NIH Public Access
`Author Manuscript
`J Crit Care. Author manuscript; available in PMC 2013 July 28.
`Published in final edited form as:
`J Crit Care. 2009 December ; 24(4): 568–574. doi:10.1016/j.jcrc.2009.05.015.
`
`A new dosing protocol reduces dexmedetomidine-associated
`hypotension in critically ill surgical patients☆,,☆☆,,★
`
`Anthony T. Gerlach, PharmD, BCPSa, Joseph F. Dasta, MS, FCCMb,c, Steven Steinberg,
`MDd, Larry C. Martin, MDe, and Charles H. Cook, MD, FCCMd
`Anthony T. Gerlach: gerlach.6@osu.edu; Joseph F. Dasta: jdasta@mail.utexas.edu; Steven Steinberg:
`steven.steinberg@osumc.edu; Larry C. Martin: larry.martin@surgery.ufl.edu; Charles H. Cook: cook.131@osu.edu
`aDepartment of Pharmacy, The Ohio State University Medical Center, Columbus, Ohio 43210,
`USA
`bThe Ohio State University, Columbus, Ohio, USA
`cUniversity of Texas, Round Rock, TX 78665, USA
`dDepartment of Surgery, The Ohio State University Medical Center, Columbus, Ohio 43210, USA
`eDepartment of Surgery, University of Florida, P.O. Box 100286, Gainesville, Fl 32610, USA
`
`Abstract
`Background—Although no ideal sedative exists, dexmedetomidine is unique because it
`produces sedation and analgesia without decreasing the respiratory drive. Hemodynamic responses
`to dexmedetomidine are variable and dependent on the patient population. Our initial experience
`was associated with an unacceptable incidence of hypotension and bradycardia. We evaluated
`occurrence of hypotension and bradycardia in critically ill surgical patients receiving
`dexmedetomidine before and after implementation of a dosing protocol.
`Methods—This is a retrospective chart review of all admissions to a university medical center–
`based, 44-bed surgical intensive care unit pre and post protocol implementation.
`Results—Forty-four patients received dexmedetomidine including 19 historic controls and 25
`dosed via protocol. Both groups had comparable demographics and initial and maximum dosages
`of dexmedetomidine. Use of the dosing protocol resulted in fewer dosage changes (mean ±
`standard deviation, 4.8 ± 3.8 compared to 7.8 ± 3.9; P = .014) and fewer episodes of hypotension
`(16% vs 68.4%; P = .0006) but did not influence bradycardic episodes (20% vs 15.5%; P > .99).
`Conclusion—We found that use of a protocol that increases the time interval between dosage
`adjustments may reduce dexmedetomidine-associated hypotension.
`
`Keywords
`Dexmedetomidine; Intensive care unit; Hypotension
`
`☆Joseph F. Dasta is a consultant and member of the Hospira Speakers Bureau for dexmedetomidine. None of the other authors have
`anything to disclose.
`☆☆No outside finances were used to fund this study.
`★Author contributions—trial design: AG, SS, LM, CC; data collection: AG; data analysis: AG, SS, LM, CC.
`© 2009 Elsevier Inc. All rights reserved.
`Correspondence to: Anthony T. Gerlach, gerlach.6@osu.edu.
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`1. Introduction
`After publication of Too Err is Human: Building a Safer Health System in 1999 by the
`Institute of Medicine, medication safety has become a top priority in health care [1]. That
`report focused on the observation that many medical errors involve medications and
`concluded that health care providers need to design safer systems [2,3]. Because of
`complexities of critical illness, patients in the intensive care unit (ICU) are considered to be
`at increased risk of medication errors and adverse drug events, particularly with intravenous
`medications [2–5]. Proposed strategies to improve medication safety in the ICU include
`intensivist-lead, multidisciplinary rounds with pharmacist participation; standardized drug
`preparation and administration; computerized prescriber order entry; bar coding technology;
`computerized intravenous infusion devices; education; and developing a culture of safety
`[2,6]. Because most medication errors and many adverse drug events are considered
`preventable, development of surveillance systems targeting strategies for improvement
`should help decrease adverse drug events in both the outpatient and the inpatient setting,
`including the ICU [6].
`
`An essential part of ICU care is to protect patients from themselves during agitation, and this
`often requires use of sedatives such as propofol or benzodiazepines [7]. In addition, opioids
`are used to treat pain, a common contributor to agitation in surgical patients. Unfortunately,
`use of these medications is associated with adverse drug events such as respiratory
`depression, resulting in increased duration of mechanical ventilation, and development of
`ventilator-associated pneumonia, all of which increase ICU length of stay [8].
