A 50-year-old man with a history of cancer and previous airway operations was admitted for a rigid direct laryngoscopy. The anesthesiologist trainee staffing the case was first-year oral maxillofacial surgical resident working in the operating room by himself. The consulting physician anesthesiologist prescribed the resident to administer ketamine to the patient as part of the general anesthesia protocol. The resident unintentionally located two vials of 100mg/mL ketamine instead of the intended 10mg/mL vials that are used routinely. The provider intended to administer 95mg of ketamine intravenously, but erroneously administered 950mg. At the conclusion of the surgical case, the patient had delayed emergence from anesthesia. During assessment of the potential causes for this delayed emergence an empty vial of ketamine of the higher concentration of 100mg/ml was found. Based on this finding a provisional diagnosis of inadvertent ketamine overdose was made. The patient remained intubated and was transferred to the intensive care unit, where he was later extubated uneventfully. He was discharged home the following day.
By Christian Bohringer MD
This incident describes a common type of adverse drug event that occurs because drugs are either available in ampules with different concentrations or they are resuspended in different concentrations when they are drawn up from the ampule.1,2 This type of event occurs more frequently in anesthesia than in other medical fields because anesthesiologists and nurse anesthetists administer drugs much more often than do other medical staff. An anesthesiologist may, in fact, inject up to a half million doses of different drugs in his/her professional tenure.3
This patient received ten times the intended dose of intravenous ketamine and he was therefore probably tachycardic during the operation and did not wake up from anesthesia at the end of the operation. A rigid direct laryngoscopy is usually performed as an outpatient procedure.4 This patient, however, had to be needlessly admitted to the intensive care unit for ongoing positive pressure ventilation and had to spend an extra day in the hospital as a direct result of this unintended ketamine overdose. Prolonged mechanical ventilation is often associated with ventilator-associated pneumonia.5 Very high doses of ketamine are often accompanied by hallucinations and other features of organic brain syndrome.6,7 This patient did not suffer these potential complications, but the unnecessary admission to the hospital and the intensive care unit were very costly.
Approach to Improving Safety
Double checking medication with a second provider
Ideally every drug administration should be double-checked by a second independent staff member. Due to the extremely high number of drug administration episodes in the operating room, it is not feasible with current staffing levels to have a second health care provider independently verify all drug administrations to every patient. The attending anesthesiologist in this case would have been able to identify the error and prevent it if he/she had been present in the operating room when the medication was drawn up into the syringe from the ampule.
Due to the very large number of medication administration episodes in the operating room it is not usual practice to have the supervising clinician observe all the medications being drawn up into the different syringes. This process is often also not feasible because in some states anesthesiologists may supervise multiple rooms at the same time and the medications are often drawn up by different providers in different rooms simultaneously.
Double checking medications may however not necessarily result in a reduction of medication administration errors.
On first impression the double checking of medication appears to be a common sense approach to error reduction. A meta-analysis concluded however that there is currently insufficient evidence that double- versus single-checking of medication administration is associated with lower rates of medication administration errors.8 Among three studies in this meta-analysis, only one showed a significant association between double-checking and fewer medication administration errors, whereas another showed no association, and a third study only reported adherence rates to the double-checking protocol. Higher quality studies are therefore needed to determine if, and in what context, double-checking produces sufficient benefits in patient safety to warrant the considerable resources required.
Adequate supervision of trainees
This case also demonstrates the importance of adequate supervision of trainees. The trainee in this case was probably inexperienced and not aware that ampules of different ketamine concentrations exist in the marketplace. More diligent supervision by the attending anesthesiologist could probably have prevented this adverse event. Trainees should be required to demonstrate that they can safely work independently before they can be expected to be responsible for a patient’s life in the operating room without direct, in-person supervision by a more experienced anesthesiologist. Enhanced clinical supervision has, in fact, been found to be associated with improved clinical and educational outcomes in anesthesia.9
Minimizing distractions when drawing up medications
It is very important that health care providers minimize distractions when drawing up medications when there is no one else present who can double check the medication with them. Drawing up medications and labelling syringes needs to be a conscious process that requires the full attention of staff. Loud music or other distractions should be avoided when carrying out this important task.10 The “Five Rights” of medication administration denoting right patient, right drug, right concentration, right route, and right time need to be assured with every drug administration. However, there are often systemic issues like labelling in tiny font on drug ampules that make it very difficult for staff to comply with these “Five Rights” during every drug administration. Health care practitioners have a duty to report these systemic problems so that they can be remedied.11,12
Use of prefilled syringes from the factory
Prefilled syringes are available in the marketplace, but are employed only infrequently in routine hospital settings because of the additional costs involved for the hospital. They do, however, provide considerable benefits to anesthesia professionals that include sterility, convenience, and perceived safety.13
Limiting the number of ampules with different drug concentrations on the hospital formulary
Intravenous drugs should ideally be offered in only one concentration by the pharmacy department of a particular hospital. This practice decreases the chance of an adverse drug event from different concentrations of the same drug.
Similar adverse drug events related to different drug concentrations in same-size ampules also happen with heparin and opioid medications.14 With heparin in particular, the diversity of concentrations available on the market has contributed to the risk of heparin dosing errors.15 This finding led the Food and Drug Administration (FDA) to mandate new labeling requirements for heparin containers.16,17
Sometimes there are cogent reasons for making medications available in different concentrations. In the case of ketamine, for example, the concentrated preparation is used for preoperative intramuscular administration for patients who refuse insertion of an intravenous cannula.18,19 The smaller volume of the higher concentration of ketamine is less painful during injection than the large volume injection that would be required with a more dilute formulation. Higher concentrations may also be useful when treating small infants in settings where the volume of intravenous fluid administered must be minimized.
