Managing Hemophilia in the ED: All Bleeding Stops Eventually

Authors: Amber Fiutko, MD (EM Resident Physician, Cook County Health & Hospitals System) and Neeraj Chhabra, MD (EM Attending Physician, Department of Emergency Medicine, Cook County Health & Hospitals System; Assistant Professor of Emergency Medicine, Rush Medical College) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case

A 16-year-old male with severe hemophilia A (factor VIII deficiency) presents to the Emergency Department lacerations to his bilateral forearms. He has wrapped the wounds in compression dressings; however, there is significant strikethrough of all bandages and the wounds continue to actively bleed when undressed. How should his bleeding be controlled?

Types of Hemophilia

Hemophilia is an X-linked deficiencyof clotting factors that is more prevalent in male patients.Deficiencies of factor VIII (hemophilia A) or factor IX (hemophilia B) are the predominant forms of hemophilia (with A more common than B). While the majority of patients with hemophilia will have congenital hemophilia, some may acquire hemophilia. Acquired hemophilia, most commonly due to Factor VIII antibody, can be caused by a variety of factors; it may be associated with the post-partum period, autoimmune diseases, malignancy (especially lymphoproliferative disorders), and use of certain medications, particularly antibiotics and anticonvulsants.  These patients may present with a range of bleeding disorders from easy bruising to hemarthrosis to life-threatening hemorrhage.  It is important to recognize bleeding complications early and treat them aggressively in the ED.

Many patients who have been diagnosed with hemophilia are trained to administer additional doses of factor when experiencing bleeding. Therefore, these patients frequently only present to the ED when episodes of bleeding are persistent or severe. At times, patients may also present if unable to obtain venous access for factor administration, particularly in pediatric or geriatric populations. Although commonly diagnosed in pediatric age groups, patients with mild to moderate factor deficiency may present later in life, so it is important to consider in those with uncontrolled or severe episodes of bleeding.2

Severity

In patients with hemophilia A or B, the severity of disease correlates with percentage of factor activity. A patient functionally will have normal clotting activity with >50% factor activity. Mild factor deficiency ranges from 5-40% of factor activity, moderate from 1-5% of factor activity, and a patient will have severe deficiency if less than 1% factor activity is present.Factors VIII and IX are located in the intrinsic pathway and will affect the aPTT, but not the PT, platelets, or bleeding time.

Indications for factor replacement

Evaluate the severity of bleeding to determine the amount of factor replacement required. For mild to moderate bleeding, including soft tissue bleeding, muscular bleeding, hemarthrosis, or epistaxis, replace up to 50% of factor. For severe bleeding, including intracranial, gastrointestinal, any bleeding around the neck or airway that could lead to airway compromise, or major trauma, replace up to 100% of factor.2

How to Replace Factor

In hemophilia A, every 1 U/kg of factor VIII replacement increases the factor activity by 2%.For example, 25U/kg of factor VIII replacement will lead to a 50% correction and should be used in cases of mild to moderate bleeding. For severe bleeding in a patient with hemophilia A, give 50U/kg of factor replacement to achieve 100% correction.

In hemophilia B, every 1 U/kg of factor IX increases the factor activity by 1%.For example, 50U/kg of factor IX will yield a 50% correction for mild to moderate bleeds, and 100U/kg will yield a 100% correction for severe bleeds.

Ideally, use the factor the patient takes at home to reduce development of inhibitors. Remember, these patients probably know their disease better than you do.

If a patient does not know their own factor activity, assume that it is 0% for purposes of correction.

