
`son’s correlation coefficient (r) was used to iden-
`tify any correlation between dexmedetomidine
`dose and vital signs. All reported p values were
`two-tailed, and values of ⱕ.05 were considered
`statistically significant.
`
`RESULTS
`
`A total of 80 patients (39 males and 41
`females) were identified (Tables 1 and 2)
`and divided into three groups: A, n ⫽ 20;
`B, n ⫽ 38; C, and n ⫽ 22. Four of these
`patients were included in our previous
`report (2). Overall there were 1999 indi-
`vidual hourly points of data collected.
`Average age and weight were 4.1 ⫾ 3.1
`months and 5.5 ⫾ 2 kg, respectively.
`Group B had a higher weight compared
`with group C (p ⫽ .01). Fourteen patients
`(17.5%) were neonates with a mean age
`and weight of 15 ⫾ 9 days and 3.2 ⫾ 0.9
`kg, respectively. Seventy-eight surgical
`procedures were adjusted for severity ac-
`cording to RACHS-1 classification and
`the median severity score was 2 (range,
`
`Age (mo)
`Weight (kg)
`Gender (M, F)
`Mechanically ventilated,
`n (%)
`On admission
`At 48 hrs
`Vital signs
`HR (bpm)
`SBP (mm Hg)
`RR (breaths/min)
`CICU length of stay (d)
`
`Group A
`(n ⫽ 20)
`
`3.9 ⫾ 3
`5.5 ⫾ 2
`9, 11
`
`8 (40)
`3 (15)
`
`149 ⫾ 19
`85 ⫾ 12
`32 ⫾ 13
`4 (1–126)
`
`Group B
`(n ⫽ 38)
`
`4.8 ⫾ 3
`6.1 ⫾ 1.9
`18, 20
`
`11 (29)
`3 (8)
`
`146 ⫾ 23
`88 ⫾ 15
`32 ⫾ 12
`3 (1–87)
`
`Group C
`(n ⫽ 22)
`
`3.2 ⫾ 3
`4.4 ⫾ 2
`15, 7
`
`18 (82)
`7 (32)
`
`152 ⫾ 24
`82 ⫾ 18
`29 ⫾ 12
`8 (2–74)
`
`p
`
`.12
`.01a
`
`.52
`.03b
`.7
`.005c
`
`CICU, cardiac intensive care unit; HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure.
`ap ⫽ .002 group B vs. C; bp ⫽ .046 group A vs. B and p ⫽ .017 group B vs. C; cp ⫽ .002 group B vs. C.
`
`655
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`

`
`1– 6). The total CICU length of stay was a
`median of 4 days (1–126). Group B had a
`shorter CICU stay when compared with
`group C (p ⫽ .002) (Table 2).
`Dexmedetomidine Dosing and Dura-
`tion. Dexmedetomidine was started at a
`mean of 4 ⫾ 6 hours after arrival from
`the operating room. A total of 24 patients
`(30%) received a 0.5–1 ␮g/kg loading
`dose at a rate of 0.1 ␮g䡠kg⫺1䡠min⫺1. The
`mean dexmedetomidine starting dose was
`0.47 ⫾ 0.29 ␮g䡠kg⫺1䡠hr⫺1 followed by a
`maintenance infusion of 0.66 ⫾ 0.26
`␮g䡠kg⫺1䡠hr⫺1. The duration of infusion
`was 25 ⫾ 13 hrs.
`Dexmedetomidine dose requirement be-
`tween mechanically ventilated and nonme-
`chanically ventilated patients did not differ,
`0.62 ⫾ 0.26 ␮g䡠kg⫺1䡠hr⫺1 vs. 0.68 ⫾ 0.26
`␮g䡠kg⫺1䡠hr⫺1 (p ⫽ .3). Similarly, there was
`no difference in dexmedetomidine dose be-
`tween patients who received fentanyl infu-
`sion (group C) and those who did not
`(groups A and B): 0.6 ⫾ 0.21 ␮g䡠kg⫺1䡠hr⫺1
`vs. 0.68 ⫾ 0.28 ␮g䡠kg⫺1䡠hr⫺1 (p ⫽ .2) (Table
`3). Dexmedetomidine duration, however, was
`longer in group C compared with A (p ⫽ .03)
`and compared with B (p ⫽ .002).
