Month: July 2019

Is Thiamine IV Push Safe?

by empharmd, posted in EM PharmD Core

Ravipal Singh, PharmD, BCCCP
Emergency Medicine Pharmacist
John Muir Health – Walnut Creek Medical Center
Walnut Creek, CA
Twitter: @RaviEMPharmD

There is a movement away from prescribing a banana bag when treating patients with acute alcohol intoxication or at risk for alcohol withdrawal. This has been covered in detail in multiple FOAM posts and literature [1]. This post will not discuss Wernicke’s encephalopathy, malnourished patients, prevention vs. treatment thiamine doses nor dosing frequency. We are going to zero in on how to get the liquid from the thiamine vial into the patient’s IV line. 

It’s important to highlight a possible exception with respect to IV thiamine administration rate. A 2003 controlled study compared the effects of varied infusion rates in 12 healthy individuals when 150 mg of thiamine was given IV over either 1 hour or 24 hours. As expected, although the rapid infusion produced a higher peak concentration, the slower infusion increased the AUC of thiamine pyrophosphate (thiamine’s active metabolite) slightly by 10% (P < 0.08) and decreased the urinary elimination from 83.6% of the dose to 57.6%, suggesting a benefit for slower administration rates when treating severe thiamine deficiency syndromes. Therefore, longer infusion times are a consideration when treating Wernicke’s encephalopathy since bolusing increased renal elimination of the drug [2]. 

Storing a thiamine 200 mg/2 mL vial in the automated dispensing cabinet to be given IV push is easier from an operations standpoint. It decreases total aggregate workload for both pharmacy and nursing and potentially decreases waste. Making a piggyback to bedside administration is labor-intensive. This involves compounding in the IV room, delivering to the RN who has to get tubing, smart pump, program the pump, and tend to any pump alarms during the infusion. There’s also the possibility of getting a missing medication or damaged bag message, which restarts the whole process. 

The purpose of this post is to explore if thiamine IV push (IVP) is safe. The heart of the issue is while thiamine has a good safety profile, concerns exist because of anaphylaxis reports. 

Let’s explore some data. 

Thiamine Anaphylaxis Case Reports:  

  • Before the 1970s, especially in 1940s, there were multiple reports of serious reactions to thiamine and then curiously, at least in the USA, no further cases were reported for 20 years, until the 1992 Tufts-New England Medical Center case report [3,4,5]. 
  • 1992 Tufts-New England Medical Center ED (Boston): 32 yo male with alcohol intoxication, slipped on ice resulting in shoulder injury, otherwise in good health. Given thiamine 100 mg IV push. Within 2 minutes, complains of nausea, at 5 minutes intensely erythematous, hypotensive, bilateral inspiratory and expiratory wheezes, no upper airway stridor, no urticaria. Got epinephrine subcutaneous and adjuncts. Recovered and discharged next day [3]. 
  • 1995 Belgium: 86 yo female, found at home, lying on the floor, history of alcohol abuse. Admitted to geriatric ward for possible alcohol withdrawal. Thiamine 250 mg intramuscular administered. 2 hours after injection, throat tightness, shortness of breath, hypotensive, barely palpable femoral pulses. Subcutaneous epi given, 10 minutes later, epi 0.5 mg IV given, subsequent ECG did not show MI. After 30 minutes, became unconscious, intubated, transferred to ICU, given fluid, started on dopamine drip, vital signs deteriorated over 2 hours, patient died in asystole. CPR not performed [6]. 
  • 2000 Lincoln Medical Center (New York): 51 yo woman h/o diabetes, chronic alcoholism, anxiety found by EMS in acute confusional state. EMS gave 25 g D50W and thiamine 100 mg IV (assuming IV push). On arrival to hospital 20 minutes later, in respiratory arrest and was intubated. Next morning, patient was extubated. 2.5 hours later, a routine thiamine infusion started. Within moments, patient complained of shortness of breath, warmth, and tightness of throat, BP 83/40, oxygen sat dropped to 70%, then reintubated. Extubated next day and discharged 2 days later with advice to avoid thiamine [7]. 
  • 2013 Denmark: 44 yo alcohol-intoxicated male with NKA c/o diffusely located chest and abdominal pain. ECG at admission showed sinus rhythm with no signs of ischemia. Thiamine 300 mg IV given (unknown if pushed or infused). Had received thiamine on several previous occasions without complications. No other drugs were given. Shortly after, patient found unresponsive with abnormal rattling respiration. CPR started, patient in PEA. ROSC at 15 minutes. Transfered to ICU, discharged in good health after 14 days. A serum tryptase obtained after 1 and 24 hours from thiamine administration, confirmed the diagnosis of anaphylaxis [8]. 

