Journal of Pain & Palliative Care Pharmacotherapy. 2014;28:243–250. Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2014.941129

CASE REPORT

Management of Refractory Status Epilepticus in an Actively Dying Patient Jennifer D. Dulin, Danielle M. Noreika, and Patrick J. Coyne A B STRA CT No consensus guidelines exist for the treatment of refractory myoclonic status epilepticus or refractory myoclonus in the palliative care setting. Evidence-based guidelines for the general medical population are often neither practical nor applicable at the end of life. Many challenges, including medication availability, route of administration, monitoring, and work-up are all unique to the palliative care setting. Two patients with refractory myoclonus versus refractory myoclonic status epilepticus are described here, illustrating the challenges involved in treatment as well the need for further research for therapy in the palliative care setting. KEYWORDS myoclonus, palliative care, refractory, status epilepticus, propofol, seizures

agonal event.7 Treatment guidelines for SE in general medical population include intravenous (IV) agents (see Table 1) and close monitoring that are often not available or typically appropriate in the palliative care setting.8,9 Per accepted guidelines, Virginia Commonwealth University’s Thomas Palliative Care Unit has a protocol for treating seizure activity with as needed benzodiazepines and escalating care versus initiation of chronic suppression based on goals of care and appropriateness (see Appendix 1). When appropriate, this may include palliative sedation to include the use of benzodiazepines, barbiturates, or propofol (see Appendix 2). Patient goals often preclude transfer to an intensive care unit setting and may require medications and dosages outside of standard treatment algorithms and range used on general medical floors. The following cases describe successful treatment of refractory myoclonic status in actively dying patients with propofol after failure of first- and secondline therapies in a palliative care unit setting.

INTRODUCTION Seizures regularly occur in palliative care but status epilepticus (SE), and myoclonic status epilepticus are less common.1,2 SE is seizure activity, either continuous or without full recovery, lasting more than 30 minutes. Refractory SE occurs in approximately 30% of all SE cases. Refractory SE does not respond to first- or second-line therapies (lorazepam/midazolam and fosphenytoin/phenytoin, respectively).3,4 Myoclonic status epilepticus is spontaneous, repetitive, unrelenting, generalized myoclonus involving the face, limbs, and axial musculature in comatose patient5,6 ; it portends vast neurological damage and is not only a poor prognostic indicator but an

Jennifer D. Dulin, MD, is Assistant Professor in the Division of Palliative Medicine, Department of Internal Medicine, at University of South Florida, Tampa, Florida, USA; and Attending Physician on the Palliative Care Service at Tampa General Hospital in Tampa, Florida, USA. Danielle M. Noreika, MD, is Medical Director of Thomas Palliative Care Inpatient Unit and Assistant Clinical Professor in the Division of Hematology, Oncology and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. Patrick J. Coyne, MSN, APRN, FAAN, is Clinical Director, Pain and Palliative Care, Thomas Palliative Care Services, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. Address correspondence to: Jennifer D. Dulin, MD, Division of Palliative Medicine, Department of Internal Medicine, University of South Florida, 12901 Bruce B Downs Boulevard, MDC19, Tampa, FL 33612, USA (E-mail: [email protected]).

CASE 1 SW was a 55-year-old female with a history of hepatitis C cirrhosis who was admitted for respiratory failure and coma after a suspected opioid 243

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TABLE 1.

Medications Used in Management of Status Epilepticus23,33,34

Drug name

Drug class

Mechanism of action

Diazepam—not shown effective in long-term treatment (i.e., suppression)

BZD

Enhances effect of GABA-A activity by receptor binding

Lorazepam

BZD

Enhances effect of GABA-A activity by receptor binding

Midazolam

BZD

Enhances effect of GABA-A activity by receptor binding

Phenytoin

AED

Fosphenytoin35

AED

Phenobarbital36

Barbiturate

Blocks frequency-, use-, and voltage-dependent neuronal sodium channels, limiting repetitive firing of action potentials Blocks frequency-, use-, and voltage-dependent neuronal sodium channels, limiting repetitive firing of action potentials Prolongs and potentiates action of GABA on GABA-A receptors