`
`Dexmedetomidine is a sedative with a unique mechanism of action that became available in
`the United States in 1999 for sedation of critically ill patients [9]. Desirable properties of
`dexmedetomidine include induction of sedation and analgesia via stimulation of α2-
`receptors without concomitant respiratory depression by γ-aminobutric acid-mimetic
`properties that accompany use of many other sedatives [9]. Additional advantages of
`dexmedetomidine include a relatively short half-life and hepatic metabolism [9]. Described
`adverse drug reactions with dexmedetomidine include altered blood pressure, nausea, and
`bradycardia [10,11]. Hypotension, which is the most commonly reported adverse effect,
`results from a sympatholytic effect mediated by activation of central α2a-receptors causing
`vasodilation [9,12]. Thus, dexmedetomidine has the desirable characteristic of inducing
`sedation without causing respiratory depression, but it also has potential side effects that
`might preclude its use during critical illness.
`
`Despite an initial enthusiasm for dexmedetomidine to treat agitation in our surgical ICU,
`data from our drug surveillance monitoring system suggested an unacceptable incidence of
`hypotension and bradycardia associated with its use. Closer evaluation revealed that
`hypotension often occurred when dexmedetomidine dosage was titrated rapidly (more
`frequently than every 20 minutes) compared with slower rates of titration [13]. Based upon
`these data, a dosing protocol for dexmedetomidine was developed that allows titration no
`more frequently than every 30 minutes. In this report, we described reduced occurrence of
`hypotension associated with dexmedetomidine in our surgical ICU after institution of this
`dosing protocol.
`2. Materials and methods
`Dexmedetomidine was added to the Formulary of Accepted Medications at The Ohio State
`University Medical Center in 2001 and was restricted to use in the surgical ICU. We
`previously reported a medication use evaluation performance improvement project of
`patients receiving dexmedetomidine in the surgical ICU between October 2001 and
`December 2004 [13]. These data suggested that hypotension occurred more frequently when
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`dexmedetomidine is rapidly titrated. Based on these data, a dosing protocol was developed
`(Fig. 1). This protocol was reviewed and approved by the surgical ICU quality committee
`with representation from surgery, nursing, and pharmacy.
`
`Between April 2005 and March 2006, patients received dexmedetomidine via this new
`protocol and were compared with historic controls that received dexmedetomidine rapidly
`titrated (<20 minutes between dosage adjustments) between October 2001 and December
`2004. Patients were excluded if they were less than 18 or more than 89 years old, pregnant,
`incarcerated, or receiving vasopressors before initiation of dexmedetomidine. Data collected
`included demographics, Acute Physiology and Chronic Health Evaluation II (APACHE II)
`score on admission, sedation score, indication, dosage titration, length of therapy, time
`between dosing adjustments, and adverse drug reactions attributed to dexmedetomidine from
`start of infusion to end of infusion. Data were retrospectively collected from our electronic
`ICU charting system (CliniComp International, San Diego, Calif). Vitals signs can be
`automatically imported at the touch of a computer key with this system. The primary
`outcome was the occurrence of hypotension, defined as a mean arterial blood pressure less
`than 60 mm Hg attributed to dexmedetomidine, as determined by one of the investigators
`(AG). Development of bradycardia was also studied and defined as heart rate less than 50
`beats per minute attributed to dexmedetomidine. Hemodynamic parameters were monitored
`for 2 hours before initiation of dexmedetomidine to 12 hours after discontinuation. Sedation
`scores (Ramsay Sedation Score was collected in the control group and Richmond Agitation
`Sedation Score [RASS] for the protocol group) were collected between 30 and 120 minutes
`of initiation and within 2 hours before or after the development of an adverse drug reaction
`[7,14]. To allow comparison between these different scales, patients are reported to be
`agitated, calm, or sedated. Our retrospective chart review received institutional review board
`exemption.
`
`Statistical analysis was performed by Fisher exact test for nominal data or Student t test for
`continuous data. The Mann-Whitney U test was used for nonparametric data. Continuous
`data are presented as mean ± standard deviation or median (25%–75% interquartile range). P
`values less than .05 were considered significant.