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Data Supporting IVP Thiamine:

Let’s go back 30 years! In 1989, a study out of Grady Memorial Hospital ED was published in Annals of Emergency Medicine [5]. 

  • Prospective evaluation of the safety of thiamine given as a 100 mg IV push, usually over 10 seconds or less, to patients at risk for thiamine deficiency or who needed fluids for other reasons

Results: 

  • Over 6 month period, 989 consecutive patients, 1,070 doses administered IVP
  • 795 men (80%); 194 women (20%); ages ranged 16 – 80 years
  • 80% of cases, alcoholism was at least partially the reason for thiamine administration
  • 49 patients on cardiac monitors at the time of the study, no arrhythmias noted 
  • 12 adverse reactions (1.1%) reported
    • minor reactions consisting of transient (lasted seconds to minutes) local irritation seen in 11 patients (1.02%)
    • 1 major reaction (0.093%) consisting of generalized pruritis
  • The authors commented that “After a review of the literature, it seems that any prejudice against IV thiamine dose in favor of other parenteral routes is unwarranted because anaphylactoid reactions seem to occur with equal frequency in IV, IM, or subcutaneous injections.”

Study Conclusion: 

  • Thiamine 100 mg IVP may be administered without undue concern. Intradermal test doses before administration are not warranted. 

A few years later these same authors wrote a rebuttal to the 1992 case report that the Tufts-New England case should not be a plea for excessive caution in administering thiamine to patients at risk for Wernicke’s encephalopathy [4]. They wrote: 

  • We estimate that during our 15 years in Atlanta, parenteral thiamine was administered at least 10,000 times per year. 
  • During 1980s, almost all thiamine was given IVP.
  • Similar data came from 2 other large inner city EDs. Both Bellevue Hospital in New York City and Denver General Hospital have given at least 10,000 IV thiamine injections per year over the past 10 years without incident (personal communications they had with Drs. Lewis Goldfrank and John Marx, 1991).
  • The chance of an allergic reaction is below what is reported for penicillin and contrast media. 

Common Practices from Around the Country

I reached out to several authors and practitioners regarding IV thiamine administration at their hospitals, and the responses are summarized below.

 University of Kentucky Medical Center

  • Doses ≤ 200 mg are given as IV push. 
  • Nursing administration guide is to push 200 mg over 2 minutes – no further dilutions required. 
  • How long has your institution been doing this? Probably 6-8 months now. When the thiamine shortage really started to impact us, we decreased our empiric dosing in ICUs from 500 mg IV q8h (IV infusion) to 200 mg IV q8h IV push. 
  • Any ADRs seen? None that I’m aware of (not formally evaluated in MUE or anything though)

Brigham and Women’s Hospital (Boston)

  • Pushing up to and including 250 mg of thiamine about 9 years.  
  • In process of publishing their work. 
  • Research snapshot published in Jan 2019 Critical Care Medicine [9]. 

Objective: Evaluate the incidence of anaphylaxis and IV site reactions associated with IV push thiamine in adult inpatients. 

Methods: single-center, retrospective chart review of all adult patients who received 100 mg, 200 mg, 250 mg, and 500 mg IV push thiamine between June 1, 2015 – July 31, 2017. 