Propofol

Anesthetic

Ketamine

Analgesic/ anesthetic

Potentiates GABA-A receptor activity Blocks sodium channels NMDA-receptor antagonist

Administration PR: 10–20 mg, repeat after 15 min—may cause rectal burning and irritation IV: 10 mg over 2–5min, repeat after 15 min IM IV: bolus 0.5–1 mg/kg; repeat after 20 min IM SL Intranasal SC PR IV: 0.1–0.3 mg/kg bolus; infusion: 0.05–0.4 mg/kg/h SC Buccal: 10 mg bolus Intranasal: 0.2 mg/kg bolus IM: 0.2–0.3 mg/kg IV: infusion 15–20 mg/kg SC IM: unpredictable absorption; tissue irritant PO IV: bolus loading: 15 mg phenytoin equivalents/kg; maintenance dose of 4–5 mg/kg/24 h IM: as IV IV: bolus 10–20 mg/kg; maintenance: 1–4 mg/kg/day SC: bolus: 100–200 mg; maintenance: 600–2400 mg/24 h IV: bolus 1 mg/kg; infusion: 1–15 mg/kg/h

IV = intravenous; IM = intramuscular; PR = per rectum; SC = subcutaneously; PO = oral; SL = sublingual; BZD = benzodiazepine; AED = antiepileptic drug.

overdose. She was encephalopathic throughout her admission, as evidenced by confusion, disorientation, and asterixis. A magnetic resonance imaging (MRI) demonstrated anoxic brain injury with laminar necrosis. The palliative care service was consulted 37 days after initial admission for worsening mental and clinical status. The patient had been actively seizing for some time, and although an electroencephalogram (EEG) was not obtained due to her goals of care, SW was believed to be in status epilepticus versus myoclonic status epilepticus as a result of severe anoxic brain injury, electrolyte abnormalities, uremia, and multiple other confounding factors. The patient’s family agreed to a course of comfort care with a transition to the palliative care unit (PCU) because of the severity of her underlying medical conditions and persistent seizures suggesting a prognosis of hours to days.

SW initially received 8 mg of IV lorazepam in multiple doses, with minimal improvement in her symptoms. Given the persistence of her symptoms, she was started on a midazolam drip with boluses as needed. This was quickly titrated, based on continued symptoms, to 15 mg midazolam per hour with minimal benefit. Because the patient was nonresponsive to benzodiazepine therapy, the likely need for propofol treatment was discussed. Prior to consideration of propofol therapy, the patient received 120 mg of IV phenobarbital, 10 mg of IV diazepam (to prevent benzodiazepine withdrawal after as needed [PRN] lorazepam and midazolam infusion), 10 mg of IV dexamethasone, 50 mg of IV diphenhydramine, levetiracetam 1 g IV every 12 hours, a loading dose of 1500 mg fosphenytoin equivalent, and methadone 1 mg IV (transitioned from scheduled morphine in the case it was triggering myoclonus10,11 ). All of Journal of Pain & Palliative Care Pharmacotherapy

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these interventions were ineffective in decreasing the patient’s symptoms. SW was then started on a propofol infusion. Per unit protocol, which describes palliative sedation to include propofol, in the palliative care unit (see Appendix 2), SW received 20 mg of propofol via IV bolus over 5 minutes and then started on a continuous rate of 10 mg per hour. This was titrated to effect by 10 mg per hour every 15 minutes. SW’s seizure activity ceased at a propofol infusion rate of 30 mg per hour and did not recur while she remained on the drip. She continued at this rate of propofol along with scheduled methadone, scheduled levetiracetam 1 g IV every 12 hours, and 10 mg IV scheduled diazepam until her death 9 hours later. Her vital signs remained stable until immediately prior to expiration.