`To assess if cumulative experience
`with the use of dexmedetomidine could
`have resulted in higher doses, we com-
`pared the dexmedetomidine dosage be-
`tween the first and the last 40 patients.
`Both starting and maintenance doses
`were significantly higher in the last 40
`patients. Starting dose was 0.34 ⫾ 0.18
`vs. 0.6 ⫾ 0.32 ␮g䡠kg⫺1䡠hr⫺1 (p ⬍ .001)
`and maintenance dose was 0.54 ⫾ 0.2
`␮g䡠kg⫺1䡠hr⫺1 vs. 0.78 ⫾ 0.26 ␮g䡠kg⫺1䡠hr⫺1
`(p ⬍ .001). Furthermore, we analyzed the
`amount of times dexmedetomidine was ad-
`ministered above the recommended adult
`maximum dose of 0.7 ␮g䡠kg⫺1䡠hr⫺1. There
`were a total of 789 recorded doses (39% of
`dexmedetomidine infusion time) above the
`maximum, the majority of which (⬎75%)
`were in the last 40 patients, 169 vs. 620.
`Rescue Sedative/Analgesic Agents.
`Groups A and B, which comprised 73% of
`patients, received dexmedetomidine
`without any other continuous analgesic
`or sedative infusion. Group C had an av-
`erage fentanyl
`infusion dose of 1.7
`␮g䡠kg⫺1䡠hr⫺1 and it continued for 18 ⫾
`15 hrs. Table 3 shows in detail the re-
`quirements of these three groups. There
`was no significant difference in rescue
`sedation/analgesia between patients who
`received fentanyl infusion and patients
`who did not, 2.8 vs. 2.6 doses per 24
`hours of dexmedetomidine infusion, re-
`spectively. Overall, fentanyl (40%), mor-
`
`656
`
`Table 3. Descriptive data on sedatives, analgesics, and hemodynamic infusions among groups A, B, and
`C during dexmedetomidine infusion
`
`Dexmedetomidine
`Dose (␮g/kg/hr)
`Duration/patient (hrs)
`Duration (total patient hrs)
`Fentanyl (␮g/kg/hr)
`Rescue dosesb (doses/24 DEX
`infusion hrs)
`Analgesics (n)
`Sedatives (n)
`Milrinone, n (%)
`Dose (␮g/kg/min)
`Duration (hrs)
`Dopamine, n (%)
`Dose (␮g/kg/min)
`Duration (hrs)
`Epinephrine, n (%)
`Dose (␮g/kg/min)
`Duration (hrs)
`Nitroprusside, n (%)
`Dose (␮g/kg/min)
`Duration (hrs)
`Esmolol, n (%)
`Dose (␮g/kg/min)
`Duration (hrs)
`
`Group A
`(n ⫽ 20)
`
`Group B
`(n ⫽ 38)
`
`Group C
`(n ⫽ 22)
`
`0.72 ⫾ 0.31
`24 ⫾ 12
`471
`
`16 (80)
`0.91 ⫾ 0.24
`23 ⫾ 11
`2 (10)
`2.9 ⫾ 3.1
`5 ⫾ 6
`0
`
`10 (50)
`2.2 ⫾ 1
`18 ⫾ 10
`0
`
`0.65 ⫾ 0.26
`22 ⫾ 11
`820
`
`143 (2.6)
`
`106
`37
`30 (79)
`0.86 ⫾ 0.24
`24 ⫾ 11
`8 (21)
`3.3 ⫾ 0.8
`13 ⫾ 9
`1 (2)
`0.04
`14
`30 (71)
`2.2 ⫾ 1
`12 ⫾ 7
`3 (7)
`157 ⫾ 42
`14 ⫾ 7
`
`0.6 ⫾ 0.21
`32 ⫾ 15
`708
`1.7 ⫾ 1
`84 (2.8)
`
`46
`38
`20 (91)
`0.84 ⫾ 0.26
`32 ⫾ 15
`6 (27)
`3.7 ⫾ 1.2
`16 ⫾ 8
`2 (9)
`0.03 ⫾ 0.02
`26 ⫾ 20
`7 (32)
`1.6 ⫾ 0.7
`16 ⫾ 7
`0
`
`p
`
`.37
`.009a
`
`.68
`.06
`
`.9
`.27
`
`.37
`.16
`
`DEX, dexmedetomidine.