`
`Forty-four patients were included in analysis, including 25 patients that received
`dexmedetomidine after protocol institution and 19 historic controls that received rapidly
`titrated dexmedetomidine. Both groups had comparable demographics and admitting
`services (Tables 1 and 2). Median {25%–75% interquartile range} APACHE II scores upon
`admission were similar between groups (21 {15–25} protocol group vs 22 {15–29} historic
`control; P = .38). The mean duration of mechanical ventilation (protocol 10.7 ± 11.1 days vs
`10.2 ± 12.1 days for controls; P = .89) and ICU length of stay (protocol 14.5 ± 11.1 days,
`controls 11.8 ± 11.4; P = .48) were similar between groups. Additional sedation was
`required in 8% of protocol patients (propofol in 1 patient with subarachnoid hemorrhage and
`lorazepam in 1 patient after trauma).
`
`The mean initial dosage of dexmedetomidine (0.24 ± 0.11 μg kg−1 h−1 protocol vs 0.22 ±
`0.07 μg kg−1 h−1 controls; P = .42), the maximum dosage (0.43 ± 0.19 μg kg−1 h−1 protocol
`vs 0.54 ± 0.16 μg kg−1 h−1 controls; P = .08), and time to maximal dosage (259 ± 429
`minutes protocol vs 153 ± 150 minutes controls; P = .4) were not statistically different
`between the groups (Table 2). Patients treated via protocol had significantly fewer dosage
`adjustments than historic control patients (protocol 4.8 ± 3.8 vs 7.8 ± 3.9 in controls; P = .
`014). Median durations of dexmedetomidine infusion were 19.2 {10.7–52.1} hours in the
`protocol group and 16.6 {7–33} hours in historic controls (P = .14). Sixteen patients
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`3. Results
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`received dexmedetomidine longer than 24 hours (11/25 [25%] for protocol, 5/19 [26%] for
`historic controls; P = .34). Two patients received loading infusions of dexmedetomidine,
`both historic controls (P = .19).
`
`Seventeen patients developed hypotension, but this occurred significantly less frequently in
`protocol patients compared with historic controls (4 [16%] vs 13 [68.4%]; P = .0006).
`Bradycardia was not significantly different between groups (5 [20%] vs 3 [15.8%]; P > .99).
`A total of 22 patients developed hypotension and/or bradycardia (6 [24%] in the protocol
`group vs 16 [84%] in the historic controls; P = .0002) including 3 patients developing both
`(2 [8%] in the protocol group and 1 [5.3%] of the controls; P > .99). The total number of
`adverse drug reactions was significantly less in patients treated via protocol (7 [28%] vs 15
`[78.9%]; P = .0019) than historic controls. For patients that developed hypotension, there
`was no statistical difference in mean arterial pressure between groups (mean nadir mean
`arterial pressure 51.8 ± 2.2 mm Hg protocol group vs 51.1 ± 7.6 mm Hg for historic
`controls; P = .87), and the mean nadir heart rates were similar for those that developed
`bradycardia (39.3 ± 9.9 beats per minutes for historic controls vs 37.8 ± 9.9 for controls).
`Time from initiation of therapy to development of hypotension was similar between protocol
`and historic control groups (4.2 ± 3.6 vs 3.8 ± 2.8 hours, respectively; P = .84) as was the
`time from initiation of therapy to bradycardia (12 ± 9.2 vs 5.9 ± 3.6 hours; P = .32).
`Hypotension (3.9 ±3 hours) tended to occur before bradycardia (9.7 ± 7.9 hours) in all
`patients, but this difference did not reach significance (P = .059). Only 2 of the 17 patients
`that developed hypotension had received dexmedetomidine for more than 24 hours (P > .99).
`For patients developing hypotension or bradycardia, all but 1 case were treated by stopping
`the dexmedetomidine infusion. In addition, hypotension was treated with administration of
`intravenous fluids in 5 patients (1 protocol patient and 4 historic controls). Four historic
`control patients required transient vasopressors, and 2 patients received atropine (1 in each
`group; P > .99).
`
`The level of sedation or agitation 30 to 120 minutes after dexmedetomidine initiation was
`documented in 41 patients (24 [96%] protocol vs 17 [89.5%] historic controls; P = .57) and
`within 2 hours of the development of an adverse effect in all but 1 patient in the control
`group (Table 3). In the first hours of sedation, the median sedation scores {25%–75%
`interquartile range} for both groups were calm (median RASS was 0 {−2,1} for the protocol
`group and median Ramsay Sedation Score was 2 {1,3} for the historical controls). Around
`the time of development of hypotension and bradycardia, the median RASS in the protocol
`group was lightly sedated (−1 {−3,1}), and the median Ramsay Sedation Score for the
`historic controls was calm (2 {1,3}). The mean time from development of an adverse effect
`and documentation of sedation levels was 0.74 ± 0.7 hours.