CASE 2 RA was a 67-year-old male who was admitted to the coronary intensive care unit after suffering a witnessed pulseless electrical activity (PEA) arrest whence his ECG demonstrated a rhythm, but he did not have a palpable pulse. He underwent cardiopulmonary resuscitation and was ultimately started on a hypothermia protocol. The American Heart Association recommends that comatose patients with return of spontaneous circulation after in- or out-ofhospital cardiac arrest be cooled to 32◦ C to 34◦ C for 12 to 24 hours. Evidence indicates that neurological injury is the most common cause of death in patients with out-of-hospital cardiac arrest; decreasing the core body temperature improves neurological and overall outcomes. Cooling is induced with cold saline and icepacks. Sedation, paralytics, vasopressors, and ventilator support are core components of management.12 On admission, he was noted to have myoclonic jerking. The neurology service’s assessment of sedation with EEG monitoring confirmed myoclonic status epilepticus. As a result, RA’s midazolam infusion was titrated, propofol was added, and levetiracetam was increased to 1500 mg IV every 12 hours for symptom control. Two days after admission, the patient was rewarmed as per the Advanced Resuscitation Cooling Therapeutics Intensive Care (ARTIC) protocol—the post cardiac arrest hypothermic protocol at Virginia Commonwealth University, which involves cooling, documentation of neurological function, and managing patient symptoms with laboratory monitoring, ventilator support, sedatives, and paralytics. His myoclonic status epilepticus persisted, requiring 12 mg per hour of midazolam as well as propo C

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fol 20 mg per hour for suppression of myoclonic activity. Given evidence of severe anoxic brain injury and poor likelihood of any meaningful recovery, the patient’s family opted to withdraw aggressive lifesustaining measures. Prior to terminal extubation, the patient’s team attempted to wean his sedation, but his myoclonic jerking recurred with minimal decreases in medication. Palliative care was consulted for assistance in symptom management as well terminal extubation. Given symptom resurgence with wean of midazolam and propofol, we recommended continuing medications at current rates with additional bolus doses available as needed for symptom control. The patient was extubated without incident, and myoclonus remained well controlled. Unfortunately, prior to transfer to inpatient palliative care unit, the patient’s propofol was discontinued. On arrival to the PCU, RA had myoclonic jerking and labored respirations, with occasional brow furrowing. Propofol was restarted and he was placed on morphine patient-controlled analgesia (PCA) at a continuous rate of 1 mg per hour with nursecontrolled analgesia. With initiation of both the propofol and morphine, the patient’s myoclonus resolved and he appeared comfortable. Medication was titrated as needed until his death approximately 36 hours after transfer to PCU.

DISCUSSION Myoclonic SE and refractory myoclonic SE are rare but can be very difficult to treat syndromes at end of life. Myoclonic SE and refractory myoclonic SE can cause great distress to patients and families as well as staff.13,14 Persistent, refractory, generalized myoclonus, seen as sudden, brief, shock-like involuntary movement secondary to muscles contractions, may result, similar to seizure activity, from metabolic abnormalities (i.e., liver or renal failure, hypoglycemia, hyponatremia), medications (especially those commonly used at the end of life, including opioids, anticonvulsants, tricyclic antidepressants, selective serotonin reuptake inhibitor antidepressants, antibiotics), central nervous system (CNS) damage, and encephalopathies.15 Although many modalities have been suggested for treatment, the treatment of choice remains correction of the underlying cause. Unfortunately, this often requires extensive evaluation that is neither warranted nor practical in the actively dying patient.16 First- and second-line therapies for SE are lorazepam/diazepam followed by fosphenytoin/

