Tag Archives: GI

1.4% Observed Adverse Reaction Treated With Flumazenil

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Flumazenil (Rx: Romazicon) has recently been described as coming into favor for two unique purposes: (1) hepatic encephalopathy and (2) paradoxical reactions to benzodiazepines.

Regarding the first, flumazenil’s use in hepatic encephalopathy has been well described recently in a Cochrane review of 113 RCTs with a total n = 805, wherein flumazenil had a significant beneficial effect on short term improvement of hepatic encephalopathy.1 This is thought to occur physiologically secondary to reversal of the origin of hepatic encephalopathy—i.e., an accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition1 (principally GABA receptors which are forefront in the stimulation of sedation). Therefore GABA receptor antagonists (such as flumazenil) can be used to directly oppose this mechanism. Effect on full recovery and survival has still not been proven with flumazenil administration.1

Secondly, flumazenil can be used for paradoxical reactions to benzodiazepines2,4 and in a 10 year review of its use, published in the Journal of Emergency Medicine,3 the real safety of this drug has once again come into question, as there were relatively few adverse outcomes even in the highest of seizure provocation risk—which occurred with co administration of pro-convulsant (e.g., TCAs) at a 2.7 % incidence (8/293)—the total incidence including all subjects bore a rate of 1.4% of seizure activity (n = 904).3

I present an example of administration in the second of indications above. I took care of a 26 yo WF with PMH of asthma, a prior severe dental cavity pending root canal and an IV heroin addiction, currently sober and progressing through the the 12 Steps program at the Healing Place. She presented in sepsis, afebrile with qSOFA of 0/3 (Labs: WBC 21.2 with left shift, procal 1.33, ESR 83, CRP 201, lactic acid 0.8 s/p 2 L NS IVFs), and AKI (Cr. 1.6) with dental as well as urinary possible sources. She was eventually discharged on day 3 with Dx of urosepsis, creatinine returned to normal, and had a negative echo for routine endocarditis rule out in the setting of PMH of IVDA.

During her ER stay she was uncomfortable, diaphoretic, pale, GCS of 15, but anxious and in pain, professing severe insomnia for 3 days, stating, “I just want to sleep”. A trial of oral Ativan 2 mg was given, as she did not want any pain medication due to her prior addiction. She noted a small temporary improvement; however 2 hours later this beneficial effect was absent. By now she had received cefepime 2g and vancomycin 25 mg/kg (for potential osteomyelitis coverage), and was requesting more anxiety medications, having already received 50 mg IV Benadryl 30 minutes prior with no improvement noted. Clinically she was GCS 15, pleasant in interaction, increasingly pale, uncomfortable, wide awake at 0445, and subjectively in pain. She was then given 2 mg IV Versed.

Immediately following the administration of midazolam she became altered to GCS 12 (E4, V3, M5), eyes wide, extremities tremulous, pulled out all of her IVs, and was trying to jump off the bed. It was clear she was paradoxically agitated and hyper-aroused. Rather than reversing her (though we doubted history of benzodiazepine use), we opted to watch and see if this reaction would subside without intervention since she responded favorably to the oral Ativan; however the rarely seen but well known paradoxical reaction to Versed was suspected. She was observed 1:1 and thereafter 3:1 for 40 minutes, at which time she appeared to be steadily worsening rather than improving. The decision was made to give an IV push of 0.2 mg of flumazenil (Rx: Romazicon). Within 30 seconds after administration she once again returned to her pleasant self, she was GCS 15, appropriate, and had no recollection of the previous hour, and had no seizure activity noted throughout her stay. She maintained a healthy mental status of GCS 15 and was AAOx4 for the rest of her evaluation and admission.

In 2010, Kreshak et al. reported a similar case and treatment. This paradoxical reaction to Versed in their report is thought to occur at less than 1% incidence, however it is described as commonly as 1.4 %.4 In the reported literature this reaction is described as a patient becoming acutely agitated, restless and aggressive2. Stiffening and jerking of the extremities, and shaking of a part of the body are also noted. When observing a patient with this reaction, after ruling out other etiologies of agitated AMS, Kreshak et al. (2010) opted to administer flumazenil 0.5mg IV, and “…immediately after which the patient became conscious, oriented and calm, the paradoxical reaction was terminated”. The patient had no recollection of the events,2 similar to the patient observed in the ULED.

Per Kreshak et al. (2010), there exist “…different theories concerning the mechanism of paradoxical reactions, involving a central cholinergic effect or the serotonin imbalance”.2 Unfortunately the exact mechanism of paradoxical reactions remains unclear.

Although difficult to locate literature, if seizures develop following flumazenil administration, pharmacology guidelines recommend Valium 20-30 mg IV then immediately switching to barbiturates; some soft EM sources also suggest going straight to propofol.5

Thank you for reading my post.

References

  1. Als-Nielsen, B., Kjaergard, L., & Gluud, C. (2001). Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy. The Cochrane Database of Systematic Reviews (Complete Reviews). doi:10.1002/14651858.cd002798
  2. Cabrera, L., Santana, A., Robaina, P., & Palacios, M. (2010). Paradoxical reaction to midazolam reversed with flumazenil. Journal of Emergencies, Trauma, and Shock J Emerg Trauma Shock, 3(3), 307. doi:10.4103/0974-2700.66551
  3. Kreshak, A. A., Cantrell, F. L., Clark, R. F., & Tomaszewski, C. A. (2012). A Poison Center’s Ten-year Experience with Flumazenil Administration to Acutely Poisoned Adults. The Journal of Emergency Medicine, 43(4), 677-682. doi:10.1016/j.jemermed.2012.01.059
  4. Tae, C. H., Kang, K. J., Min, B., Ahn, J. H., Kim, S., Lee, J. H., . . . Kim, J. J. (2014). Paradoxical reaction to midazolam in patients undergoing endoscopy under sedation: Incidence, risk factors and the effect of flumazenil. Digestive and Liver Disease, 46(8), 710-715. doi:10.1016/j.dld.2014.04.007
  5. (n.d.). Retrieved August 23, 2016, from http://www.goodfriendem.com/2013/05/flumazenil-romazicon-is-probably-safer.html

Finally

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I am quite excited about this study but sad I was not the one to publish it. Out of South Florida, a study of 72 patients who received a NONCONTRAST CT Abdomen for various locations of abdominal pain.

