Evaluation of the safety of 500 mg intravenous push thiamine at a tertiary academic medical center

Abstract

Background: Thiamine, also known as vitamin B1, is an essential water-soluble micronutrient. Although thiamine has minimal safety concerns, parenteral administration has been associated with rare cases of anaphylactic shock, cardiac arrest, and injection site reaction. The objective of this analysis is to evaluate the incidence of anaphylaxis and injection site reactions associated with the administration of thiamine 500 mg as an intravenous (IV) push in adult patients. Method: This single-center, retrospective analysis was performed at Brigham and Women's Hospital in Boston, Massachusetts. Electronic health records were used to identify all adult patients who were ordered for thiamine 500 mg IV push between July 1, 2020, and December 31, 2020. For the major and minor endpoints, anaphylaxis and injection site reactions were assessed, respectively. Descriptive statistics were used as appropriate. Results: A total of 463 doses of thiamine in 69 patients were evaluated. Thiamine was administered peripherally for 392 (84.7%) doses and centrally for 68 (14.7) doses. No anaphylactic reactions were observed. A total of 4 injection site reactions (0.86%) were noted with 4 unique doses. All reactions were classified as low-grade based on our institutional grading system. All injection site reactions were classified as “possible” (Naranjo score of 1–4). Conclusion: Administration of IV push 500 mg thiamine was not associated with anaphylactic events and was associated with a low rate of injection site reactions.

Background

Thiamine, also known as vitamin B1, is an essential water-soluble micronutrient that acts as a cofactor in converting carbohydrates into adenosine triphosphate.^1,2 Thiamine is not endogenously synthesized, and adequate levels are maintained through dietary intake. ³ Thiamine deficiency is most commonly seen in patients with alcohol use disorder and/or critical illness. ³ Deficiency may present with central nervous system sequelae in Wernicke-Korsakoff syndrome and dry beriberi, or with cardiovascular system sequelae wet beriberi.^1,2 The recommended treatment consists of thiamine intravenous (IV) administration followed by oral supplemental therapy. ⁴ The Royal College of Physicians recommends 500 mg of thiamine once daily given parenterally for three to five consecutive days for the treatment of Wernicke's Encephalopathy. ⁵

Parenteral administration (intermittent infusion and IV push) of thiamine has minimal safety concerns with a few allergic reactions reported, however; it has been associated with uncommon cases of angioneurotic edema, anaphylactic shock, and cardiac arrest.^6,7 Current literature suggests thiamine up to 250 mg is most likely safe to be administrated as an IV push. However, there are insufficient data to support the safety of thiamine IV push with doses greater than 250 mg.^8,9 Thiamine IV push administration provides the ability of rapidly start the action of thiamine and has operational advantages.^8,9 To date, two small studies have evaluated the safety of thiamine 500 mg IV push, with no anaphylaxis, phlebitis or infiltration reported.^8,9 The objective of this analysis is to further evaluate the incidence of anaphylaxis and injection site reactions associated with the administration of thiamine 500 mg as an IV push in adult patients.

Methods

This single-center, retrospective study was performed at Brigham and Women's Hospital in Boston, Massachusetts. This study was conducted according to the World Medical Association Declaration of Helsinki. Our study was exempted by Mass General Brigham Institutional Review Board. Protection forms were not utilized in our study due to the non-interventional retrospective design of the study. Non-patient's specific identifier data was saved in a secure cloud with access only to study staff via password protection. Electronic health records were used to identify all adult patients who had orders for thiamine 500 mg IV push over 1 to 2 min, between July 1, 2020, and December 31, 2020. Patients were included if they were older than 18 years old and received at least one dose of thiamine 500 mg undiluted IV push (concentration, 100 mg/1 mL) via peripheral or central line. Patients were excluded if thiamine was administered orally, via intramuscular injection, or as a diluted infusion, or if their medical records were incomplete (missing proper documentation on the line of administration, dose administrated, and the duration of administration) or duplicated.

Data assessed included patient demographics; medical history; patient location at the time of thiamine administration; type and size of intravenous line; the number of days that the associated central or peripheral line was in place; the presence of a drug and food allergy history; and antihistaminic drug use defined as diphenhydramine, famotidine, or hydroxyzine administered within three days before thiamine administration and cetirizine, fexofenadine, or loratadine administration within seven days before thiamine administration.