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phenytoin, respectively.17,18 One study demonstrated equal effectiveness of lorazepam, phenytoin, diazepam with phenytoin, and phenobarbital in said treatment.19 When these therapies fail, midazolam, barbiturates, and propofol are treatment options.20 Lorazepam is the first-line agent for treatment of SE for multiple reasons, including duration of action and rapid onset.21 The response rate of generalized tonic-colonic SE to lorazepam is 85% to 89%.22 It also appears to be the most effective treatment of postanoxic myoclonic status epilepticus and, thus, should be its first-line therapy.23 Like lorazepam, midazolam is a benzodiazepine. Similarly, it binds at γ -aminobutyric acid (GABA)-A receptors in the central nervous system.24 . Increasing doses lead to decreases in repetitive neuronal firing similar to the mechanism of antiepileptic drugs (AEDs) such as carbamazepine25 ; it can be administered subcutaneously (SC), IV, orally, bucally, or rectally. Midazolam is often readily available in the palliative care setting and is frequently used for palliative sedation26 ; however, side effects are more common with continuous infusion and tachyphylaxis may occur.27 Propofol is an IV anesthetic with rapid onset of action and rapid recovery. The distribution half-life is 2 to 8 minutes, with an elimination half-life of 30 to 60 minutes. It is rapidly metabolized in the liver and excreted in the urine.24,28 Propofol decreases peripheral resistance, often causing hypotension during administration; apnea can occur during bolus dosing. In addition to its use in inducing and maintaining analgesia, propofol has been described as treatment for refractory SE.29,30 One of the many advantages is its rapid onset of action. Propofol’s mechanism of action against seizures in uncertain but may be due to increasing the inhibitory effects of GABA.29 Propofol, given the risk of apnea, hypotension, and bradycardia, is generally used in a highly monitored setting; however, when used for control of distressing symptom at the end of life, the risk and benefits are carefully considered and this often mitigates the need for monitoring. Administration of the aforementioned medications often requires monitoring along with access to resuscitative resources. Great care must be taken in timing, dosing, and combinations of medications administered. Palliative care undoubtedly provides a challenging setting, as these resources are often not available; however, the goals of our patients often allow for aggressive comfort treatment despite the lack of said resources. Medications are titrated by experienced clinicians and nursing staff to affect symptoms while exquisite care is taken not to hasten death or create or worsen patient symptoms.31,32 For

the rare patients who have significant brain injury and refractory myoclonus at end of life, managing propofol in a palliative care unit setting when other agents have failed allows a chance for a peaceful death away from a critical care support setting.

CONCLUSION Refractory myoclonus can be very distressing for patients and families at end of life as well as very difficult to treat: in patients who are resistant to first- and second-line treatments, consideration can be safely made to institute or continue therapy with propofol in a palliative care unit setting. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

REFERENCES [1] Droney J, Hall E. Status epilepticus in a hospice inpatient setting. J Pain Symptom Manage. 2008;36:97–105. [2] Juba KM, Weiland D. Seizure management in a complex hospice patient. J Pain PalliatCare Pharmacother. 2010;24:27–32. [3] Allredge BK, Lowenstein DH. Status epilepticus: new concepts. Curr Opin Neurol 1999;12:183–190. [4] Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry. 2001;70(Suppl 2):II22–II27. [5] English WA, Griffin NJ, Nolan JP. Case report: myoclonus after cardiac arrest: pitfalls in diagnosis and prognosis. Anaesthesia. 2009;64:908–911. [6] National Institute of Neurological Disorders and Stroke. Myoclonus Fact Sheet. Bethesda, MD: National Institutes of Health; July 2012. NIH Publication No. 12-4793. [7] Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol. 1994;35:239–243. [8] Walker M. Status epilepticus: an evidence based guide. BMJ. 2005;331:673–677. [9] Prasad K, Al-Roomi K, Krishnan PR, Sequeira R. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2005;(4):CD003723. [10] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #57; Neuroexcitatory Effects of Opioids: Patient Assessment. Available at: www.eperc.mcw.edu. Accessed March 12, 2014. [11] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #58; Neuroexcitatory Effects of Opioids: Treatment. Available at: www.eperc.mcw.edu. Accessed March 12, 2014. [12] Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: postcardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):s768–s786. [13] Golf M, Paice J, Feulner E, et al. Refractory status epilepticus. J Palliat Med. 2004;7:85–88. [14] Waterhouse EJ, DeLorenzo RJ. Status epilepticus in older patients: epidemiology and treatment options. Drugs Aging. 2001;18:133–142.