Other Options

Although factor replacement is the first-line option, there are other treatment options if factor is not available:

  • Cryoprecipitate contains 80-100 units of factor VIII per single donor bag and can be used to replace factor in patients with hemophilia A. It has no role in hemophilia B.6
  • DDAVP is recommended for acute bleeding in patients with mild hemophilia A. It increases factor VIII by 3-5x by promoting release of endogenous factor VIII. The recommended dose is 0.3 mcg/kg/dose IV, and onset is approximately 30 minutes, with peak action at 90-100 minutes.3, 7
  • FFP is another option for hemophilia A, however, there is only 1 unit of factor/mL of FFP, and complete replacement of factor activity requires a large volume.6
  • PCC can be used as it contains factors II, VII, IX, and X, though there are potentially thrombogenic side effects.3
  • TXA is recommended for mucosal bleeds and stabilized clot formation. The recommended dose is 10 mg/kg IV or 25 mg/kg PO.8

Hemophilia with inhibitors

Some patients with hemophilia may develop antibodies or inhibitors to exogenous factor. Options in these scenarios include NovoSeven (recombinant factor VIIa) or FEIBA (factor eight inhibitor bypassing agent). Activated factor VII directly activates factor X, bypassing the need for factors VIII and IX. Be aware that both recombinant factor VIIa and FEIBA contain activated clotting factors and a risk for thrombogenic effects.2,9

Case Conclusion

The patient received 25 U/kg of his own exogenous factor VIII for a correction of 50%. Hemostasis was achieved within 30 minutes allowing for irrigation and repair of his wounds. Upon follow up for suture removal, the patient stated that the wounds remained hemostatic following the initial ED visit. He had continued to use his normal factor dosing following the ED visit and did not require additional extra doses.

Clinical Pearls

  • Replace factor with a patient’s own exogenous factor whenever available.
  • For MSK bleeds and epistaxis, replace up to 50% of factor. For severe bleeds, replace 100% of factor.
  • Each U/kg of factor VIII in hemophilia A increases factor by 2%Each U/kg of factor IX in hemophilia B increases factor level by 1%.
  • Aim for 50% correction in moderate bleeds and 100% correction for severe.
  • Cryoprecipitate, DDAVP, and FFP can be used as second-line agents in hemophilia A.
  • TXA can be useful for mucosal bleeding.
  • Patients with inhibitors may require recombinant factor VIIa or FEIBA.

 

References / Further Reading

  1. Delgado, Julio, et al. “Acquired Haemophilia: Review and Meta-Analysis Focused on Therapy and Prognostic Factors.” British Journal of Haematology, vol. 121, 2003, pp. 21–35., doi:10.1046/j.1365-2141.2003.04162.x.
  2. Singleton, Tammuella, et al. “Emergency Department Care for Patients with Hemophilia and Von Willebrand Disease.” The Journal of Emergency Medicine, vol. 39, no. 2, Aug. 2010, pp. 158–165., doi:10.1016/j.jemermed.2007.12.024.
  3. Bhat, Rahul, and Whitney Cabey. “Evaluation and Management of Congenital Bleeding Disorders.” Emergency Medicine Clinics of North America, vol. 32, no. 3, Aug. 2014, pp. 673–690., doi:10.1016/j.emc.2014.04.009.
  4. Hemphill, Robin R. “Hemophilias and von Willebrand’s Disease.” Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e Eds. Judith E. Tintinalli, et al. New York, NY: McGraw-Hill, 2016, http://accessmedicine.mhmedical.com.ezproxy.rush.edu/content.aspx?bookid=1658&sectionid=109444198.
  5. Kulkarni, Roshni, and J. Michael Soucie. “Pediatric Hemophilia: A Review.” Seminars in Thrombosis and Hemostasis, vol. 37, no. 07, 2011, pp. 737–744., doi:10.1055/s-0031-1297164.
  6. Bansal, Deepak, et al. “Approach to a Child with Bleeding in the Emergency Room.” The Indian Journal of Pediatrics, vol. 80, no. 5, 27 Dec. 2012, pp. 411–420., doi:10.1007/s12098-012-0918-2.
  7. Nolan, B., et al. “Desmopressin: Therapeutic Limitations in Children and Adults with Inherited Coagulation Disorders.” British Journal of Haematology, vol. 109, no. 4, 24 Dec. 2001, pp. 865–869., doi:10.1046/j.1365-2141.2000.02067.x.
  8. Noble, Sarah, and Jaydeep Chitnis. “Case Report: Use of Topical Tranexamic Acid to Stop Localised Bleeding.” Emergency Medicine Journal, vol. 30, no. 6, 25 July 2012, pp. 509–510., doi:10.1136/emermed-2012-201684.
  9. Gouw, Samantha C., et al. “Factor VIII Products and Inhibitor Development in Severe Hemophilia A.” New England Journal of Medicine, vol. 368, no. 3, 17 Jan. 2013, pp. 231–239., doi:10.1056/nejmoa1208024.