Excluded were: trauma, pregnant, surgery in past 30 days, pain more than 3 days, MD discretion (thought usually to be suspicion for vascular emergency), unable to be reached for 7 day follow up, would not consent, unstable, suspected renal stone (as this is already the standard of care), known cancer, BMI < 18. Sounds like a lot of exclusions but this pared the population down to the general population of patients in whom I would consider the noncontrast CT abd for nonspecific abdominal pain. Notice suspicion for appendicitis was not an exclusion, many studies have shown minimal benefit to oral contrast in appendicitis. They also did not exclude very acute abdominal pain (ie using a minimum number of hours of pain).

The results: 0/72 patients had a missed diagnosis on the initial noncontrast CT. 3/72 had repeat contrasted studies which added little. Of the 31 patients discharged, no one had surgery, death, or repeat CTs done.

This is obviously a small sample at one hospital. Selection bias can be a factor, as MD discretion was an exclusion. I would love to see more studies like this, possibly RCTs. As more and more centers get the higher resolution CTs, we should see less and less contrast given for CT of the abdomen and pelvis.

Acute Cholecystitis, Classic

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Interesting case from a couple weeks ago.

20ish yo white male, no significant past medical diagnoses. Overweight. Family history of gallbladder disease. No OTC or Rx medications. Patient smokes, does not drink, and has used IV drugs in the past.

Here in the ER due to RUQ abdominal pain for one week, was coming and going and is now constant. On further questioning, admits that his mom made him come because of her history of gallstones and cholecystectomy. On exam patient has jaundiced sclera and urine on table is dark brown, pain in right upper quadrant of abdomen is exquisite. States he has been vomiting especially after eating and all food makes him sick. No documented fevers, but feeling chills.

Urine: Large bilirubin, otherwise normal

Pertinent blood: WBC 8.4, Hgb 14.2, Plt 430. Alk Phos 140, AST 734, ALT 1417, Total Bili 9.5. Lipase 22. Tylenol neg.

Didn’t expect this guys ‘acute chole’ to cause liver failure.  Either way, he was getting further imaging to find out more. No ultrasound coverage at 5am so CT for now, then ultrasound at 7am. Added tox screens and hepatitis panel at this time.

CT abdomen/pelvis with contrast: “Markedly thickened/edematous wall of the gallbladder indicating cholecystitis. No calcified stone visualized. Additional imaging maybe obtained with ultrasound.” Also, normal liver.

The results of the ultrasound showed a “nondistended gallbladder with marked wall thickening, edema and a positive sonographic Murphy sign. Given lack of clear visualization of the posterior wall, highly worrisome for complicated cholecystitis, possibly gangrenous or with a focal posterior perforation.” Normal liver and mildly dilated bile duct.

Now with labs showing liver failure and two forms of imaging showing acute cholecystitis, it had to be. Admitted to the general surgery team though the ‘acalculous cholecystitis’ with liver failure was enough to peak my interest in follow-up.

Hepatitis panel comes back later same day showing reactivity for Hep C. Discharge 5 days later, no surgery, no acute interventions, with down-trending liver function panel and follow-up with the GI clinic.

While most commonly associated with cholecystitis, a quick literature search reveals multiple reasons besides cholecystitis to have gallbladder wall thickening… congestive heart failure (right sided), gallbladder carcinoma, adenomyomatosis (chronic gallbladder inflammation or degeneration), renal failure, pancreatitis, cirrhosis and other forms of liver failure.

The Hypercoagulable Liver Failure Patient?

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Hey Guys,
Just listened to a portion of April EM:RAP (so if you’ve heard it already here’s a little repetition) and was surprised to hear their Notes from the Community Section about coagulopathy in Liver Disease, which basically informed me that many liver patients are at just a high of risk of thrombosis as they are of bleeding.

3 Articles were referenced:
– Tripodi A, Mannucci PM. The coagulopathy of chronic
liver disease. N Engl J Med. 2011 Jul 14;365(2):147-56.
– Villanueva C et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11-21.
– DeLoughery TG et al. Invasive line placement in critically ill patients: do hemostatic defects matter? Transfusion. 1996 Sep;36(9):827-31.

Summary:
– The liver makes both procoagulant and anti-coagulant proteins which can be actually reduced close to equally rendering the patient basically in equilibrium (thus not so hypercoagulable).
– No study has shown that coagulation defects predict issues with procedures (but the experience of the clinician performing the procedure does).
– INR is not standardized in Liver Failure patients (like it is with Warfarin) and thus is not that helpful.
– PT & PTT may also not be helpful in patients with liver failure (due to the variability of loss of clotting factors)
**Fibrinogen may be low in liver failure patients, and you may consider replacement of this with Cryoprecipitate (10 units of Cryo increases the Fibrinogen by 100mg/dl).
– Raising intravascular volume with pRBCs may make them bleed more.

For the full references & discussion see the EM:RAP written summary. Perhaps this is something we should discuss with our GI colleagues and/or MICU people. Any thoughts?