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J. D. Dulin et al. [15] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #114; Myoclonus. Available at: www.eperc. mcw.edu. Accessed March 12, 2014. [16] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #229; Seizure Management in the Dying Patient. Available at: www.eperc.mcw.edu. Accessed March 12, 2014. [17] Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol. 2006;13:445–450. [18] Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia. 1999;40(Suppl 1):S59–S63. [19] Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339:792–798. [20] Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia.2002;43: 146–153. [21] Sorel L, Mechler L, Harmant J. Comparative trial of intravenous lorazepam and clonazepam in status epilepticus. Clin Ther. 1981;4:326–336. [22] Levy RJ, Krall RL. Treatment of status epilepticus with lorazepam. Arch Neurol. 1984;41:605–611. [23] Vincent FM. Lorazepam in myoclonic seizures after cardiac arrest. Ann Intern Med. 1986;104:586. [24] Katzung B. Drugs that act in the central nervous system. Basic Clin Pharmacol. 9th Ed. New York: Lange Medical Books/ McGraw Hill, 2004:336–441. [25] MacDonald RL, McLean MJ. Anticonvulsant drugs: mechanisms of action. In: Delgado-Escueta AV, Ward AA Jr, Woodbury DM, Porter RJ, eds. Advances in Neurology. Volume 44. Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. New York: Raven Press; 1986: 713–716. [26] Kumar A, Bleck TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med. 1992;20: 483–488.

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[27] Bassin S, Smith TL, Bleck TP. Clinical review: status epilepticus. Crit Care. 2002;6:137–142. [28] Wijdicks EF. Propofol in myoclonus status epilepticus in comatose patients following cardiac resuscitation. J Neurol Neurosurg Psychiatry. 2002;73:94–95. [29] Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia. 1998;39:18–26. [30] Parvianen I, Uusaro A, Kalviainen R, Mervaala E, Ruokonen E. Propofol in the treatment of refractory status epilepticus. Intensive Care Med. 2006;32:1075–1079. [31] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #106; Controlled Sedation for Refractory Suffering—Part I. Available at: www.eperc.mcw.edu. Accessed March 12, 2014. [32] End-of-Life/Palliative Education Resource Center. Fast Fact and Concept #107; Controlled Sedation for Refractory Suffering—Part II. Available at: www.eperc.mcw.edu. Accessed March 12, 2014. [33] Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996;46(6 Suppl 1):S24–S28. [34] Mattson RH. Parenteral antiepileptic/anticonvulsant drugs. Neurology. 1996;46(6 Suppl 1):S8–S13. [34] Shaner DM, McCurdy SA, Herring MO, Gabor AJ. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology. 1988;38:202–207. [35] Fischer JH, Patel TV, Fischer PA. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42:33–58. [36] Stirling LC, Kurowska A, Tookman A. The use of phenobarbitone in the management of agitation and seizures at the end of life. J Pain Symptom Manage. 1999;17:363–368.

RECEIVED: 27 May 2014 REVISED: 23 June 2014 ACCEPTED: 1 July 2014

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APPENDIX 1

APPENDIX 2 Thomas Palliative Care Guidelines Palliative Sedation I. Purpose: To establish a guideline for the delivery of parenteral or subcutaneous sedation to provide comfort during the final phase of life for patients who:

• Have an established “Do Not Resuscitate” order, • Are Terminally ill, • Are experiencing refractory symptoms, seizures and/or restlessness • Whose treatment options have been discusses with members of the interdisciplinary team and with the patient and/or family Team member consults that should be sought include: palliative care attending, fellow/advanced practice nurse, staff nurse, and chaplain. The depth and duration of sedation needed may vary, depending on the symptoms being palliated and the goals of treat-

ment. This treatment will be administered only on the Palliative Care Unit. Drugs that may be used include: midazolam, propofol, and phenobarbital or pentobarbital. The purpose of this intervention is to relieve symptoms and suffering and not to hasten death. It is not a form of conscious sedation, euthanasia or physician assisted suicide. II. Definitions: 1. Controlled sedation is the judicious controlled application of medications to reduce or alter consciousness in order to relieve refractory symptoms or suffering that are not responsive to less aggressive interventions. The level of sedation may be increased or decreased due to patient and family needs or concerns. 2. This guideline addresses the use of midazolam, propofol, or barbiturates for the purposes of palliation of symptoms, seizures, and/or restlessness that have been refractory to standard palliative therapy. Journal of Pain & Palliative Care Pharmacotherapy