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Ketamine continuous infusion: a reasonable alternative to traditional sedatives and analgesics?

Authors: Kayvan Moussavi, PharmD, BCCCP (Clinical Pharmacy Specialist – Emergency Department, Loma Linda, CA) and Bert Matsuo, PharmD (PGY2 – Cardiology, Loma Linda, CA) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Acknowledgements: The authors would like to thank Raymond Ngo, PharmD, BCPS (Clinical Pharmacy Specialist- Emergency Department, Loma Linda, CA), Liz Fierro, MD (Pediatric Emergency Medicine Fellow, Loma Linda University Health), and Natasha Li, MD (Pediatric Emergency Medicine Fellow, Loma Linda University Health) for editing this article.

Case

A 60 y/o, 100 kg male with a past medical history of hypertension, diabetes mellitus, and obesity presents to your emergency department with altered mental status for one day.  The patient’s wife states that yesterday he was feeling ill and thought he had the flu.  He did not take any of his routine medications yesterday or today.  This morning she had trouble waking him up, so she called 911. Upon initial assessment, the patient is pale, tachypnic, and altered (GCS 7).

  • Vitals include: BP 88/49, HR 110, RR 27, Sat 90% on RA, T 101.3 F, GCS 7
  • Point of care glucose: 179 mg/dL
  • Home medications: hydrochlorothiazide, benazepril, metformin

You successfully intubate the patient with etomidate and rocuronium.  Chest X-ray suggests the patient has pneumonia, so you order ceftriaxone, azithromycin, and 3 liters of lactated ringer’s.  Because the patient appears to be fighting the ventilator, you order fentanyl 50 mcg IV x 1.  Thirty minutes later, the nurse states the patient continues to fight the ventilator (RASS+2) and asks for a sedative.  The patient’s BP is now 86/45.

What options do you have for sedation in this patient?

Introduction

Propofol, dexmedetomidine, and opioids are commonly used for patients requiring continuous sedation or analgesia, such as for those receiving mechanical ventilation.Although these medications are generally safe, some may be unable to tolerate them due to hemodynamic status.2-7

Ketamine is a rapid acting, dissociative anesthetic used frequently in the emergency department for sedation and, more recently, pain relief.8-10 Ketamine use during procedural sedation in the emergency department and perioperative setting has been shown to provide sedation and pain relief without the negative hemodynamic and pulmonary effects of traditional sedatives and analgesics.11-16 These findings suggest ketamine may be an ideal agent for continuous sedation in critically ill patients.

Let’s examine ketamine and the evidence assessing its use as a continuous infusion for critically ill patients.  We will focus on high dose (i.e. doses needed to provide continuous sedation) rather than low dose infusion used for depression or pain relief alone.