Better labelling of ampules by the pharmaceutical industry
All ampules should be clearly labelled with large letters that are easy to read. Both the drug name and the concentration should be clearly visible in large font. It is unfortunate that drug ampules continue to be labelled with tiny letters that are difficult to read. Most information printed on ampules is primarily for legal or business purposes, and does not really enhance patient safety. A subcommittee of the American Society of Testing and Materials consisting of anesthesiologists, nurses, pharmacists, manufacturers, and FDA label experts was therefore created to address the legibility of labels and to coordinate the use of colors.20 Further regulation of the labelling of ampules could potentially improve this situation in the future.
Smaller ampules for more concentrated medications
Concentrated solutions of drugs should be provided in smaller ampules than those provided for dilute solutions to reduce the likelihood of this type of administration error. Concentrated and dilute solutions of the same drug should not be stored directly next to each other, especially when the ampules are of the same size.
Take Home Points
- Double-check all drug administrations with another staff member whenever possible
- Supervision of trainees must be adequate and tasks should not be delegated to trainees unless they have had enough experience to perform these tasks safely
- Pay conscious attention when drawing up medications
- Prefilled syringes reduce dilution and labelling errors
- Limit the number of different drug concentrations on the hospital formulary
- Labels on ampules should display drug name and concentration in a large, easy-to-read font
- Concentrated medications should be in smaller ampules; same-size ampules with different concentrations should be avoided and should never be stored next to each other
Professor of Clinical Anesthesiology
Department of Anesthesiology and Pain Medicine
UC Davis Health
- Tariq RA, Vashisht R, Sinha A, Scherbak Y. Medication Dispensing Errors And Prevention. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 17, 2020.
- Wittich CM, Burkle CM, Lanier WL. Medication errors: an overview for clinicians. Mayo Clin Proc. 2014;89(8):1116-1125. doi:10.1016/j.mayocp.2014.05.007
- Dhawan I, Tewari A, Sehgal S, Sinha AC. Medication errors in anesthesia: unacceptable or unavoidable?. Braz J Anesthesiol. 2017;67(2):184-192. doi:10.1016/j.bjane.2015.09.006
- Gallagher TQ, Hartnick CJ. Direct laryngoscopy and rigid bronchoscopy. Adv Otorhinolaryngol. 2012;73:19-25. doi:10.1159/000334293
- Kalanuria AA, Ziai W, Mirski M. Ventilator-associated pneumonia in the ICU [published correction appears in Crit Care. 2016;20:29. Zai, Wendy [corrected to Ziai, Wendy]]. Crit Care. 2014;18(2):208. Published 2014 Mar 18. doi:10.1186/cc13775
- Orhurhu VJ, Vashisht R, Claus LE, Cohen SP. Ketamine Toxicity. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 15, 2020.
- Bohringer C, Astorga C, Liu H. Response: Ketamine hallucination and dose limits rebutted. Transl Perioper & Pain Med. 2020;7(1):174-75.
- Koyama AK, Maddox CS, Li L, Bucknall T, Westbrook JI. Effectiveness of double checking to reduce medication administration errors: a systematic review. BMJ Qual Saf. 2020;29(7):595-603. doi:10.1136/bmjqs-2019-009552
- Riveros Perez E, Jimenez E, Yang N, Rocuts A. Evaluation of Anesthesiology Residents' Supervision Skills: A Tool to Assess Transition Towards Independent Practice. Cureus. 2019;11(2):e4137. Published 2019 Feb 26. doi:10.7759/cureus.4137
- Gui JL, Nemergut EC, Forkin KT. Distraction in the operating room: A narrative review of environmental and self-initiated distractions and their effect on anesthesia providers. J Clin Anesth. 2021;68:110110. doi:10.1016/j.jclinane.2020.11011
- The five rights: A destination without a map. ISMP: Institute for Safe Medication Practices (An ECRI Affiliate) Jan 25,2007. Available at: https://www.ismp.org/resources/five-rights-destination-without-map. Accessed January 2021.
- Grissinger M. The five rights: A destination without a map. Pharmacy and Therapeutics 2010;35(10):542.
- “No Read” errors related to prefilled syringes. Anesthesia Safety Foundation Newsletter. June 2018. Available at: https://www.apsf.org/article/no-read-errors-related-to-prefilled-syringes/. Accessed Janaury 2021.
- Mc Donnell C. Opioid medication errors in pediatric practice: four years' experience of voluntary safety reporting. Pain Res Manag. 2011;16(2):93-98. doi:10.1155/2011/739359.
- Riley M, Meyers R; Advocacy Committee for the Pediatric Pharmacy Advocacy Group. Position Statement on Heparin Safety Concerns. J Pediatr Pharmacol Ther. 2016;21(6):530-532. doi:10.5863/1551-6776-21.6.530
- US Food and Drug Administration. FDA Drug Safety Communication: Important change to heparin container labels to clearly state the total drug strength. January 19, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm330695.htm. Accessed January 2021.
- US Food and Drug Administration. Heparin sodium injection: Safety labelling changes approved by FDA center for drug evaluation and research (CDER) http://www.fda.gov/safety/MedWatch/SafetyInformation/ucm219000.htm.
- Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016;37(7):865-872. doi:10.1038/aps.2016.5.
- Marland S, Ellerton J, Andolfatto G, Strappazzon G, Thomassen O, Brandner B, et al. Ketamine: Use in anesthesia. CNS Neurosci Ther 2013;19(6):381-89.
- Rendell-Baker L. Better labels will cut drug errors. Anesthesia Safety Foundation Newsletter 1987;2(4)