International TroumoCore (ITACCS)
`
`www.iic1ccs.com
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`PRESIDENT’S MESSAGE
`
`Dexmedetomidine and Hextend:
`
`Their Role in Trauma Care
`
`James Gordon Cain, MD
`President, International TraumaCare
`Immediate Past—president,
`West Virginia State Society ofAnesthesiologists
`Director; Trauma Anesthesiology, Children ’5 Hospital of Pittsburgh
`Associate Professor; University of Pittsburgh
`Pittsburgh, Pennsylvania 15312 USA
`jamesgcain@yahoo.com
`
`review of another innovation in trauma anesthesia practice—the use
`of Hextend during trauma surgery.
`Opening the issue is an extensive systems-based literature
`review, compiled by Joseph D. Tobias, MD, from the University of
`Missouri. Dr. Tobias discusses the preoperative, perioperative, and
`postoperative scenarios in which dexmedetomidine is, could be, and
`is not effective. Following a brief overview of the drug's
`pharmacokinetics, the article continues with a comprehensive
`discourse on the end-organ effects and clinical applications of
`dexmedetomidine. Cardiovascular and hemodynamic effects are
`described, as are effects on the sympathetic and central nervous
`systems. The passage on respiratory effects includes summaries of
`studies of drug combinations, emphasizing the need for careful
`monitoring of the respiratory function of patients receiving
`dexmedetomidine. It should be kept in mind that the amount of
`narcotics typically required to achieve comfort in the setting of
`dexmedetomidine is generally cut in half. Thus, if this is not
`accounted for, one may effectively give a patient a narcotic
`overdose, thereby blunting the respiratory drive.
`Tobias introduces interesting thoughts regarding the
`anticonvulsant/proconvulsant effects of dexmedetomidine in brain—
`injured patients and the mechanism of action for the drug's
`neuroprotective effect. It is clear that dexmedetomidine offers
`distinct advantages for the control of shivering and opioid-induced
`muscle rigidity, again of particular importance in the trauma patient,
`particularly in head-injured patients in whom some degree of
`hypothermia may be desired for cerebral protection.
`Other issues of importance in the intensive care unit include
`gastrointestinal motility, adrenocortical function, and inflammatory
`response. Tobias provides an illuminating review of
`dexmedetomidine's influence on these aspects of postoperative care
`and how, in contrast to other commonly used sedation medications,
`dexmedetomidine either supports or at least does not depress
`anabolic activities in the critically ill.
`In clinical applications, Tobias notes that dexmedetomidine has
`been used as a premedication, as an intraoperative infusion, by
`intraoperative bolus dosing, and for postoperative sedation in
`intubated and nonintubated patients. The drug has been used in
`patients undergoing gynecologic procedures, hand surgery, and
`craniotomy. In balanced anesthetic technique, dexmedetomidine can
`decrease anesthetic requirements and improve intraoperative stability.
`It also may find a role as part of monitored anesthesia care with a
`regional anesthetic technique. Its postoperative analgesic effects are
`well established, and it may serve as a useful adjunct to epidural
`analgesia or patient-controlled analgesia (PCA). In my practice with
`bariatric surgery patients receiving postoperative dexmedetomidine
`infusions, I noted, as have others, a nearly halved utilization of PCA
`narcotic doses over the first 24 postoperative hours.
`Several studies have documented the successful use of
`
`
`
`Anesthesia now seems so safe that sometimes one may wonder
`how to further improve our patients' perioperative care. Perhaps we
`fine-tune existing strategies, such as adding the volatile agent
`sevoflurane, which improved acceptance of inhalation induction,
`decreased hemodynamic perturbations, and markedly impacted care
`of pediatric patients. Nonetheless, this may be just a reinvention of
`the same old wheel. When I first began practicing anesthesiology, I
`often imagined characteristics of an ideal perioperative drug. Ideally
`it would offer an easily arousable sedation, provide pain relief while
`not depressing respiratory drive, and have relatively mild
`hemodynamic effects. At a meeting in the spring of 2000 I found out
`that just such a drug, dexmedetomidine, a specific az-adrenergic
`agonist that induces a sleep—like state, was soon to be introduced to
`the United State market. Iquickly envisioned the utility of
`dexmedetomidine and, as chief of anesthesiology at my hospital,
`requested that dexmedetomidine be added to the fonnulary as soon
`as possible. Initially, I was interested in its potential for bariatric
`surgery patients, patients at significant risk for airway obstruction,
`atelectasis, and hypoxernia, but quickly realized its vast potential to
`augmenting perioperative pain control while maintaining respiratory
`drive with a predictable hemodynamic effect.