Ketamine Basics

  • Mechanism of action
    • Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks glutamate, giving rise to a dissociative state. Ketamine may also enhance the pain-relieving effects of the mu opioid receptor and cause other central or peripheral nervous system neurotransmitter alterations that result in analgesia, hyperadrenergic state, or psychosis.8,10,17
  • Indications17
    • Labeled: Induction and maintenance of general anesthesia.
    • Off-label: Sedation/analgesia in critically ill patients, complex regional pain syndrome, refractory depression, refractory status epilepticus, status asthmaticus, rapid sequence intubation, bronchospasm, and restless leg syndrome.
  • Benefits17-21
    • Rapid onset (1-2 mg/kg IV: 30-40 sec, 4-5 mg/kg IM: 3-4 min, 3-6 mg/kg IN: 8-12 min)
    • Short duration (1-2 mg/kg IV: 5-10 min, 4-5 mg/kg IM: 12-25 min, 3-6 mg/kg IN: 45-60 min)
    • Predictable dose-response relationship
    • Available to be given IV, IM, IN, PO, SC, PR
    • Hypotension and respiratory depression appear to be uncommon18,19
    • Decreased opioid consumption20
  • Possible Adverse Drug Events (ADEs)8,11,17
    • Cardiovascular: Hypertension, hypotension, tachycardia, bradyarrhythmia
    • Neurologic: Emergence reactions, agitation
    • Ophthalmic: Nystagmus
    • Immunologic: Anaphylaxis, rash
    • Respiratory: Laryngeal spasm, pulmonary edema, apnea, respiratory depression
    • Muscular: Hypertonicity, purposeless movement
    • Gastrointestinal: Hypersalivation, emesis
  • IV Bolus Dosing21
    • Adults: 0.5-4.5 mg/kg
    • Peds: 0.5-2 mg/kg

How should I dose ketamine if I want to use a continuous infusion?

There have been several recent articles evaluating the use of continuous ketamine infusion for sedation.  These articles give us an idea of dosing, efficacy, and safety of ketamine infusion.22-26

To summarize:

  • There are currently no large prospective trials examining ketamine continuous infusion use.
  • Continuous infusion use has mostly been evaluated retrospectively in critically ill adults and children.
  • Ketamine was often used in combination with other sedatives or analgesics.
  • Dosing ranged from 0.04 to 4 mg/kg/hr, with one study using up to 10 mg/kg/hr.
  • Some patients received ketamine boluses prior to infusion (up to 5 mg/kg for RSE).25
  • Ketamine helped achieve sedation goals and decrease opioid use in some studies.22,23,26
  • ADEs occurred in up to 13% of patients and were most often tachyarrhythmias (included tachycardia, ventricular tachycardia, supraventricular tachycardia, and atrial fibrillation), delirium, agitation, or emergence reaction.

What if my patient has renal or hepatic dysfunction?

There are no recommended dosing adjustments for hepatic or renal impairment per the package insert.17  However, it is reasonable to start at the lower end of the dosing range and titrate to desired effect if organ dysfunction is present (e.g. 0.25-0.5 mg/kg/hour).

How should I ask the pharmacy to prepare the ketamine drip?

Vials may be further diluted in D5W or NS to prepare an infusion with a final concentration of 1-2 mg/mL.17 There is evidence that ketamine is stable at concentrations up to 25 mg/mL.27 A more concentrated solution would be less likely to contribute to fluid overload, especially in patients with organ dysfunction receiving other IV solutions (e.g. crystalloids, antibiotics, vasopressors, etc.).  Our institution prepares ketamine as a 10 mg/mL solution (1000 mg/100 mL NS in adults or 500 mg/50 mL NS in pediatrics).

Case Resolution

Due to the patient’s hypotension, you are hesitant to start propofol or dexmedetomidine.  You decide to initiate ketamine continuous infusion at 0.5 mg/kg/hour titrated by 0.25 mg/kg/hr every 30 min to RASS goal -1.  You also start norepinephrine at 5 mcg/minute titrated by 2.5 mcg/min every 5 min to MAP 65-70.  You bolus ketamine 50 mg IV prior to starting the ketamine drip.  Thirty minutes later, the nurse notes the BP is 100/60, HR 91, RASS -1.  The patient is then transferred to the ICU.  Success!

Take home points

  • Ketamine continuous infusion can be considered for adult and pediatric patients that may not tolerate propofol, dexmedetomidine, or opioids.
  • Ketamine has analgesic and sedative properties and may be less likely to cause hypotension, bradycardia, or respiratory depression compared to other agents.
  • Literature supporting use as a continuous infusion is mostly limited to retrospective studies.
  • Ketamine may decrease opioid or other sedative requirements.
  • Tachyarrhythmias and psychiatric reactions appear to be the most common ADEs.
  • Dosing reported in literature ranges from 0.04-10 mg/kg/hr.
  • Ketamine can be prepared as 1000 mg/100 mL NS in adults or 500 mg/50 mL NS in pediatrics.