Results: 

  • 8530 administrations in 2591 patients
  • 5494 peripheral administrations; 1641 centrally; remainder – unknown
Thiamine IV push DOSE# of doses
100 mg7566
200 mg412
250 mg533
500 mg19
  • No anaphylactic or anaphylactoid reactions were observed. 
  • 24 (0.28%) infusion site reactions noted in 19 patients.
    • Phlebitis noted 11 times (grade one:2; grade two: 3; ungraded: 6)
    • Infiltration noted 13 times (grade two: 1; grade three: 3; ungraded: 9)
    • Further assessment of the reactions with Naranjo Nomogram classified:
      • 18 reactions – possible likelihood caused by IVP thiamine
      • 6 reactions – probable likelihood caused by IVP thiamine 

Conclusions:

  • IV push thiamine not associated with any anaphylactic events
  • Low incidence of IV site reactions
  • IV push thiamine in doses ranging from 100 mg to 250 mg may be considered safe for administration
  • A signal that thiamine 500 mg IV push dose may be safely administered 

University of North Carolina Medical Center

  • Yes, we push all doses of 100 and 200mg IV thiamine. We have always pushed 100mg doses for as long as I have been at UNC, which is 30 years. We started pushing 200mg doses in April of 2013. It’s pushed and not diluted. I am not aware of any issues since the MUE was completed. This is our normal practice and we do it daily. 
  • In process of publishing work.
    • abstract PDF available on the internet – Google Search “University of North Carolina and thiamine”–> Evaluation of the safety of intravenous thiamine administration in a large academic medical center [10]. 

Background: 

Due to high utilization of thiamine IVP for 200 mg doses within the institution, they sought to evaluate the safety of this practice compared to administration by infusion. 

Methods:

  • Single-center, retrospective cohort study performed from June 2017 to October 2017
  • Included patients at least 18 years old and received one dose of IV thiamine 200 mg or greater
  • 2 groups: 200 mg IVP (n = 100) or 200 mg or greater as an IV infusion (n = 100)

Results:

  • On average, included patients were 55 years old and male
  • Most common reasons for admission: altered mental status (12%); alcohol withdrawal (9.5%); cirrhosis (3.5%)
  • Patients received average of 2000 mg of thiamine and 7 total doses
  • 50% received 200 mg IVP only
  • 30% received IV infusion only
  • 20% received both IV infusion and IVP
  • Adverse reactions possibly due to thiamine administration occurred in 4 patients (2%)
    • 1 received 200 mg thiamine via IV infusion
    • 3 received 200 mg via IV push
    • no significant difference (p=0.640) in rate of adverse reactions between IVP and IV infusion administrations
    • reactions noted included shortness of breath and/or wheezing and abdominal pain
  • Anaphylaxis, hypersensitivity, syncope, and cardiac arrest were not observed in the patient population studied
  • No patients developed shock which could be attributed to thiamine administration


Conclusions:

  • Data supports administering thiamine doses 200 mg or less as an IV push
  • Given lack of robust safety data, authors recommended to continue to dilute thiamine doses greater than 200 mg and infuse over 30 minutes 

Abbott Northwestern Hospital (Minneapolis, Minnesota)

  • Doses ≤ 200 mg are given as IV push
  • How long has your hospital been doing this? At least as long as I have been here, which is 14 years
  • Any specific administration or dilution comments: Give as slow IV push over 2-5 minutes
  • Have not seen any ADRs, and we have not conducted any specific MUE
  • This process is for all Allina sites. Abbott Northwestern is the largest of the Allina Hospitals. 

Grady Health System (Atlanta)

  • Been giving thiamine IV push for > 15 years. 
  • Doses ≤ 100 mg can be given IV push.  

SHARP Grossmont Hospital (San Diego)

  • Most of our patients are getting either thiamine IV push, or a thiamine-folate IVPB, if unable to take PO. 
  • Our hospital has been using a ton of IV push thiamine over the past couple years now – only for 100 mg (anything more requires IVPB), with the following order comments: “Give slow IV push over 5 minutes.  Anaphylactoid/hypersensitivity reaction associated with rapid administration”. Not heard of any instances of adverse reaction since we switched to IVP.