For the major endpoint, anaphylaxis was evaluated by searching patient charts for keywords such as anaphylaxis, rash, hives, reaction, and desaturation. Anaphylaxis was assessed based on the 2014 European Academy of Allergy and Clinical Immunology Anaphylaxis guidelines and defined as rapid onset with life-threatening airway, breathing, or circulatory decompensation with or without associated with skin and mucosal change. ¹⁰ Data on tryptase levels and administration of medications related to thiamine anaphylaxis, including antihistamines, corticosteroids, epinephrine (0.3 mg), and bronchodilators, were collected if a patient experienced anaphylaxis. For minor endpoints, the incidence of injection site reactions, such as phlebitis or infiltration, were assessed as documented per our institutional grading system. Assessment of injection reactions occurred for the full duration of IV catheter placement after the administration of thiamine. Insertion, maintenance, and removal of all peripheral IV catheters were regulated by institutional policies. All vascular access sites were routinely assessed for signs of phlebitis and infiltration per the institutional policy by the bedside nurse or the IV therapy nursing team (Figure 1).

Figure 1.

Institutional grading of intravenous injection site reaction.

The Naranjo Nomogram for adverse drug reaction assessment was used to assess the potential impact of thiamine on all line-site adverse drug reactions. ¹¹ Descriptive statistics were used to describe the resulting data. Data are presented as frequency and percentages or mean and standard deviation, as appropriate.

Results

A total of 463 doses of thiamine in 69 patients were identified and included in this analysis. No patients were excluded. History of food, medication or environmental allergies were reported in 46.6% of patients. Patients’ demographics are summarized in Table 1. Doses were predominantly administered in an intensive care unit (34.3%), followed by medical step-down units (27.9%), the emergency department (20.1%), and surgical step-down units (17.7%).

Table 1.

Patents demographics.

Characteristic	Thiamine patients (n = 69)
Age, years*	60 [53.5–65.5]
Gender, male †	43 (62.3)
Comorbidities †	55 (79.7)
Hypertension	30 (43.5)
Seizure disorders	13 (18.8)
Diabetes mellitus	12 (17.4)
Arrhythmia	7 (10.1)
Stroke	6 (8.7)
Chronic obstructive disease	6 (8.7)
Coronary artery disease	5 (7.2)
Congestive heart failure	5 (7.2)
End-stage renal disease on hemodialysis	3 (4.3)
Traumatic brain injury	3 (4.3)
Peripheral vascular disease	3 (4.3)
Asthma	3 (4.3)
History of food, medication, or environmental allergies †	32 (46.6)

^*Median [IQR].

^†n (%).

Antihistamines were administered within the time period of 3 days prior to thiamine administration with 110 (23.8%) doses with famotidine and hydroxyzine being the most common in 64 (13.8%) and 13 (2.8%) doses, respectively. Diphenhydramine was administered with 12 (2.6%) doses and cetirizine was administered with 9 (1.9%) doses. Fexofenadine and loratadine were administered with 6 (1.3%) doses each. Thiamine was administered peripherally for 392 (84.7%) doses. Sites of administration are summarized in Table 2. Twenty-gauge catheters were utilized for 226 (57.7%) doses, followed by 18, 22, and 16 gauge catheters in 128 (32.7%), 31 (7.9%), and 7 (1.8%) doses, respectively.

Table 2.

Site of administration.

Line site	Total number of doses (n   =   463)
Peripheral †	392 (84.7)
Antecubital	113 (28.8)
Forearm	159 (40.6)
Hand	68 (17.3)
Upper Medial	10 (2.6)
Wrist	42 (10.7)
Central †	68 (14.7)
Line is not documented †	3 (0.6)

^†n (%).

Anaphylactic events were not noted in any patients regardless of the site of administration. Based on our institutional IV injection reaction grading system, a low prevalence of peripheral injection sites reactions was observed. A total of 4 injection site reactions were noted in 4 unique doses among 4 patients, accounting for a total incidence of 0.86%. Two doses were associated with phlebitis and infiltration; one dose was associated with phlebitis only, and one dose was associated with infiltration only. Among the phlebitis events, grade level 1 was reported in 2 (66.7%) doses and grade level 2 in 1 (33.3%) dose. Moreover, all phlebitis events were evaluated as “possible” (Naranjo score of 1–4). All three infiltration events were graded as level 1 and were evaluated as “possible” (Naranjo score of 1–4).

Discussion

This single-center analysis showed that 500 mg IV push thiamine was not associated with anaphylactic events and was associated with an acceptable low rate of injection site reactions (0.86%). ¹² These findings suggest that IV push administration of 500 mg thiamine is safe.