`4. Discussion
`This study suggests that occurrence of hypotension associated with dexmedetomidine use in
`postoperative ICU patients can be significantly reduced by implementation of a dosing
`protocol. Although hypotension is a potential adverse effect of any sedative agent [15–22],
`our initial experience with dexmedetomidine showed a somewhat higher incidence of
`hypotension (approximately 69%) than reported by others (Table 4) [16,17,23]. Some have
`suggested that dexmedetomidine-associated hypotension and bradycardia are consequent to
`activation of α2-receptors resulting in sympatholysis [11,15,17], and others have reported
`that administration of dexmedetomidine without loading infusions can achieve satisfactory
`sedation [21,23]. We chose a slightly different approach, which was to slow down the rate of
`titration, and report that our protocol may reduce dexmedetomidine-associated hypotension
`to levels lower than previously reported (16%) [13,16,17,23].
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`Although the cause is not known for certain, there are several possible mechanisms for
`development of dexmedetomidine-associated hypotension, especially in patients receiving
`rapid dosage titration. The first is an opposing effect on α2a and α2b receptors. Work by
`others has shown that heart rate, cardiac output, and norepinephrine concentrations decrease
`progressively with increasing dexmedetomidine concentrations, but dexmedetomidine
`causes a biphasic change in blood pressure [24]. At low concentrations (<1.9 ng/mL), mean
`arterial pressure decreases, followed by increasing mean arterial pressures observed with
`increasing dexmedetomidine concentrations [24]. It is thought that activation of peripheral
`α2b-receptors at higher concentrations causes vasoconstriction, thereby offsetting the
`vasodilation from activation of α2a-receptors. Critically ill patients receiving a maximum
`dosage of 0.7 μg kg−1 h−1 have demonstrated peak serum dexmedetomidine concentrations
`of 1.2 ng/mL with a range of 0.71–1.7 ng/mL [25]. This is below the point where the
`activation of α2b starts to predominate and may explain why hypotension is the most
`common adverse effect.
`
`A second possible mechanism contributing to hypotension induced by dexmedetomidine
`relates to its pharmaco-kinetic properties. Dexmedetomidine requires extensive metabolism
`by the liver but appears to have minimal interaction with the cytochrome p450 enzymes
`[10,11]. Dexmedetomidine exhibits linear pharmacokinetics with distribution (α) half-life
`range of 6.0 to 8.6 minutes and elimination (β) half-life of approximately 2 to 3.1 hours in
`both healthy volunteers and critically ill patients [10,11,25]. Thus, completion of distribution
`from the central to peripheral compartments requires approximately 30 to 45 minutes,
`whereas steady-state drug concentrations do not occur until approximately 10 to 15 hours.
`Rapid titration (sooner than every 20–30 minutes) therefore provides additional drug before
`distribution of the previous dose is complete. This could therefore result in drug
`accumulation in the central compartment with development of hypotension after completion
`of distribution. There was a trend toward lower mean maximum dosage in the protocol
`group (0.43 ± 0.02 vs 0.54 ± 0.16 μg kg−1 h−1; P = .08). Because we did not measure
`dexmedetomidine serum concentrations, this remains a hypothesis consistent with our
`clinical data that can be tested in future studies.
`
`The optimal method to safely titrate dexmedetomidine in critically ill patients has not been
`definitively established, but available data support the practice of slower titration. Timing of
`dexmedetomidine titration has only been described in 2 studies of critically ill patients: one
`in adults and one in children [26,27]. In adult ICU patients receiving dexmedetomidine
`longer than 24 hours (median, 71.5 hours), dexmedetomidine was titrated no sooner than
`every 15 minutes [26]. Mean systolic blood pressures decreased approximately 16% within
`2 to 4 hours of initiating therapy, and the lowest single systolic blood pressure was reported
`12 hours after starting therapy. Beyond 12 hours (presumably at/near steady state), systolic
`blood pressures showed minimal change (± 10%) during dexmedetomidine infusion. In
`pediatric ICU patients (median age, 5 months) receiving dexmedetomidine without loading
`infusions titrated with changes more than 1 hour apart, there were no episodes of
`dexmedetomidine-associated hypotension [27]. One patient (6%) developed hypotension
`when dexmedetomidine was titrated less than 1 hour after the previous change. Thus, these
`studies taken together with the current study suggest that a slow titration may minimize the
`incidence of hypotension; once again, further studies are needed to confirm.