Mercy Health Saint Mary’s (Grand Rapids, Michigan)

  • 100 mg given IV Push. 
  • Responder been at this hospital x 2 years and 100 mg IV push has been there since
  • Order comments: IV push to administer up to 20 mg/min. No dilution required. 
  • Not aware of any ADRs

University of Chicago Medical Center

  • Up to 100 mg as IV push. 
  • Unsure how long this has been in practice, no anecdotal ADR, no MUE performed. 
  • Default administration instructions: Administer via IV push over 1-2 minutes

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Bottom Line

The data involving a large number of both IVP doses and patients without adverse reactions to thiamine IVP gathered from decades-old literature, new literature, and recent responses from practitioners around the USA strongly suggests that thiamine 100 mg IVP is reasonably safe, and 200 mg IVP may be considered safe, too. 

Even though publications are in the works, conducting more studies or sharing an MUE abstract is encouraged because people tend to like recent data. Moreover, maybe your hospital has already been doing IVP thiamine for years without issue and it’s not even on your radar, but I’m sure there is another hospital on the cusp to make a decision to change from IVPB to IVP that would benefit from your experience. Never underestimate the power of sharing knowledge, you can literally help change and improve practice. 

IMG_5536.jpg

Reviewed and edited by: Craig Cocchio, Pharm.D, BCPS

References: 

  1. Flannery AH, Adkins DA, Cook AM. Unpeeling the Evidence for the Banana Bag: Evidence-Based Recommendations for the Management of Alcohol-Associated Vitamin and Electrolyte Deficiencies in the ICU.Crit Care Med Aug 2016;44(8)1545-1552. (PMID 27002274)
  2. Drewe J, Delco F, Kissel T, et al. Effect of intravenous infusions of thiamine on the disposition kinetics of thiamine and its pyrophosphate. J Clin Pharm Ther 2003 Feb;28(1):47-51. 
  3. Stephen JM, Grant R, Yeh CS. Anaphylaxis From Administration of Intravenous Thiamine. Am J Emerg Med 1992 Jan;10(1):61-63. (PMID 1736919) 
  4. Wrenn KD, Slovis CM. Is Intravenous Thiamine Safe? Am J Emerg Med 1992 Mar;10(2):165.   (PMID 1586415) 
  5. Wrenn KD, Murphy F, Slovis C. A Toxicity Study of Parenteral Thiamine Hydrochloride. Ann Emerg Med 1989 Aug;18(8):867-870  (PMID 2757284)
  6. Van Haecke P, Ramaekers D, Vanderwegen L, Boonen S. Thiamine-induced anaphylactic stock. Am J Emerg Med 1995 May;13(3):371-372. (PMID 7755837)
  7. Johri S, Shetty S, Soni A, Kumar S. Anaphylaxis From Intravenous Thiamine – Long Forgotten? Am J Emerg Med 2000 Sep;18(5):642-643. (PMID 10999594)
  8. Juel J, Pareek M, Langfrits CS, et al. Anaphylactic shock and cardiac arrest caused by thiamine infusion. BMJ Case Rep 2013. (PMID 23853017)
  9. McLaughlin K, Joyal K, Lee S, et al. 1329: Safety of Intravenous Push Thiamine Administration At A Tertiary Academic Medical Center. Research Snapshot Theater: Quality & Patient Safety. Crit Care Med Jan 2019;47 (Suppl 1):641. 
  10. Jean S, Tjugum S, Hedrick T, et al. Evaluation of the safety of intravenous thiamine administration in a large academic medical center. Accessed 18 July 2019, https://pharmacy.unc.edu/files/2018/05/Stephanie-Jean-REPS-abstract.pdf

Cannabinoid Hyperemesis Syndrome (CHS): Getting “Into the Weeds” on a Complication of Chronic Marijuana Use

by empharmd, posted in Classic EM PharmD

Post by: D. Evan Mulvihill
PGY2 Emergency Medicine Pharmacy Resident

Sharp Chula Vista Medical Center/Touro University California


Cannabinoid Hyperemesis Syndrome (CHS) is a sequela of long-term heavy cannabis use that involves cyclic bouts of nausea, vomiting, and diffuse abdominal pain. The treatment of CHS is unique in that your traditional anti-emetics and GI cocktails like Zofran, metoclopramide, and acid reducers, are fairly ineffective in controlling symptoms. CHS patients often receive extensive gastrointestinal (GI) work-ups in the ED, and may even be admitted when there are much simpler treatments to attempt first.