`ap ⫽ .03 group A vs. C and p ⫽ 0.002 group B vs. C; bgroup A and group B rescue doses are
`presented as one group; Values are presented as mean ⫾ SD.
`
`Table 4. Sedation and pain scores
`
`Group A (n ⫽ 20)
`
`Group B (n ⫽ 38)
`
`Group C (n ⫽ 22)
`
`Sedation score (0–3)
`Pain score (0–10)
`
`1.0 ⫾ 0.4
`1.7 ⫾ 0.9
`
`1.2 ⫾ 0.5
`2.0 ⫾ 1
`
`1.4 ⫾ 0.4
`1.9 ⫾ 0.7
`
`p
`
`.28
`.62
`
`Values are presented as mean ⫾ SD.
`
`phine (20%), and chloral hydrate (15%)
`were the most common rescue drugs
`used. Midazolam,
`lorazepam, and ket-
`amine were used less frequently.
`Sedation/Analgesia. The overall mean
`sedation score was 1.2 ⫾ 0.5. Normal
`sleep, defined as easily arousable patient
`without drowsiness, to moderate sedation
`was documented 94% of the time. In re-
`gards to analgesia, the mean pain score
`was 1.9 ⫾ 0.9 and no pain to mild pain
`was documented 90% of the time. Among
`groups A, B, and C, sedation and pain
`scores were similar (Table 4).
`Cardiovascular Effects. Average SBP
`and HR were statistically lower after
`dexmedetomidine was initiated. Blood
`pressure decreased from 89 ⫾ 15 mm Hg
`at baseline, to an average of 85 ⫾ 11 mm
`Hg (5% decrease, p ⫽ .006). HR de-
`creased from 149 ⫾ 22 bpm to 129 ⫾ 16
`bpm (13% decrease, p ⬍ .001) (Fig. 1).
`Further analysis between baseline and av-
`
`erage lowest values showed a decline in
`the SBP to 69 ⫾ 11 mm Hg (22% de-
`crease) and HR to 113 ⫾ 15 bpm (24%
`decrease). Changes in dexmedetomidine
`dose correlated negatively with HR (r ⫽
`⫺.65, p ⬍ .001), and had no correlation
`with SBP (r ⫽ ⫺.2, p ⫽ .22).
`Because of lack of data and because
`the timing of starting dexmedetomidine
`was not uniform in all patients after sur-
`gery, it was difficult to differentiate if
`hemodynamic changes were secondary to
`a potential presence of low cardiac output
`syndrome (LCOS) or dexmedetomidine.
`Nonetheless, the HR trend and the corre-
`lation with dexmedetomidine dosage did
`not support a worsening LCOS because of
`dexmedetomidine (Fig. 1). As noted
`above, the overall HR was lower after
`initiating dexmedetomidine, in contrast
`to the expected higher HR seen in LCOS
`state (7). Additionally, we noticed that
`during the first 8 hrs, when dexmedeto-
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
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`

`
`failed extubation while receiving dexme-
`detomidine. Three had complex CICU
`courses, with chronic lung disease and
`previous prolonged intubation, and two
`were found to have hemidiaphragm pa-
`ralysis that needed surgical intervention.
`Among the patients who were not in-
`tubated at the initiation of dexmedetomi-
`dine, none required intubation during
`the study period. None of the patients had
`any documented episodes of apnea.