`
`The optimal dosage and dosing titration frequency that balance safety and efficacy are also
`unknown. Dexmedetomidine was approved for use in the United States, based on 2
`randomized, double-blind, placebo-controlled trials with the maximum dosage of 0.7 μg
`kg−1 h−1 [9,16]. In our study, the maximum dosage of dexmedetomidine was also 0.7 μg
`kg−1 h−1, although many studies have reported higher dosages [9]. The revised labeling for
`procedures or surgery in nonintubated patients increases the maximal dosage to 1.0 μg kg−1
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`h−1 [10]. In a phase II trial in 12 medical patients, Venn et al [28] have reported maximal
`dosages of 2.5 μg kg−1 h−1 after their first 4 patients required additional sedation.
`Pandharipande et al [17] compared sedation with dexmedetomidine or lorazepam in 106
`critically ill patients and used a maximal dosage of dexmedetomidine of 1.5 μg kg−1 h−1.
`Hypotension, reported as a systolic blood pressure less than 80 mm Hg, occurred in 25% of
`those receiving dexmedetomidine and 20% of those receiving lorazepam (P = .51), but
`significantly more patients receiving dexmedetomidine developed bradycardia (17% vs 4%;
`P = .03). Riker et al [22] compared dexmedetomidine to midazolam in a randomized trial
`where 61% of 244 patients received between 0.71 and 1.4 μg kg−1 h−1 of dexmedetomidine.
`Significantly more patients receiving dexmedetomidine developed bradycardia compared
`with those receiving midazolam (42.2% vs 18.9%; P < .001), with similar incidence of
`hypotension (56.1% vs 55.7%; P > .99). In our study, rate of titration did not appear to
`influence incidence of bradycardia, but we used a lower maximum dosage and our sample
`size may be too small to detect a change. Further studies are needed to determine if dosages
`greater than 0.7 μg kg−1 h−1 are associated with a higher rate of hypotension or bradycardia.
`
`The time to hypotension and bradycardia was documented in only a few studies [16,18].
`Venn et al [16] report 18 of 66 patients receiving dexmedetomidine after general or cardiac
`surgery developed hypotension and/or bradycardia. Most of these events (11/18) occurred
`with the loading infusion. The other 7 patients developed hypotension between 1 and 11
`hours of initiation. Herr et al [18] reported that hypotension occurred in 24% of 148 patients
`receiving dexmedetomidine, and 8% developed hypotension within an hour and most during
`the loading infusion. In 20 critically ill patients, Shehabi et al [26] report that when
`dexmedetomidine is started without a loading infusion at 0.4 μg kg−1 h−1 and titrated to
`Ramsay Sedation Score between 2 and 4 for a median of 71.5 hours, mean systolic blood
`pressure dropped 16% within 2 hours then gradually stabilized. Heart rate decreased
`gradually over 12 hours by 21% with minimal changes thereafter. This is similar to our
`results where the mean time to hypotension was 3.9 hours compared to 9.7 hours for
`bradycardia. It could be that hypotension occurs sooner in critically ill patients than
`bradycardia, especially if the patients have intravascular volume depletion and are
`dependent on their adrenergic response, and this was not measured in our study.
`
`Use of the protocol did not seem to compromise sedation, but because there were not
`consistent time points mandated for sedation documentation, this comparison was not
`perfect. At initiation of therapy, the groups had comparable sedation levels with the median
`in each group reported as calm (RASS 0, Ramsay Sedation Score 2) (Table 3). Our best
`surrogates of later sedation were sedation scores around the time of adverse drug effects or
`need for additional sedation. Sedation scores were documented within 2 hours of the
`development of hypotension or bradycardia in all but 1 patient, and median scores were
`similar between the protocol and control groups (protocol group median RASS −1 [light
`sedation] vs control group median Ramsey sedation score 2 [calm]). Use of additional
`sedation was allowed in the protocol, but additional sedation was required in only 2 (8%)
`patients, which is consistent with other comparative studies [17,20,22]. Nonetheless,
`because the level of sedation was not documented during the occurrence of each adverse
`drug event, it is unknown if there was truly a difference in this retrospective review.