`Over the intervening years, I have expanded my use of
`dexmedetomidine to include nearly all patient categories, ranging
`from same—day surgery to congenital cardiac surgery patients, and of
`course critically ill and injured trauma patients. Unfortunately, when
`the Food and Drug Administration approved the use of
`dexmedetomidine (Precedex, Hospira Inc., Lake Forest, Illinois) in
`1999, it was for the limited indication of sedation for initially
`intubated and mechanically ventilated adult patients in intensive care
`units and limited to a 24-hour infusion. This relatively narrow
`indication limited use of dexmedetomidine in some medical centers,
`while in many other facilities, its off-label utilization grew as
`experience and comfort with dexmedetomidine expanded and
`clinicians realized the utility of this new class of medications.
`This issue of TraumaCare contains three articles by clinicians
`with substantial experience with and interest in the use of
`dexmedetomidine in a variety of clinical settings. Their reports cover
`not only the approved uses of this powerful and selective sedative
`but also the extensions of its use into scenarios in which short-term
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`blunting of physical responses is beneficial, as is the ability to
`arouse the patient by verbal stimuli. The issue concludes with a
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`dexmedetomidine to prevent emergence agitation and delirium
`following general anesthesia with sevoflurane or desflurane. In
`addition, dexmedetomidine seems to decrease the incidence of
`coughing on emergence from anesthesia.
`Although dexmedetomidine is effective for sedation during
`nonpainful procedures such as computed tomography and radiation
`Dr. Cain is also the Guest Editor of this issue that deals primarily with the subject of dexmedetomidine and presents a retrospective study relating the intraoperative use of Hextend.
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1035 — Page 4
`
`

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`Vol. 17, No. l, 2007
`
`International TroumoCare (ITACCS)
`
`therapy (especially useful for calming children undergoing such
`procedures), it is not sufficient, when used alone, for painful
`invasive procedures such as gastroduodenoscopy unless extremely
`high doses (between 10 and 20 times the standard sedating doses)
`such as those used by Ramsey to provide a general anesthesia are
`given to the patient, as noted in Tobias’ article. Unfortunately, such
`large doses result in excessive and prolonged sedation, making
`dexmedetonridine difficult to consider using as a full general
`anesthetic agent in the outpatient setting.
`Tobias concludes the article with sections on the best known
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`uses of dexmedetomidine: during mechanical ventilation and for the
`management of withdrawal symptoms. In numerous studies,
`dexmedetonridine has decreased the need for narcotics (i.e..
`morphine); however, other investigators have found no advantage
`offered by dexmedetomidine over those associated with propofol.
`For the management of withdrawal from opioids, benzodiazepines,
`and alcohol, dexmedetonridine has the advantages of a relatively
`short half-life and titratability. Reports on the administration of
`dexmedetonridine to mechanically ventilated children are beginning
`to emerge, cautiously documenting promising results. In my clinical
`experience, a majority of the pediatric congenital heart surgery
`patients I care for receive dexmedetomidine for postoperative
`sedation in our cardiac intensive care unit with a safe and
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`satisfactory sedation.
`In the second article, Rafi Avitsian, MD, Mariel Manlazaz, MD,
`and John Doyle, MD, PhD, from the Cleveland Clinic, describe the
`benefits conveyed to patients and practitioners in trauma scenarios
`requiring awake intubation. These authors compare
`dexmedetomidine with other (ll-receptors that have been used in
`clinical practice for decades. The unique features of
`dexmedetonridine include its shorter half-life, which allows titration
`as an intravenous infusion; its insignificant effect on respiratory
`function and gas exchange; and its ability to effect sedation yet
`preserve the ability to arouse the patient. This latter characteristic is
`particularly useful during awake intubation of patients with potential
`cervical instability. Patients brought to a resuscitation unit following
`traumatic injury. particularly injuries of the head and neck, are
`understandably anxious, and thus can be uncooperative with airway-
`management procedures. Adnrinistration of dexmedetonridine allows
`the physician to achieve a desired level of sedation for awake
`intubation and to retain the ability to arouse the patient through
`verbal stimulation so that neurologic status can be monitored. In my
`own clinical practice, I have been using dexmedetonridine for awake
`fiberoptic intubations since shortly after I fust gained access to the
`medication. I find that a convenient way to facilitate these fiberoptic
`intubations is to initiate an infusion of l mcglkglhr of
`dexmedetonridine and at the same time administer a nebulized
`
`lidocainc and Pontocaine treatment to augment topicalization of the
`airway. In the roughly ten nrinutes it takes for the nebulizer
`treatment, the patient will typically be comfortably sedated with the
`dexmedetonridine and ready for their awake intubation. In the rare
`circumstances when the patient still appears to need a bit more
`sedation, I may consider small doses (0.5—l mcglkg) of fentanyl
`and/or rnidazolam (OJ-0.2 mg/kg), dosed in increments until an
`acceptable degree of sedation is obtained.