`There was no significant change be-
`tween baseline and overall mean RR, 31 ⫾
`12 breaths/min to 31 ⫾ 9 breaths/min (p ⫽
`.83). However, a comparison between base-
`line and the lowest mean RR, 20 ⫾ 6
`breaths/min [35% drop] showed a signifi-
`cant difference (p ⬍ .001). There were 31
`patients with 108 recorded episodes consis-
`tent with low RR for age (5% incidence).
`When we analyzed dexmedetomidine
`dose in relation to the RR, we did not
`find any significant correlation (r ⫽
`⫺.05, p ⫽ .76).
`ABGs were statistically different when
`baseline values were compared with the
`most abnormal ABGs while on dexme-
`detomidine. These changes included
`lower pH level, 7.40 ⫾ 0.1 to 7.37 ⫾ 0.1
`(p ⫽ .006), mild CO2 retention, 45 ⫾ 8 to
`50 ⫾ 12 mm Hg (p ⫽ .001), and lower
`PO2 levels, 91 ⫾ 67 mm Hg to 66 ⫾ 29
`mm Hg (p ⫽ .005). The timing of these
`most abnormal ABGs ranged from 2 to 25
`hrs after starting dexmedetomidine, with
`an average of 4 ⫾ 7 hrs. These ABG
`changes did not differ among groups A, B,
`and C (Table 6).
`Gastrointestinal Effects. Twenty-one pa-
`tients (26%) were fed during the dexme-
`detomidine infusion. One episode of vom-
`iting was documented in one patient.
`Neonates vs. Infants. A subgroup anal-
`ysis was performed comparing neonates
`(n ⫽ 14) with infants (n ⫽ 66) (Table 7).
`Dexmedetomidine dose was statistically
`lower in neonates (p ⫽ .003). Sedation
`and analgesia scores and rescue sedatives
`were similar in both groups. HR and RR
`were statistically higher and SBP was
`lower in neonates.
`Safety and Adverse Events. Two pa-
`tients had changes in the cardiorespira-
`tory variables that may have been attrib-
`uted to dexmedetomidine and thus it was
`discontinued. The first was a 2-mo-old
`patient with aortic coarctation repair who
`had received dexmedetomidine for 8 hrs
`before discontinuation (0.4 ␮g䡠kg⫺1䡠hr⫺1).
`At the time, this patient was simulta-
`neously treated with nitroprusside (2
`␮g䡠kg⫺1䡠min⫺1) for hypertension when a
`
`657
`
`Figure 1. Average heart rate (HR), systolic blood pressure (SBP), and dexmedetomidine (DEX) dose in
`all patients.
`
`Table 5. Hemodynamic variables in groups A, B, and C during dexmedetomidine infusion
`
`Group A (n ⫽ 20)
`
`Group B (n ⫽ 38)
`
`Group C (n ⫽ 22)
`
`SBP (mm Hg)
`HR (bmp)
`RR (br.pm)
`
`85 ⫾ 9
`128 ⫾ 15
`32 ⫾ 8
`
`88 ⫾ 11
`126 ⫾ 13
`30 ⫾ 8
`
`82 ⫾ 11
`136 ⫾ 17
`34 ⫾ 11
`
`p
`
`.19
`.03a
`.34
`
`SBP, systolic blood pressure; HR, heart rate; RR, respiratory rate.
`ap ⫽ 0.01 group B vs. C. Values are presented as mean ⫾ SD.
`
`midine dose increased steadily, there was
`a large negative correlation with HR (r ⫽
`⫺.9, p ⬍ .001). During the 9- to 17-hour
`period, there was no correlation (r ⫽ .04,
`p ⫽ .9); and during the 18- to 28-hour
`period, when there was a steady decline
`in the dexmedetomidine dose, there was
`also a significant negative correlation
`(r ⫽ ⫺.7, p ⫽ .07). These indirect find-
`ings do not support worsening LCOS.
`Figure 1 shows graphically the HR and
`SBP trend in relation to dexmedetomi-
`dine dose and duration. Because vital
`signs were documented only every hour,
`we were not able to detect further
`changes that may have occurred during
`the loading dose or with increased
`dexmedetomidine infusion rate.