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3. A refractory symptom is one that cannot be adequately controlled despite aggressive efforts to identify a tolerable therapy that does not compromise consciousness. In deciding when a symptom is refractory, the clinician must perceive that further invasive and non-invasive interventions are incapable of providing adequate relief, are associated with excessive and intolerable acute or chronic morbidity, or are unlikely to provide relief within a tolerable time frame. 4. Opioids should be continued, in conjunction with the use of sedation, to avoid withdrawal and for the treatment of presumed pain. III. Pharmaceutical Consideration: A. Midazolam (IV or SQ) a. Description – Versed is a very short acting benzodiazepine (onset of action within 35 minutes after intravenous injection with peak effect seen in 20-60 minutes), used most frequently as an induction agent for general anesthesia or to provide conscious sedation during brief invasive diagnostic procedures. Versed infusion has also been shown to be a safe and effective therapy in palliative care for the management of symptoms, including anxiety, pain control, seizures and restlessness that have been refractory to standard therapy. This drug is stable in solution for 30 days, so the PCA technicians can prepare the bags in advance (1:1 concentration in 100ml bags) and one will be stored on the palliative care unit. Midazolam is administered via a PCA pump. b. Dosing - Starting dose is midazolam 0.51mg per hour continuous infusion following a loading dose of 2.5-5 mg. Midazolam may be bolused at a dose equal to the hourly basal rate every 15 minutes as needed. If symptoms are unrelieved, the basal rate may be titrated every 4 hours based on the average hourly needs for the previous 4 hours until relief is achieved. Usual maintenance dose ranges 20-120 mg/day. B. Propofol (IV only) a. Description - Propofol is an injectable sedative hypnotic agent used for general anesthesia. In much lower doses it is used for its sedative properties. The onset of effect is within 30 seconds and the duration of effect of a bolus dose is 3-10 minutes. The terminal elimination half-life is 200 minutes. Pain at the injection site is a common adverse reaction which can be minimized by dilution (no less than 2mg/ml) and using a large  C

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vein if possible. Propofol also has antiemetic properties. The drug will be given by the IV route with an infusion pump (not pca) since it must be in a glass bottle with nitroglycerin tubing. It should be ordered from the pharmacy as an IV infusion of 10mg/mL. b. Dosing – Recommended bolus dose of 20mg over 5 minutes (the pump would be set at 24 ml/hr x 5 minutes with an RN in attendance). Usual starting dose 5-10 mg/hr (0.5-1mL/hr). May titrate by 10mg/hr every 15-20 minutes. Average range 500mg1100mg/day. C. Barbiturates a. Description – Phenobarbital and Pentobarbital are intermediate-duration barbiturates used for insomnia, anxiety, and as anticonvulsants. The onset of effect is within 1530 minutes after IV injection and the halflife is approximately 19 hours. An IV pump (not a PCA) will be used when giving by IV route due to short stability times. Will need a loading dose prior to starting infusion or maintenance dose. Barbiturates can be potent inducers of hepatic enzymes (be aware of potential drug interactions). b. Dosing 1. Phenobarbital (IV or SQ) comes in a 130mg/mL vial. Loading dose 100mg200mg (can easily give 130mg or entire vial), followed by 100-320 mg slow IV infusion 2-3 times/day. Average maintenance dose 600 mg/day. 2. Pentobarbital (IV only) - the typical loading of 2mg/kg (∼150mg) would be given IV push over 5 minutes. The infusion would be ordered from pharmacy as 25mg in 250ml NS or D5W (0.1mg/ml). Starting dose 1mg/hr (or 10ml/hr) and titrate upward to maintain sedation. IV. Protocol: 1. Controlled sedation, administered by subcutaneous or intravenous routes, may be used on the Palliative Care unit only, for the treatment of refractory symptoms, seizures and/or restlessness. This protocol does not address the use of midazolam, propofol, or barbiturates in other clinical areas. 2. In more difficult cases, more than one medication may be needed to sedate a patient adequately. 3. The medication dose should not be increased unless there is evidence of inadequate sedation.