`The third article on dexmedetomidine, written by Mohanad
`Shukry, MD, from the Oklahoma University College of Medicine,
`and myself, focuses on the use of this drug to mitigate the agitation
`and confusion that accompany withdrawal from alcohol,
`benzodiazepines, and narcotics. Animal studies have shown that
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`dexmedetomidine is as effective as diazepam in easing withdrawal
`from alcohol. Extrapolation to alcohol-dependent humans awaits
`further study. Dexmedetonridirre has proven effective in treating
`several withdrawal symptoms in patients addicted to cocaine,
`narcotics, and benzodiazepines and in intensive care unit patients who
`received dexmedetomidine during hospital procedures. The value of
`dexnredetonridine in the management of withdrawal symptoms in
`children and teenagers has been documented in recent case reports.
`We also review reports of the use of dexrrredetornidine in children
`undergoing tonsillectomy and other surgical procedures. Although the
`pharmacokinetics and pharmacodynamics of dexmedetonridine are
`not completely understood, the drug seems to hold great promise
`when administered properly, under close clinical scrutiny. for the
`prevention and treatment of postprocedural agitation in adults and
`children. At this author’s institution, the pharmacy now offers
`premixed syringes of dexnredetonridine (10 mL with 4 mcglmL) for
`use as both a component in a balanced anesthetic and in preventing
`postanesthesia agitation and delirium. Dexmedetomidine is also used
`as a rescue drug in the care of these pediatric patients exhibiting such
`postanesthesia agitation. In both these settings, when used as bolus
`doses, the drug is most commonly delivered in 0.25—0.5 meg/kg
`doses. When bolus doses of more than 0.5 meg/kg are used, the initial
`aI-agonist effect predominates for the first 5 minutes or so after
`induction, causing an increase in blood pressure and a decrease in
`heart rate, which in some patients may be undesirable.
`The fourth article reviews the intraoperative use of Hextend, a
`colloid delivered in a balanced salt solution, and another compound
`that is a relatively new component for trauma care. Hextend may be
`simply thought of as a hetastarch in a lactated Ringer's solution.
`This contrasts to the older Hespan, effectively a hetastarch in 0.9%
`normal saline. Hespan is accepted to induce coagulopatlries when
`delivered to patients in volumes above 1.5-2 liters. Hextend does not
`appear, in vivo, to precipitate coagulopatlries even in doses up to 5
`liters. Based on a retrospective review, Drs. Karl Wagner,
`Ramachandra Avula, and Charles E. Smith, from MetroHealth
`Medical Center in Cleveland, compare outcomes in two groups of
`patients who underwent surgery during the first day after adrrrission
`to a trauma center. Despite the patients in the study receiving
`Hextend being sicker than those receiving crystalloid infusions when
`assessed by injury severity scores, there was no difference in
`morbidity or mortality in the Hextend group. While we await a
`prospective, randomized, double-blind study on the use of Hextend
`in the perioperative care of the trauma patients, this article provides
`us a measure of comfort in using Hextend, in the same fashion as the
`SAFE (saline vs. albumin) trial established that it is not harmful to
`use albumin in the critically ill.
`In closing, this issue of the journal offers a view of two
`innovations in trauma care. Dexmedetonridine is, for all practical
`purposes, a new class of medication, perhaps offering some ideal
`characteristics for use in the trauma setting: easily arousable sedation
`and pain control along with a predictable hemodynamic response
`without significant respiratory depression. Hextend offers a colloid
`with a balanced salt solution that appears to have no significant
`deleterious effects. and may perhaps offer an efficient means for
`volume expansion in the critically injured trauma patient. This
`author’s hope is that the readers of this journal edition will be
`stimulated to firrther investigation themselves, and perhaps by
`pursuing quality research, provide answers to some of the questions
`elicited by these articles.
`
`
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLc — Exhibit 1035 - Page 5
`
`