Analysis Identifies Multiple Common Causes of Norepinephrine Errors

Problem: Norepinephrine is a high-alert medication that is administered intravenously (IV) as a continuous infusion. It is a vasopressor typically titrated to maintain adequate blood pressure and end-organ perfusion in critically ill adult and pediatric patients with severe hypotension or shock that persists after adequate fluid volume replacement. Even minor titration or dose-related errors or delays in therapy may result in harmful adverse events. A multi-site health system recently sent ISMP the results of a common cause analysis (CCA) of 106 norepinephrine errors that occurred in 2020 and 2021. Using CCA to examine multiple events allows an organization to aggregate the shared root causes and system vulnerabilities. Data from the organization’s reporting program and smart infusion pumps were used to identify potential errors. 

ISMP received a total of 16 reports involving norepinephrine in 2020 and 2021 through the ISMP National Medication Errors Reporting Program (ISMP MERP). About one-third of these reports were hazards related to look-alike names, labeling, or packaging, for which no actual error occurred. We have published seven of the reported norepinephrine errors that reached patients: four dosing errors (April 16, 2020; August 26, 2021; February 24, 2022); one wrong concentration error; one wrong drug titration error; and one accidental discontinuation of a norepinephrine infusion. All 16 ISMP reports were added to the multi-site health system CCA (n=106), and the combined results (N=122) for each phase of the medication-use process are presented below. A reported error is included to provide an example of certain common causes. 

Common Causal Factors

Prescribing. We identified several causal factors associated with prescribing errors, including the unnecessary use of verbal orders, prescribing norepinephrine without using an order set, and unclear or undefined titration goals and/or parameters (especially if an order set was not used). Occasionally, the prescribed titration parameters were too rigid or unrealistic (e.g., ordered in too large of an increment), making it difficult for nurses to follow the order while controlling the patient’s blood pressure. In other cases, prescribers were able to order either weight-based or non-weight-based doses, which were occasionally mixed up. This nonstandard prescribing approach made it more likely that practitioners downstream would make errors, including pump programming errors, as both dosing options were available in the pump library. Also, delays from needing to clarify orders were reported when prescribers’ orders included both weight-based and non-weight-based dosing instructions.

A physician asked a nurse to enter a norepinephrine order for a patient with an unstable blood pressure. The nurse entered the order exactly as the physician had verbally prescribed it: 0.05 mcg/kg/minute IV to titrate to a goal mean arterial pressure (MAP) above 65 mm Hg. But the physician’s administration instructions mixed both a non-weight-based dosing increment and a maximum weight-based dose: titrate by 5 mcg/minute every 5 minutes to a maximum of 1.5 mcg/kg/minute. The organization’s smart infusion pumps were unable to titrate doses in mcg/minute to a maximum weight-based dose, mcg/kg/minute. The pharmacist had to clarify the instructions with the physician, resulting in a delay in care.

Preparation and Dispensing. Many of the preparation and dispensing errors were related to a demanding pharmacy workload, exacerbated by the need for pharmacy staff to compound maximum concentration (32 mg/250 mL) norepinephrine infusions (which are available from 503B compounding pharmacies but were not purchased at all sites). The demanding workload led to multitasking and fatigue. Other common causes of dispensing errors included hidden norepinephrine labels due to light-protective bags, and the pharmacy staffs’ lack of knowledge about the urgency of dispensing norepinephrine.        

An error occurred with norepinephrine and niCARdipine compounded infusions in light-protective amber bags. For light-protected infusions, the dispensing system printed two labels, one to affix to the actual infusion bag, and one for the outside of the amber bag. Prior to dispensing the products, which were intended for different patients, the norepinephrine infusion was accidentally put into the amber bag labeled as niCARdipine, and vice versa. The error was not noticed prior to dispensing or administration. The patient who was prescribed niCARdipine was given norepinephrine, but she suffered no long-term harm.

Administration. Common mistakes included wrong dose or concentration errors, wrong rate errors, and wrong drug errors. Most of these errors were caused by incorrectly programming smart infusion pumps, partly due to having both weight-based and non-weight-based dosing options in the drug library; storage errors; leaving a discontinued or paused infusion connected to the patient and restarting the wrong infusion; or not labeling lines and tracing them when starting or restarting infusions. A few errors occurred in the emergency department and the operating room, where smart pump interoperability with the electronic health record (EHR) was not available. Extravasations that resulted in tissue damage were also reported.  

A nurse administered a norepinephrine infusion that was prescribed to run at 0.1 mcg/kg/minute. Instead of programming the pump to deliver 0.1 mcg/kg/minute, the nurse programmed the pump to administer 0.1 mcg/minute. Thus, the patient received 80 times less norepinephrine than prescribed. When the infusion was titrated to effect and reached a rate of 1.5 mcg/minute, the nurse thought she had reached the prescribed maximum limit of 1.5 mcg/kg/minute. Since the patient’s MAP was still not within range, a second vasopressor was added.

Inventory and Storage. Most errors occurred when filling automated dispensing cabinets (ADCs) or when replacing vials of norepinephrine in code carts. The primary causal factor for these stocking errors was look-alike labeling and packaging. However, other common causes were identified, such as low par levels of norepinephrine infusions in ADCs that were insufficient for the patient care unit, which led to delays in therapy if the pharmacy had to compound the infusion due to a backorder. Failing to scan the barcode of each norepinephrine product when stocking an ADC was another common cause of the errors.       

