All bleeding stops — but does idarucizumab (Praxbind) make it stop faster?

PraxBind3.5 out of 5 stars

Persistent life-threatening hemorrhage after administration of idarucizumab. Alhashem HM et al. Am J Emerg Med 2016 June 30 [Epub ahead of print]

Reference

Dabigatran (Pradaxa) is a direct thrombin inhibitor approved for stroke and embolism prophylaxis in patients with non-valve-related atrial fibrillation. When it was first released in 2008, a major disincentive to widespread use was the lack of a reliable reversal agent to treat major bleeds, or to administer before necessary invasive procedures.

In October 2015, the U.S. Food and Drug Administration approved idarucizumab (Praxbind), a monoclonal antibody that avidly binds to dabigatran. under its accelerated approval program. As described by an FDA release, this program:

. . . allowed drugs for serious conditions that filled an unmet medical need to be approved base on a surrogate endpoint.”

In the case of idarucizumab, the surrogate end-points involved normalization of laboratory parameters of anticoagulation. As far as I can determine, there have been no studies that demonstrate convincingly any clinical patient-oriented benefit. In fact, in the major study addressing this issue,  it took a median of 11.4 hours to restore hemostatis after administration of idarucizumab. There was not control group, so we have no idea if this is better than simple watchful waiting. Clearly, it seems far too long to be useful in true life-threatening hemorrhage.

This case report illustrates the point.

A 65-year-old man recently started on dabigatran for atrial fibrillation presented to the emergency department weakness and dyspnea that started approximately 1 hours before. He gave a history of melena for 3 days. On arrival he ws tachycardia (122 ppm) and hypotensive (BP 74/52 mmHg.)

Digital rectal examination confirmed the presence of melena, and a nasogastric tube returned 300 ml bright red blood that did not clear with irrigation. The patient remained unstable despite administration of fluids and packed red blood cells.

The authors note that a markedly elevated thrombin time (120 sec, reference 15-19 sec) indicated significant dabigatran activity. After idarucizumab (5 gm) was administered intravenously. the coagulation tests improved but the patient remained unstable. Upper endoscopy revealed ongoing hemorrhage from a vessel in the duodenum. Several attempts to control the site of bleeding failed, and the patient ultimately underwent angiography with embolization of the gastroduodenal artery. This successfully stopped the bleeding and the patient was discharged after a 4-day hospital stay.

According to Wikipedia, the hospital acquisition cost of a 5 gm dose of idarucizumab is $3500. Although it clearly improves coagulation lab values, it is not clear if if stops significant or life-threatening hemorrhage, or allows for safer procedures such as hemodialysis.

An excellent post at REBEL EM discussed many of the problems with the major study of idarucizumab mentioned above, including industry sponsorship, lack of power, dicey inclusion criteria, and poor study design without blinding or randomization.

Bottom line: idarucizumab had accelerated approval by the FDA as a reversal agent for dabigatran because of biological plausibility. There is still no real proof of its effectiveness. However, in cases of truly life-threatening hemorrhage, many clinicians will no doubt administer the drug if no other treatment options seem available.

Related points:

Case report: hemodialysis for dabigatran overdose

The many potential problems with using dabigatran

Case series: four patients with dabigatran-associated bleeding

Review: the bleeding patient on dabigatram

Dabigatran and the elderly

 

 

 

 

REMI 2146. Tromboembolismo venoso en la sepsis

ARTÍCULO ORIGINAL: VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Kaplan D, Casper TC, Elliott CG, Men S, Pendleton RC, Kraiss LW, Weyrich AS, Grissom CK, Zimmerman GA, Rondina MT. Chest 2015; 148(5): 1224-1230. [Resumen] [Artículos relacionados]
   
INTRODUCCIÓN: Las guías de práctica clínica para la sepsis recomiendan la tromboprofilaxis como a cualquier paciente crítico, y reconocen que no existen estudios específicos sobre esta cuestión en pacientes con sepsis, a los que se presume un riesgo de enfermedad tromboembólica venosa (ETV) similar o superior al de otros pacientes críticos [1].
    