`
`Because of its retrospective nature, this study has several additional limitations. The results
`are hypothesis generating, and there is a potential for selection bias in our historical control
`group. Next, there were no predefined clinical criteria to insure that patients in each group
`had comparable volume status. It is also possible that protocol patients developed less
`hypotension because they received slightly less dexmedetomidine, but this question will
`require a larger sample size. Finally, we switched from using the Ramsay Sedation Scale to
`the Richmond Agitation Sedation Scale during the study period, and as mentioned,
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`frequency of documentation for sedation scores was variable between patients. Although we
`attempted to equate the 2 sedation scores by normalizing the values, this has not been tested.
`For these reasons, we feel that our results will need to be confirmed independently, taking
`care to address these issues.
`5. Conclusions
`Dexmedetomidine is a sedative agent with several unique properties that make it attractive
`for use in critically ill patients. Although our initial experience demonstrated an
`unacceptably high incidence of hypotension, use of a dosing protocol was associated with
`significant reduction in hypotension incidence. Further prospective studies will be required
`to validate this protocol for use during critical illness and to determine the influence of
`preadministration volume status upon dexmedetomidine complications.
`
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`17. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TG, Miller R, et al. Effect of sedation with
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`2003; 17:576–84.
`19. Venn RM, Grounds RM. Comparison between dexmedetomidine and propofol for sedation in the
`intensive care unit: patient and clinician perceptions. Br J Anaesth. 2001; 87:884–90.
`20. Corbett SM, Rebuck JA, Greene CM, Callas PW, Neale BW, Healey MA, et al. Dexmedetomidine
`does not improve patients satisfaction when compared to propofol during mechanical ventilation.
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`21. Ickeringill M, Shehabi Y, Adamson H, Reuttimann U. Dexmedetomidine infusion without loading
`infusion in surgical patients requiring mechanical ventilation; hemodynamic effects and efficacy.
`Anaesth Intensive Care. 2004; 32:741–5. [PubMed: 15648981]
`22. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine
`vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009; 301:489–99.
`[PubMed: 19188334]
`23. Dasta JF, Kane-Gill SL, Durtschi AJ. Comparing dexmedetomidine prescribing patterns and safety
`in the naturalistic setting versus published data. Ann Pharmacother. 2004; 38:1130–5. [PubMed:
`15173557]
`24. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma
`concentrations of dexmedetomidine in humans. Anesthesiology. 2000; 93:382–94. [PubMed:
`10910487]
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`of postoperative patients requiring intensive care. Br J Anesth. 2002; 88:669–75.
`26. Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M. Dexmedetomidine infusion for
`more than 24 hours in critically ill patients: sedative and cardiovascular effects. Intensive Care
`Med. 2004; 30:2188–96. [PubMed: 15338124]
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`Pharmacotherapy. 2008; 28:51–7. [PubMed: 18154474]
`28. Venn RM, Newmann PJ, Grounds RM. A phase II study to evaluate the efficacy of
`dexmedetomidine for sedation in the medical intensive care units. Intensive Care Med. 2003;
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`J Crit Care. Author manuscript; available in PMC 2013 July 28.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1020 – Page 8
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`Gerlach et al.
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`Page 9
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`Fig. 1.
`Dexmedetomidine dosing protocol.
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`J Crit Care. Author manuscript; available in PMC 2013 July 28.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1020 – Page 9
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`Galach et al.
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`Page 10
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`Demographics and admitting services
`
`Won-=25) Historicalconh'ol(l=]9)
`
`p
`
`Table 1
`
`Age (y)
`
`Female (95)
`
`APACHE H a
`
`ICU length ofstay (d)
`
`47.1 :i: 13.3
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`24
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`21 {15—25}
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`13.7 1 10.6
`
`Days with mechanical vulilafim
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`9.5 :t: 9.6
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`Admitting swims, n (94)
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`Ttannn
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`Neurosurgery
`
`Caldiothmacic surgery
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`Gem-n! SWIM
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`Paiplnal vascular surgery
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`12 (48)
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`10 (40)
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`1 (4)
`
`2 (3)
`
`0
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`.15
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`.71
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`.38
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`.61
`
`.85
`
`55.5 :i: 19.9
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`15.5
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`22 {IS—B}
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`1 1.8 $11.4
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`10.2 :I: 12.1
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`6 (31.6)
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`6 (31.6)
`
`4 (21.0)
`
`o
`
`3 (15.8)
`
`Maplesmudasistandatddcvialion
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`aDataal'e ptuenlnd as median {2596—7536 intu'quanile my}.
`
`ICtit Catt. Author manuscript available in PMC 2013 July 28.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc - Exhibit 1020 - Page 10
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`Garlachetal.
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`Page 11
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`Dosing and