`Twenty-seven patients (34%) had at
`least one episode of hypotension and 10
`patients (12.5%) at least one episode of
`bradycardia. Overall, from the 1999 hourly
`recordings, there were 58 hypotensive
`events (3%) and 44 bradycardic events
`(3%). Crystalloid or colloid fluids boluses
`were administered in 23 patients (29%);
`however, we could not determine whether
`these were a part of the postoperative car-
`diac care or if they were associated with
`dexmedetomidine administration.
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
`Sixty-six patients were on some ino-
`tropic support before dexmedetomidine
`was started. Table 3 shows the inotropic
`agent requirements among groups A, B,
`and C, and Table 5 shows the hemody-
`namic variables. Overall there was no
`substantial difference in the hemody-
`namic infusions, SBP or RR. HR was sta-
`tistically higher in group C compared
`with group B (p ⫽ .01). A total of 50
`patients had significant postoperative sys-
`temic hypertension requiring sodium ni-
`troprusside (47 patients) and esmolol
`(three patients). Thirty-three of these be-
`longed to group B.
`Nine patients had an arrhythmia be-
`fore starting dexmedetomidine. The types
`of arrhythmias included five patients with
`junctional ectopic tachycardia, two with
`first and one with third-degree atrioven-
`tricular block, and one patient with junc-
`tional accelerated rhythm. All arrhyth-
`mias recovered to normal sinus rhythm
`before discharge from the CICU.
`Respiratory Effects. Thirty-seven pa-
`tients (46%) were already intubated at
`the initiation of the dexmedetomidine in-
`fusion. Twenty-four of these were weaned
`off and extubated while receiving dexme-
`detomidine. Five patients subsequently
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1045 – Page 657
`
`

`
`Table 6. Comparison of arterial blood gas changes in groups A, B, and C
`
`Group A (n ⫽ 20)
`
`Group B (n ⫽ 38)
`
`Group C (n ⫽ 22)
`
`pH
`Baseline
`Lowest
`CO2, mm Hg
`Baseline
`Highest
`PO2, mm Hg
`Baseline
`Lowest
`Base excess, mmol/L
`Baseline
`Lowest
`
`7.4 ⫾ 0.06
`7.37 ⫾ 0.05
`
`45 ⫾ 6
`54 ⫾ 19
`
`86 ⫾ 54
`73 ⫾ 36
`
`2 ⫾ 4
`1 ⫾ 4
`
`Values are presented as mean ⫾ SD.
`
`Table 7. Neonates vs. infants
`
`7.41 ⫾ 0.06
`7.38 ⫾ 0.05
`
`46 ⫾ 7
`48 ⫾ 8
`
`100 ⫾ 72
`69 ⫾ 26
`
`4 ⫾ 4
`2 ⫾ 4
`
`7.39 ⫾ 0.09
`7.36 ⫾ 0.06
`
`45 ⫾ 11
`50 ⫾ 8
`
`79 ⫾ 71
`55 ⫾ 25
`
`3 ⫾ 6
`1 ⫾ 3
`
`p
`
`.6
`.2
`
`.9
`.4
`
`.1
`.07
`
`.4
`.5
`
`Neonates (n ⫽ 14)
`
`Infants (n ⫽ 66)
`
`p
`
`Group A, B, C (n)
`Dexmedetomidine
`Dose (␮g/kg/hr)a
`Duration (hrs)a
`Rescue sedative/analgesic doses n
`(doses/24 DEX infusion hrs)
`Pain scoreb
`Sedation scoreb
`Vital signs
`HR (bpm)a
`SBP (mm Hg)a
`RR (breaths/min)b
`RACHS–1b
`CICU stay (d)b
`
`3, 7, 4
`
`0.47 ⫾ 21
`27 ⫾ 17
`43 (2.6)
`
`2 (0.8–2.4)
`1.4 (0–2)
`
`140 ⫾ 10
`77 ⫾ 9
`37 (17–55)
`3 (1–4)
`8 (2–30)
`
`17, 15, 34
`
`0.69 ⫾ 25
`25 ⫾ 13
`184 (2.7)
`
`2 (0–4)
`1 (0–2.3)
`
`127 ⫾ 15
`87 ⫾ 10
`28 (18–68)
`2 (1–6)
`4 (1–126)
`
`.003
`.6
`
`.5
`.06
`
`.001
`⬍ .001
`.009
`.1
`.67
`
`DEX, dexmedetomidine; HR, heart rate; SBP, systolic blood pressure; RR, respiratory rate; CICU,
`cardiac intensive care unit; RACHS-1, Risk Adjustment for Congenital Heart Surgery Classification.