RESUMEN: Se llevó a cabo un estudio prospectivo en tres UCI que incluyó 113 pacientes con sepsis o shock séptico, a fin de conocer la incidencia y factores de riesgo de ETV. En todos los casos se realizó una valoración sistemática de signos clínicos y ultrasonografía de compresión de miembros inferiores y de miembros superiores cuando existía un catéter venoso central (CVC). El 54% de los pacientes presentaron shock, el 77% recibieron ventilación mecánica y el 53% presentaba obesidad. El 61% fueron portadores de CVC. Todos los pacientes recibieron tromboprofilaxis correcta, y a pesar de ello el 37,2% presentaron ETV (IC 95% 28,3-46,8%), de los cuales el 88% se consideró clínicamente significativa. Entre los pacientes con CVC, el 23,2% presentaron trombosis venosa profunda de extremidades superiores. Los pacientes que presentaron ETV tuvieron una estancia en UCI más prolongada (18,2 ± 9,9 frente a 13,4 ± 11,5 días; P < 0,05) y mayor mortalidad a los 28 días (28,6 frente a 17,6%; P = 0,18). En análisis multivariable fueron factores predictivos de ETV la presencia de CVC y la duración de la ventilación mecánica.
   
COMENTARIO: El estudio muestra una elevada incidencia de ETV clínicamente relevante en pacientes con sepsis, superior a la señalada en otros estudios en pacientes críticos [2], a pesar de una tomboprofilaxis correcta. Ello indica un riesgo elevado de tromboembolismo en la sepsis, con consecuencias claras: 1) hay que replantearse la intensidad de la tromboprofilaxis en estos pacientes; 2) hay que tener un alto grado de sospecha clínica de ETV en los pacientes con sepsis, pues sus manifestaciones clínicas son muy inespecíficas. Junto a la tromboprofilaxis farmacológica o mecánica hay que tener en cuenta la importancia de otras medidas para reducir el riesgo de ETV, como la retirada precoz de los CVC y las estrategias dirigidas a disminuir la duración de la ventilación mecánica. Aunque se trata de un estudio de pequeño tamaño cuya generalizabilidad es cuestionable, sirve de alerta sobre esta cuestión y justifica la realización de estudios de mayor tamaño.
 
Eduardo Palencia Herrejón
Hospital Universitario Infanta Leonor, Madrid.
© REMI, http://medicina-intensiva.com. Julio 2016.
      
ENLACES:
  1. Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock 2012. [PDF]
  2. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, Geerts W, Guyatt G. Crit Care Med 2005; 33: 1565-1571. [PubMed]
BÚSQUEDA EN PUBMED:
  • Enunciado: Enfermedad tromboembólica en pacientes críticos
  • Sintaxis: thromboembolism[mh] AND critical illness[mh] 
  • [Resultados]

Platelet Count After Spleen Injury

In most trauma textbooks, the most commonly injured solid organ is the spleen. There is a lot of work available that tells trauma professionals how to detect and manage spleen injuries. However, the treatment of the sequelae is less clear cut. We know that the platelet count generally rises after spleen injury, and especially if it is removed. We think we know that we should be on alert if the platelet count goes over 1 M per microliter (ul) to avoid thrombisis.

What happens during the usual hospital course? Is venous thrombosis actually a problem? A group at St. Michael’s Hospital in Toronto performed a 5 year retrospective review of their patients with splenic injury to try to answer these questions. Children and patients with known pre-existing coagulopathy or that were taking anticoagulants were excluded. All were managed with prophylactic low molecular heparin, although the specific product or protocol were not described. 

Here are the factoids:

  • A total of 156 patients were enrolled over 5 years. - This is a relatively low number (31/year). In contrast, here in bustling metropolitan St. Paul we see 80-100 per year.
  • Nonoperative management was performed in 84% of cases, with angio-embolization added in another 8%. The other 8% were taken to OR, where most underwent splenectomy. - This is spot on with national data. However, looking at their injury grade breakdown, it seems like they take out a higher than usual number of low grade spleens.
  • Platelet count rose steadily after admission, peaking at day 16-17.
  • Splenectomy patients had a mean peak platelet count of 890K/ul.
  • Nonop management patients had a mean peak of 604K/ul.
  • Extreme thrombocytosis (counts > 1M/ul) occurred in 25 patients (16%). It occurred in 41% of splenectomy patients, but only 6% of nonop patients. 
  • Although DVT and PE occurred in these patients (8%, which seems a bit high), there was no association with thrombocytosis, extreme thrombocytosis, or aspirin use. - This is most likely due to the small size of the study. 

Bottom line: This small study provides some interesting and important information regarding the platelet count trend after splenic injury. Although there was not enough power to look at the association with DVT, PE, and the value of aspirin treatment for extreme thrombocytosis, the platelet count trend info was very interesting. It looks like we should be checking a platelet count about 2-3 weeks after injury to make sure it’s not reaching extreme levels. This can be scheduled during their postop or post-discharge visit. A reminder should also be sent to the primary care physician to be on the lookout for extreme thrombocytosis for the first three weeks post-injury.

Related posts:

Reference: Thrombocytosis in splenic trauma: In-hospital course and association with venous thromboembolism. Injury, in press, 2016.