Case in point: the New York Times described one CHS patient named Thomas Hodorowski who received many unnecessary therapies and invasive procedures because CHS was not diagnosed early. They write: “[Hodorowski] had been to the emergency room dozens of times, tried anti-nausea drugs, anti-anxiety medications, and antidepressants, endured an upper endoscopy procedure and two colonoscopies, seen a psychiatrist and had his appendix and gallbladder removed.”

This blog post is intended to give you a quick and dirty introduction to CHS, and to implement strategies that will educate providers to cast a wider umbrella for diagnosis, so that effective pharmaceutical treatment is delivered in a timely fashion.

Introduction to CHS

Heavy use of cannabis for extended periods of time (usually on the scale of years) can lead to a cyclic vomiting syndrome known as CHS, which is characterized by nausea, vomiting, and diffuse abdominal pain.  Patients report that hot showers or baths relieve symptoms, and long bathing often becomes a compulsive behavior. Estimates on the prevalence of CHS are difficult to find, but a 2009 study at a Colorado found that the incidence of CHS doubled from 41 per 113,262 visits to 87 per 129,095 visits in the year after legalization of marijuana, although absolute numbers of ED visits were low.

CHS are frequent utilizers of ED care and often receive extensive GI/abdominal pain work-ups. Episodes typically last 24-48 hours but can last up to 7-10 days. The condition will resolve with cannabis cessation.

Pathophysiology

The exact pathological mechanism of CHS is poorly understood, but current literature implicates a receptor called TPRV1 (transient receptor potential vanilloid subtype 1) most heavily. Cannabis has classically been known to activate 2 types of receptors: CB1 and CB2. CB1 receptors are found in the central nervous system (CNS) and are responsible for the sensations of being “stoned” (euphoria, relaxation, sedation, those intractable munchies, possible anxiety/paranoia, etc.). CB2 receptors are located in the peripheral nervous system and immune system, especially the GI tract, and is responsible for the antiemetic effect endorsed by users. CB2 receptors were originally considered to be the most likely culprit for CHS, however, more evidence now points to TPRV1 based on successful treatment of CHS using TPRV1 agonists, including capsaicin and heat (hot showers/baths).

TPRV1 is expressed in the GI tract, CNS, and dermis. It is known to promote gastric mobility and has potent anti-emetic effects when activated, which may involve depletion of substance P (SP) in neural circuits. SP is known to activate neurokinin 1 (NK1) receptors and cause nausea, hence the anti-emetic effect of direct NK1 antagonists such as aprepitant. Other currently described agonists of TPRV1 include cannabinoids, capsaicin, nociceptive heat above 43 C, and acid.

Chronic cannabis use is thought to lead to decreased levels of TPRV1 in the body based on desensitization and downregulation. Lower levels of TPRV1 receptors may thus result in impaired ability to deplete SP, and effects such as emesis and altered gastric motility. It is unclear why the syndrome is cyclic rather than constant but may have to do with increased sensitivity to fluctuations in endogenous SP levels.

Management of CHS

There is only one published guideline on the management of CHS, which was created by the San Diego Emergency Medicine Oversight Committee. The expert panel stated that cannabis cessation is the only failproof treatment. The panel also recommended to avoid opioids for abdominal pain due to addiction potential and to avoid advanced imaging, radiation, and invasive procedures during work-up.

The supportive therapies endorsed by the panel included IV fluids for dehydration, traditional antiemetics (ondansetron, promethazine, metoclopramide), benzodiazepines (lorazepam, diazepam), diphenhydramine, antipsychotics (haloperidol, olanzapine), and lastly capsaicin cream. The panel does not privilege one treatment over the others but states that topical capsaicin is the first-line treatment in cases of a clear diagnosis. They recommend a dose of 0.075% strength cream applied topically 3 times daily to the abdomen or back of arms, although there is little evidence to privilege one strength over another. 