`aValues as mean ⫾ SD; bvalues as median with range.
`
`dose of hydralazine was administered. The
`patient’s SBP decreased from a baseline of
`81 to 65 mm Hg, a 19% change, and the
`decision was made to discontinue both the
`nitroprusside and dexmedetomidine infu-
`sions. Blood pressure returned to baseline
`within 15 mins. The second patient was
`also a 2-mo-old with coarctation of the
`aorta repair who had received dexmedeto-
`midine for 11 hrs (0.7 ␮g䡠kg⫺1䡠hr⫺1). The
`patient’s HR had decreased from baseline of
`115 bpm to 89 bpm, a 23% change and
`although normotensive at the time with no
`signs of LCOS, a precautionary decision
`was made by the physician on call to dis-
`continue dexmedetomidine. HR recovered
`to 127 bpm within 1 hr without any further
`interventions.
`
`DISCUSSION
`
`Dexmedetomidine has been increas-
`ingly used in our CICU for sedation, an-
`algesia, and other off-label indications.
`With growing experience, we have ex-
`
`panded its use from adolescents and
`young adults to infants and neonates, and
`to more complex cardiac surgeries. In
`our previous study, although only seven
`patients were younger than 1 yr, we no-
`ticed that this younger population had a
`tendency toward a higher dexmedetomi-
`dine dose requirement (2).
`In this report, which included only
`infants and neonates, the dexmedetomi-
`dine dose was higher compared with our
`previous results in older children, 0.66
`␮g䡠kg⫺1䡠hr⫺1 vs. 0.4 ␮g䡠kg⫺1䡠hr⫺1 (2).
`We also found that with increasing expe-
`rience, the dose had increased to 0.78
`␮g䡠kg⫺1䡠hr⫺1. Although these dose
`ranges are relatively high, they are still
`within the range published in both adult
`and pediatric literature (8 –10). Two pe-
`diatric pharmacokinetic studies by Petroz
`et al (11) and Diaz et al (12), although
`limited by the number of
`infants in-
`cluded, showed that children had similar
`and predictable pharmacokinetics com-
`
`658
`
`pared with adults. In reference to our
`minority neonatal subgroup of patients,
`we found that the dexmedetomidine dose
`was lower compared with the older infant
`population. Given the small number of
`patients, we can only speculate why there
`was such a difference. One possibility is
`that due to the immature neonatal kidney
`function, the renally excreted dexmedeto-
`midine accumulates over time and thus
`the requirement is less. The lower SBP
`and higher RR and HR are likely ex-
`plained by the age difference.
`Dexmedetomidine decreases opioid
`and benzodiazepine requirements, possi-
`bly due to a synergistic or additive effect,
`and in some studies it has been used as a
`single agent for sedation (13, 14). In 25%
`of the patients in this report, dexmedeto-
`midine was administered as the sole sed-
`ative/analgesic agent; approximately half
`of the patients required occasional rescue
`boluses and 27% required an additional
`low-dose fentanyl infusion. A comparison
`between patients who received additional
`fentanyl infusion and those who did not
`showed that there was no difference in
`either sedation or pain score and both
`groups received equal amounts of rescue
`sedative/analgesic boluses. Providing an
`adequate level of analgesia with the least
`amount of side effects is of paramount
`importance, and has been shown to de-
`crease cardiorespiratory morbidity and,
`therefore, hospitalization time. This is
`rather important, taking into consider-
`ation that most CICU patients have sev-
`eral noxious stimuli,
`including chest
`tubes and chest incisions as well as the
`need for mechanical ventilation. Our re-
`sults are in agreement with those of
`Tobias and Berkenbosch (15), who dem-
`onstrated that the use of dexmedetomi-
`dine in pediatric ICU patients was supe-
`rior to midazolam infusion based on
`supplemental rescue dose requirements.