To the best of our knowledge, this is the largest retrospective analysis to evaluate 500 mg IV push thiamine. McLaughlin, et al. evaluated 19 doses, with no anaphylaxis, phlebitis or infiltration reported. ⁸ Tjugum, et al. demonstrated similar outcomes among 39 doses of 500 mg IV push thiamine. ⁹ Our results are comparable to the previously referenced studies as we demonstrated 500 mg IV push thiamine is safe with a very low rate of phlebitis and infiltration and no cases of anaphylactic events.

The average time required for compounding a sterile product is 3.38–9.1 min. However, it may take up to 220 min for medications to be available for administration when also considering the time for order verification, obtaining materials for sterile compounding, verifying the product, and delivery time.^13–15 IV push administration optimizes workflow and allows for immediate availability in an automated dispensing cabinet on the unit for administration after order verification. Although thiamine (200 mg/2 mL injection vial) is a relatively inexpensive drug with a $5.41 wholesale acquisition cost (WAC), transitioning its administration from a sterile compounded mixture to an IV push provides operational benefits. Transition to IV push administration reduces the time from order verification to administration and overall streamlines workflow from a nursing and pharmacy perspective. Moreover, IV push administration provides fewer limitations on IV drug incompatibility and reduced fluid administration.^14–16 There are documented risk factors for developing phlebitis and infiltration, such as female gender, elderly, large catheter gauge (≥20), and patients with comorbidities.^17,18 Among the 4 patients in our study who experienced phlebitis and infiltration, only 1 patient was an elderly (>60 year old) female without comorbidities where a 20 gauge catheter was used. The remaining 3 patients were male, 2 of which were greater than 60 years of age. All 3 male patients had at least 1 concomitant disease state and a catheter gauge ≥20 was used in 2 out of 3 male patients.

Our study has some strengths. First, we included higher doses of thiamine compared to other previous studies. Second, we included patients who received thiamine via peripheral and central line. There are some limitations to our study. First, inaccurate documentation is possible given the design of this study was a retrospective, single-center analysis. Second, IV-line maintenance policies and procedures practiced at our institution may not be reflective of other institutions’ practices. Third, this was a retrospective hypothesis-generating study. Finally, as our objective was to evaluate the safety, we did not assess efficacy.

Conclusion

In this analysis, IV push administration of thiamine 500 mg did not result in anaphylactic events and it was associated with an acceptably low rate of injection site reactions (0.86%). Based on the results of this analysis, if appears thiamine 500 mg is safe to be administered as an IV push.

Author biographies

Mohammed Aldhaeefi, B.Sc. Pharm., Pharm.D., BCCCP currently serves as a Clinical Assistant Professor at Howard University College of Pharmacy in Washington, DC. Dr. Mohammed completed his Pharm.D. at the Medical University of South Carolina, then his PGY1 and PGY2 critical care pharmacy residency training at Brigham and Women's Hospital in Boston, Massachusetts. His interest revolves around acute respiratory distress syndrome, shock, and ECMO.

Kevin McLaughlin, Pharm.D., BCCCP, BCPS, is a Critical Care Clinical Pharmacy Specialist at Brigham and Women's Hospital in Boston, Massachusetts. Dr. McLaughlin practices in the cardiovascular surgery ICU, and he completed his PGY1 and PGY2 critical care pharmacy residency training at Brigham and Women's Hospital.

Melanie Goodberlet, Pharm.D., BCCCP, BCPS, is currently a Critical Care Clinical Pharmacy Specialist at Brigham and Women's Hospital in Boston, Massachusetts. Dr. Goodberlet completed her Pharm.D. at Northeastern University, then her PGY1 and PGY2 critical care pharmacy residency training at Brigham and Women's Hospital. Dr. Goodberlet practices in the neurointensive care unit.

Paul M. Szumita, PharmD, RPh, FCCM, BCCCP, BCPS, is a Clinical Pharmacy Practice Manager at Brigham and Women's Hospital in Boston, Massachusetts. Dr. Szumita also serves as the PGY2 critical care pharmacy residency program director. As a former Clinical Specialist and current practicing clinical pharmacist in critical care, Dr. Szumita has an active role in bedside education, clinical research, and guideline development/implementation, focusing on inpatient glucose management, ICU pain, agitation and delirium, and hemodynamics in shock states, and therapeutic hypothermia.