Blunt Trauma: what do we miss/how can we improve?

Authors: Carling Macdonald1, Anthony Scoccimarro, MD2, and Muhammad Waseem, MD, MS2 (St. Georges University Grenada West Indies1; Lincoln Medical & Mental Health Center Bronx, New York2) // Edited by Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Stephen Alerhand, MD (@SAlerhand, EM Resident Physician, Icahn School of Medicine at Mount Sinai)

Missed injuries are fortunately rare, yet the injured trauma patient may present a unique diagnostic challenge. Missed injuries and delay in diagnosis remain a concern for ED physicians caring for trauma patients. Delayed diagnosis of intra-abdominal injuries, for instance, results in significantly increased morbidity and mortality. Literature suggests an 8.1% incidence of patients with missed injuries, which may be an underestimation of the true incidence of missed injuries.[i]

Evaluation of Blunt Trauma
  • Stabilization and identification of life-threatening injuries
  • Physical examination
    • Primary survey
      • Primary goal: identify and prioritize the most life-threatening injuries
      • Includes: Airway, Breathing, Circulation, Disability, Exposure
    • Secondary Survey
      • Identify and address all other injuries
    • Diagnostic testing options
      • Bedside ultrasound (FAST examination)
        The focused assessment with sonography in trauma (FAST) examination for the evaluation of injured patients is not sensitive enough to exclude all intra-abdominal injuries. Patients with small amounts of free fluid may have false-negative FAST examination.[ii]
      • CT scan
        Should be obtained only in hemodynamically stable patients in whom there is no apparent indication for an emergent laparotomy.
      • Potential useful laboratory tests
        • CBC, CMP, lipase, UA
          • Laboratory evaluation is generally of limited value and should be considered as an adjunct to the clinical assessment.
What body parts are at higher risk for missed injuries?

The most commonly involved body region of missed injuries was the head/neck, followed by the chest and extremities.[iii]

Spine[iv],[v]
Abdomen[vi],[vii],[viii]
Extremities[ix]

What are commonly missed injuries in blunt trauma?
  • Rib fractures
  • C-spine injuries in elderly[x]
  • Spleen and liver (especially if an initial FAST examination is negative)
How do we miss?
  • Multiple injuries, or distracting injuries, potentially unavoidable factors such as other life-threatening injuries and severe head injuries. In one study, 9% of patients with multiple injuries sustained injuries that were not discovered during the primary and secondary surveys.[xi] Certain factors such as a younger age, more severe injury, poly-trauma, and the absence of soft-tissue injuries are significantly associated with missed injuries. In addition, patientswith missed injuries may have lower Glasgow Coma Scale scores and may have required pharmacologic paralysis. CT may miss gastrointestinal, diaphragmatic, and pancreatic injuries.
  • Inadequate or incomplete clinical assessment
  • Hemodynamic instability
  • Radiological misinterpretation
  • False-negative FAST examination
    • The FAST examination for the evaluation of injured patients is NOT sensitive enough to exclude all abdominal injuries.
    • The FAST examination is not designed to reliably detect injuries to the solid organs, intestine, mesentery, diaphragm, or the retroperitoneal area (often associated with pelvic fractures).
    • Volumes less than 400 mL in RUQ have been hard to distinguish.
    • Pelvic views are limited if the bladder is empty or there is a Foley placed
    • Delayed presentation: free fluid remains anechoic until it begins to clot and difficult to differentiate from the surrounding tissue.[xii]
  • Over-reliance on the physical examination: clinical examination as a screening tool for evaluation of thoracolumbar spine injuries is inadequate. In a study, physical examination missed 6.9% of all fractures and 15.4% of those that were clinically significant. The sensitivity and specificity of clinical examination for TL spine fractures were 48.2% and 84.9%, respectively, for all fractures and 78.6% and 83.4% for those that were clinically significant.[xiii]
Does non-operative management increase risk for missed injuries?

With increasing rates of non-operative management, there has been concern that these associated injuries may become missed injuries. Data suggest that missed injury is more common in conjunction with liver (2.3%) rather than splenic injury with increased rate of bowel and pancreatic injuries. It may be that more force is needed to injure the liver as compared with the spleen.[xiv]