Capsaicin

Ashkan Khabazian, an EM pharmacist at Sharp Memorial Hospital in San Diego, CA, says that the concentration matters little compared to the total quantity used. “Physicians tend to order 0.1% for CHS, but the actual concentration is a moot point,” he wrote in an email to us. “More depends on the quantity used.” To that point, we recommend applying a small quarter-sized portion to the abdomen, and then add more if the drug produces a reduction in emetic symptoms and is well tolerated (i.e. no severe dermatological reaction).

Multiple case reports and case series have documented the success of capsaicin therapy, usually after the failure of other therapies. A patient described by Moon, Buckley, and Mark failed IV fluids, ondansetron,

metoclopramide, prochlorperazine, fentanyl, a GI cocktail, and pantoprazole. The patient’s nausea and abdominal pain was reported to be completely resolved after application of capsaicin 0.075% cream to a 15 x 25 cm area in the periumbilical region every 4 hours for 4 doses.

A case series published by Dezieck and colleagues found that capsaicin facilitated discharge for 13 patients who failed other therapies. They noted that there was no obvious difference in response between 7 patients who received 0.25% and 6 who received 0.075%.

Caption: Eight of 13 patients in the Dezieck study were given capsaicin as the last drug prior to discharge, usually only staying 1 to 4 hours afterward. Source: Dezieck 2016

Lastly, a report from Lapoint (the lead author on the San Diego Emergency Medicine Committee expert panel paper) showed that 5 patients saw rapid and significant decreases in abdominal pain scores after administration of capsaicin.

Haloperidol

The evidence for haloperidol use in CHS is also limited to case reports. The mechanism of action is unclear but may relate to D2 receptor antagonism in the chemoreceptor trigger zone.

In a case published by Hickey, a patient failed morphine, ondansetron, and normal saline bolus but haloperidol 5mg IV once resolved his symptoms. Witsil and Mycyk described 4 patients who failed standard therapy but improved with haloperidol. Jones and Abernathy described a patient who failed ondansetron, promethazine, prochlorperazine, metoclopramide, lorazepam, and omeprazole. However, the patient reported that a trial of haloperidol 5mg PO daily completed resolved her symptoms within 1 day of starting treatment, but was subsequently lost to follow-up.

A Canadian randomized clinical trial is in progress to compare 3 pharmacologic interventions for CHS: ondansetron 8mg IV, haloperidol 0.05 mg/kg IV, and haloperidol 0.1 mg/kg IV. Patients will serve as their own controls with a minimum 7-day washout period.

Conclusions and Clinical Pearls

This table is compiled from the existing evidence and my personal opinion on which therapies are most effective. The treatments are arranged from top to bottom in the order of what I would try first, and then move on if it failed.

DrugRecommended Starting DoseAdverse EffectsComments
CapsaicinAny strength cream topically TID-q4h prn (0.075% if stocked), test with a quarter-sized area first then apply to larger areaRedness, stinging at the administration siteLittle evidence to say any particular strength is more efficacious
Haloperidol5 mg PO or IV prnQTc prolongation, sedation, EPSCan trial haloperidol 5 mg po daily in an outpatient setting if capsaicin fails, or if there is concomitant psychiatric disease
Lorazepam1 mg PO or IV prnSedation, the addiction potential
Ondansetron4-8 mg PO or IVQTc prolongation
IV Fluids0.5-1 L NS IV x 1Fluid overload

I recommend against: placing an IV line unless it is necessary for other medical needs, giving IV or PO opioids, and invasive work-ups.

Future Research Questions 

A few questions have come up for me while studying CHS. First, why is the syndrome cyclic instead of constant? The cyclic nature of it may have something to do with increased TRPV1 receptor sensitivity to fluctuations in SP. But, if the syndrome is indeed caused by TRPV1 downregulation and subsequent SP excess, why isn’t there at least a mild undercurrent of constant nausea?

I also wonder about what risk factors are needed so that we can more accurately rule in and rule out CHS. Approximately how many years of heavy marijuana use are needed to put patients at risk for CHS? Can it happen with lighter use over a longer period of time? Will the effect be seen in edibles and new cannabis products like CBD?

Another question I have is if CHS can eventually become resistant to capsaicin or haloperidol. What other treatment options are there then besides hot showers and baths?