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4. Vital signs with pulse oximetry will be assessed prior to administration of the drug and then as ordered. 5. Infusion pumps will be labeled “Sedation” with tape as a safety precaution. 6. An orientation, education and competency program for nurses employed on the Palliative Care Unit regarding the appropriate and safe use and monitoring of controlled sedation is required. 7. Only Registered Nurses oriented, educated and who have achieved competency for controlled sedation can be assigned to a patient receiving this therapy. V. References 1. Cherny NI. The use of sedation in the management of refractory pain. Principles and practice of supportive oncology Updates. 2000 3:1-11 2. Cherny NI and Portenoy RK. Sedation in the management of refractory symptoms: guidelines for evaluation and treatment, J. Pall. Care 10:2/1994; 31-38. 3. Cherny, N., Commentary: Sedation in response to Refractory Existential Distress: Walking the Fine Line, J Pain Symptom Manage, 1998 Dec; 16(6): 404-5. 4. Cherny, NI, Sedation for the Care of Patients with Advanced Cancer, Nat Clin Pract Oncol. 2006 Sept; 3(9):492-500. 5. Charter S et al. Sedation for intractable distress in the dying-a survey of experts. Pall Med 1998; 12:255-269. 6. Braun TC et al. Development of a clinical practice guideline for palliative sedation. J Pall Med 2003; 6:345-350. 7. Hallenbeck, J., Terminal sedation for intractable distress, West J Med. 1999 Oct; 171(4):222-3. 8. Muller-Busch, H., etal, Sedation in palliative care? A critical analysis of 7 years experience, BMC Palliative Care. 2003 May 13; 2(1):2.

9. Rousseau, P., Existential suffering and palliative sedation: a brief commentary with a proposal for clinical guidelines, Am J Hosp Palliat Care, 2001 May-Jun; 18(3): 151-3. 10. Rousseau, P., Palliative Sedation I the Management of Refractory Symptoms, Supportive Oncology. 2004 March/April; 2(2): 181-186. 11. Berger, AM, Ed, et al, Principles and Practice of Palliative Care and Supportive Oncology, Philadelphia, PA: Lippincott Williams & Wilkins, 2002. 12. Quill, TE, Responding to Intractable Terminal Suffering: The Role of Terminal Sedation and Voluntary Refusal of Food and Fluids, Ann Intern Med, 2000; 132: 408-414. 13. Sykes, N., Sedative Use in the Last Week of Life and the Implications for End-of-Life Decision Making. Arch Intern Med, 2003 Feb 10; 163: 341-344 14. deGraeff, A and Dean, M., Palliative Sedation Therapy in the Last Weeks of Life: A Literature Review and Recommendations for Standards, J Palliative Med. 2007, 10(1): 67-85. 15. Del Fabbro, E., et al. Palliative Sedation: When the Family and Consulting Service See no Alternative, J Pall Med, 2007; 10(2):488492. 16. Rousseau, P, The Ethical Validity and Clinical Experience of Palliative Sedation, Mayo Clin Proc. 2000;75: 1064-1069. 17. Cheng, C. et al, When Midazolam Fails, J Pain and Symptom Management. 2002; 23(3): 256-265. 18. Knight,P., and Espinosa, L., Sedation for Refeactory Symptoms and Terminal Weaning. Oxford Textbook of Palliative Nusing, Oxford University Press 2010 pp 525-543. 19. HPNA Position Statement on Palliative Sedation http://www.hpna.org/DisplayPage. aspx?Title=Position%20Statements Original 2008 Revised 2010 Revised October 2012

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Management of refractory status epilepticus in an actively dying patient.

No consensus guidelines exist for the treatment of refractory myoclonic status epilepticus or refractory myoclonus in the palliative care setting. Evi...
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