How do we improve?
  • Obvious clinical signs of trauma, such as abdominal distension or hematoma should prompt careful physical examination.
  • The absence of abdominal pain or tenderness on physical examination does not rule out significant abdominal injury
  • In the absence of hepatic or splenic injuries, the presence of free fluid in the abdominal cavity may suggest an injury to gastrointestinal tract or its mesentery.
  • When attempting to avoid a false-negative FAST examination, one can repeat the exam at regular intervals. This is especially warranted if the clinical status changes and this approach can be used to increase the sensitivity of the examination.
  • Look for common physical examination patterns that are associated with intra-abdominal injury caused by blunt trauma:
    • Lap belt marks
    • Steering wheel contusions
    • Abdominal distension
    • Abdominal guarding
    • Hypotension
    • Rebound tenderness
    • Concomitant femur fracture
  • Established well-thought-out protocol helps to organize the resuscitation and assessment of the trauma patient and minimize the chance of missed injury.
  • The ATLS course of the American College of Surgeons defines two surveys for the trauma patient: the primary survey, which is designed to identify all immediately life-threatening injuries within minutes of arrival and to treat those injuries in the emergency department as they are discovered; and a secondary survey, which is designed to be a “head-to-toe” search for all other injuries the patient has sustained. Know this cold, however be able to step outside of it when the patient in front of you requires it. Go here for further discussion: http://www.emdocs.net/traumatic-cardiac-arrest/
  • The tertiary trauma survey is very important as majority of clinically significant missed injuries are detected by tertiary trauma survey. This survey should be standardized which may result in a decrease in missed injuries.[xv] The following should be included:
    • Re-evaluation of laboratory tests obtained
    • Review of initial radiographs obtained
    • Assessment for the effective detection of occult injuries
Take-home points/Pearls
  • Some missed injuries may be due to inadequate clinical assessment; therefore an accurate assessment is very critical to identify injuries.
  • A false negative FAST examination is NOT sensitive enough to rule out all abdominal injuries.
  • The absence of abdominal pain or tenderness does not rule out significant injury.
  • Following ATLS protocol may be helpful for an adequate assessment.

Go here for further reading related to this topic: http://www.emdocs.net/the-cleared-trauma-patient-what-could-we-be-missing/

 

References / Further Reading

[i] Buduhan G, McRitchie DI. Missed injuries in patients with multiple trauma. J Trauma. 2000 Oct;49(4):600-605

[ii] Laselle BT, Byyny RL, Haukoos JS, Krzyzaniak SM, Brooks J, Dalton TR, Gravitz CS, Kendall JL. False-negative FAST examination: associations with injury characteristics and patient outcomes. Ann Emerg Med. 2012 Sep;60(3):326-34.e3

[iii] Chen CW, Chu CM, Yu WY, Lou YT, Lin MR. Incidence rate and risk factors of missed injuries in major trauma patients. Accid Anal Prev. 2011 May;43(3):823-8

[iv] Anderson S, Biros MH, Reardon RF. Delayed diagnosis of thoracolumbar fractures in multiple-trauma patients. Acad Emerg Med.1996;3:832-839

[v] Ryan M, Klein S, Bongard F. Missed injuries associated with spinal cord trauma. Am Surg.1993;59:371-374

[vi] Wisner DH, Victor NS, Holcroft JW. Priorities in the management of multiple trauma: intracranial versus intra-abdominal injury. J Trauma.1993;35:271-276

[vii] Onuora VC, Patil MG, Al-Jasser AN. Missed urological injuries in children with polytrauma.Injury.1993;24:619-621

[viii] Sung CK, Kim KH. Missed injuries in abdominal trauma. J Trauma. 1996;41:276-278

[ix] Ward WG, Nunley JA. Occult orthopaedic trauma in the multiple injured patient. J Orthop Trauma.1991;5:308-312

[x] Goode T, Young A, Wilson SP, Katzen J, Wolfe LG, Duane TM. Evaluation of cervical spine fracture in the elderly: can we trust our physical examination? Am Surg. 2014 Feb;80(2):182-184

[xi] Enderson BL, Reath DB, Meadors J, Dallas W, DeBoo JM, Maull KI. The tertiary trauma survey: a prospective study of missed injury. J Trauma.1990; 30:666-669

[xii] Williams SR, Perera P, Gharahbaghian L. The FAST and E FAST in 2013: trauma ultrasonography: overview, practical techniques, controversies, and new frontiers. Crit Care Clin. 2014 Jan;30(1):119-150

[xiii] Inaba K, DuBose JJ, Barmparas G, Barbarino R, Reddy S, Talving P, Lam L, Demetriades D. Clinical examination is insufficient to rule out thoracolumbar spine injuries. J Trauma. 2011 Jan;70(1):174-179

[xiv] Miller PR, Croce MA, Bee TK, Malhotra AK, Fabian TC. Associated injuries in blunt solid organ trauma: implications for missed injury in non-operative management. J Trauma. 2002 Aug;53(2):238-242

[xv] Pfeifer R, Pape HC. Missed injuries in trauma patients: A literature review. Patient Saf Surg. 2008 Aug 23;2:20

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