`The study by Tobias and Berkenbosch
`was a small randomized trial, in me-
`chanically ventilated infants and chil-
`dren, and it compared dexmedetomi-
`dine infusion at two different doses, 0.25
`␮g䡠kg⫺1䡠hr⫺1 and 0.5 ␮g䡠kg⫺1䡠hr⫺1 with
`midazolam 0.22 mg䡠kg⫺1䡠hr⫺1. At a dose
`of 0.25 ␮g䡠kg⫺1䡠hr⫺1, dexmedetomidine
`was equivalent to midazolam. At 0.5
`␮g䡠kg⫺1䡠hr⫺1, dexmedetomidine pro-
`vided more effective sedation as demon-
`strated by the need for fewer bolus doses
`of morphine, a decrease in the 24-hr re-
`quirements for supplemental morphine,
`as well as a decrease in the total number
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1045 – Page 658
`
`

`
`of sedation assessment points outside of
`the desired range.
`Dexmedetomidine causes minimal re-
`spiratory depression, making it a poten-
`tially useful agent in nonintubated pa-
`tients. Overall, 95% of the patients in this
`study who were either nonintubated at
`baseline or extubated while receiving
`dexmedetomidine had no clinically sig-
`nificant respiratory compromise. Five pa-
`tients who failed extubation had other
`significant underlying pathologies and
`their failure was not directly attributed to
`dexmedetomidine. Nevertheless, in con-
`trast to our previous study, we did see
`changes in the respiratory variables, and
`although transient, they still warrant at-
`tention. These changes included mild hy-
`percapnia, lower pH, and PO2 levels and
`lower RR. These results are consistent
`with findings from earlier studies by
`other authors, where it was shown that
`both low- and high-dexmedetomidine bo-
`lus, 0.25 ␮g/kg and 2 ␮g/kg, decreased
`resting ventilation and ventilatory re-
`sponse to hypercapnia (16). Other studies
`also demonstrated that dexmedetomidine
`can cause mild decreases in the PO2 levels
`or oxygen saturation, and mild hypercap-
`nia (17). These respiratory changes most
`often are clinically insignificant. How-
`ever, caution is warranted since such al-
`terations can potentially cause significant
`fluctuations in the pulmonary vascular
`resistance and thus change the hemody-
`namic profile in patients with single ven-
`tricle physiology as well as in patients
`with potentially labile pulmonary vascu-
`lar resistance, i.e., after repair of com-
`plete atrioventricular septal defect, trun-
`cus arteriosus, etc.
`The more frequently reported adverse
`events associated with dexmedetomidine
`include a dose-related hypotension and
`bradycardia (13, 17, 18). In this study, the
`prevalence of these side effects was simi-
`lar to that reported in the literature. In
`general, there was only a small drop in
`the SBP and HR, but transiently we saw
`up to 22% and 24% changes, respectively.
`A recent small, prospective study by
`Hammer et al (19) investigated the elec-
`trophysiologic effects of dexmedetomi-
`dine in 12 children who underwent car-
`diac catheterization for possible ablation.
`Although the study was performed in the
`presence of ketamine and propofol, both
`of which may have a negative electro-
`physiologic effect, Hammer et al found
`that dexmedetomidine depressed both si-
`nus and atrioventricular nodal function.
`Dexmedetomidine appears to have a wide
`
`Pediatr Crit Care Med 2009 Vol. 10, No. 6
`
`safety margin; however, its sympatholytic
`properties should be respected and it
`should be used with extreme caution in
`patients at risk for any bradyarrhythmias,
`and in patients who are receiving medi-
`cations that cause vasodilation or have
`negative chronotropic effects (20, 21).
`A less frequent adverse effect de-
`scribed in adults is nausea and