 

References / Further Reading:

  1. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263-306.
  2. Panharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298(22):2644-2653.
  3. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs. midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301(5):489-499.
  4. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs. midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012; 307(11): 1151-60.
  5. Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy 2005; 25(5 Pt2):8S-18S).
  6. Pisani MA. Considerations in caring for the critically ill older patient. J Intensive Care Med 2009; 24(2): 83-95.
  7. Jungguist CR, Smith K, Nicely KL, et al. Monitoring hospitalized adult patients for opioid-induced sedation and respiratory depression. Am J Nurs 2017; 117(3 suppl 1):S27-S35.
  8. Erstad BL, Patanwala AE. Ketamine for analagosedation in critically ill patients. J Crit Care 2016 Oct; 35:145-9.
  9. Patanwala AE, Martin JR, Erstad BL. Ketamine for analagosedation in the intensive care unit: a systematic review. J Intensive Care Med 2017 Jul; 32(6): 387-395.
  10. Domino EF. Taming the ketamine tiger. Anesthesiology 2010; 113: 678-86.
  11. Green SM, Roback MG, Kennedy RM, et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med 2011; 57(5): 449-61.
  12. Schmittner MD, Vajkoczy SL, Horn P, et al. Effects of fentanyl and S (+) – ketamine on cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with intracranial pathologies: a pilot study. J Neurosurg Anesthesiol 2007; 19: 257-262.
  13. Hopper AB, Vike GM, Castillo EM, et al. Ketamine for acute agitation in the emergency department. J of Emerg Med 2015; 48(6): 712-719.
  14. Yan JW, McLeod SL, Iansavitchene A. Ketamine-propofol versus propofol alone for procedural sedation in the emergency department: a systematic review and meta-analysis. Academic Emergency Medicine 2015; 22:1003-1013.
  15. Riddell J, Tran A, Bengiamin R, et al. Ketamine as a first-line treatment for severely agitated emergency department patients. Am J Emerg Med 2017; 35(7): 1000-1004.
  16. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicenter randomized controlled trial. Lancet 2009; 374(9686): 293-300.
  17. Ketamine [package insert]. Par Pharmaceutical: Chestnut Ridge, NY; 2017.
  18. Buchheit JL, Yeh DD, Eikermann M, Lin H. Impact of Low-Dose Ketamine on the Usage of Continuous Opioid Infusion for the Treatment of Pain in Adult Mechanically Ventilated Patients in Surgical Intensive Care Units. J Intensive Care Med. 2017;885066617706907.
  19. Neunhoeffer F, Hanser A, Esslinger M, et al. Ketamine Infusion as a Counter Measure for Opioid Tolerance in Mechanically Ventilated Children: A Pilot Study. Pediatr Drugs. 2017;19(3):259-265.
  20. Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015;16(7):1402-9.
  21. Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc; April 8, 2018.
  22. Golding CL, Miller JL, Gessouroun MR, Johnson PN. Ketamine Continuous Infusions in Critically Ill Infants and Children. Ann Pharmacother. 2016;50(3):234-41.
  23. Groetzinger LM, Rivosecchi RM, Bain W, et al. Ketamine Infusion for Adjunct Sedation in Mechanically Ventilated Adults. Pharmacotherapy. 2017
  24. Umunna BP, Tekwani K, Barounis D, Kettaneh N, Kulstad E. Ketamine for continuous sedation of mechanically ventilated patients. J Emerg Trauma Shock. 2015;8(1):11-5.
  25. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013;54(8):1498-503.
  26. Pruskowski KA, Harbourt K, Pajoumand M, Chui SJ, Reynolds HN. Impact of Ketamine Use on Adjunctive Analgesic and Sedative Medications in Critically Ill Trauma Patients. Pharmacotherapy. 2017;37(12):1537-1544.
  27. Trissel’s™2 Clinical Pharmaceutics Database. Lexicomp Online [database online]. Hudson, OH: Lexicomp; April 8, 2018.

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