A pharmacy technician mistakenly restocked an ADC with a 32 mg/250 mL concentration of a pharmacy-prepared norepinephrine infusion in a drawer intended for 4 mg/250 mL manufacturer premixed infusions. A nurse discovered the error when attempting to retrieve a 4 mg/250 mL norepinephrine infusion from the ADC. The barcode on each individual infusion was not scanned prior to placement in the ADC. When the nurse realized there were only 32 mg/250 mL bags in the ADC (which should have been in the refrigerated section of the ADC), she requested the correct concentration. Due to a backorder of the manufacturer premixed 4 mg/250 mL bags, the pharmacy did not have any norepinephrine infusions in a 4 mg/250 mL concentration, resulting in a delay in care while compounding the infusion. 

Monitoring. Incorrectly monitoring the patient, titrating the norepinephrine infusion outside of the order parameters, and not anticipating when the next infusion bag was needed were the most common causes of errors related to monitoring.

A patient who was at the end of her life and had a “do not resuscitate” order was receiving a norepinephrine infusion to keep her alive long enough for her family to say goodbye. The norepinephrine infusion ran out and there were no back-up bags in the ADC. A nurse called the pharmacy to request a new bag right away. The pharmacy did not have enough time to compound the medication before the patient passed away and before her family could say goodbye.

Hazards. All of the hazards that had not yet resulted in errors were reported to ISMP and involved look-alike labels or drug names. Most of the reports noted that the packaging and labeling on various concentrations of norepinephrine infusions compounded by 503B outsourcers looked nearly identical.

Safe Practice Recommendations: Consider the following recommendations when establishing or reviewing your facility’s error-reduction strategies for the safe use of norepinephrine (and other vasopressor) infusions:

Prescribing

Limit the concentrations. Standardize to a limited number of concentrations to treat pediatric and/or adult patients. Designate weight-based limits for the most concentrated infusions, which should be reserved for patients who are fluid restricted or require larger doses of norepinephrine (to minimize bag changes).  

Choose a single dosing method. Standardize the prescribing of norepinephrine infusions to either weight-based (mcg/kg/minute) or non-weight-based (mcg/minute) to reduce the risk of errors. The American Society of Health-System Pharmacists (ASHP) Standardize 4 Safety initiative recommends using mcg/kg/minute dosing units for norepinephrine. Some hospitals may standardize to mcg/minute dosing due to prescriber preference—either is acceptable, but do not allow both dosing options.

Require prescribing via a standard order template. Require norepinephrine infusions to be prescribed using a standard order template with required fields for the desired concentration, a measurable titration goal (e.g., MAP, systolic blood pressure), titration parameters (e.g., starting dose, dose range, incremental units and frequency of dosing changes either up or down), route of administration, and a maximum dose that should not be exceeded and/or the dose at which the prescriber should be called. The processing time should default to “stat” to prioritize these orders in the pharmacy queue.  

Limit verbal orders. Limit verbal orders to true emergencies or circumstances in which the prescriber is physically unable to electronically enter or write orders. Prescribers should enter their own orders, except during extenuating circumstances.

Dispensing

Purchase available premixed solutions. Use concentrations of manufacturer premixed norepinephrine solutions and/or solutions prepared by an outsourcer (e.g., 503B company) to decrease pharmacy preparation time, reduce delays in therapy, and avoid pharmacy compounding errors.

Differentiate the concentrations. Prior to dispensing, differentiate various concentrations by making them visually distinctive.

Ensure adequate ADC par levels. Stock ADCs with an adequate supply of norepinephrine infusions to match patient needs. Monitor usage and adjust par levels as needed.

Establish a process for batching and/or on-demand compounding. Since time may be needed to compound maximum concentrations that are not purchased, pharmacies can use various strategies to prioritize timely preparation and delivery, including batching and/or on-demand preparation triggered by nursing or electronic notification when containers are within several hours of being empty.

Scan each bag/vial. To avoid errors during preparation, dispensing, or stocking, scan the barcode on each individual norepinephrine infusion bag or vial for verification prior to preparation, dispensing, or stocking it in the ADC. A barcode should only be available on the label placed directly on the bag.

Verify the label on the bag. During routine dispensing checks, if light-protective bags are used, temporarily take the norepinephrine infusion out of the bag for verification. Or, the light-protective bag should be left on top of the infusion until it is verified and then placed inside the bag immediately after verification.

Administration

Establish guidelines. Establish guidelines (or a protocol) for the titration of norepinephrine (or other titratable) infusions that include standardized concentrations, safe dosage ranges, typical titration dose increment(s), frequency of titration (minutes), maximum dose/rate, administration via a primary line, and monitoring requirements. If possible, link the guidelines to the titration order on the medication administration record (MAR).

Use smart pumps. Use smart infusion pumps with an engaged dose error-reduction system (DERS) to infuse and titrate all norepinephrine infusions so the DERS can alert healthcare providers about potential prescribing, calculation, or programming errors.

Implement interoperability. When possible, implement bidirectional smart infusion pump interoperability with the EHR. Interoperability enables the verified prescriber’s ordered infusion parameters to prepopulate the pump (at least at the start of titration), and can also improve pharmacy awareness of the amount left in titratable infusions.  

Label the lines and trace the tubing. Label each infusion line above the pump and near the patient’s access site. Also, trace the tubing by hand from the solution container to the pump, and then to the patient, for verification of the proper pump/channel and route of administration immediately before starting or changing the bag or rate of a norepinephrine infusion.

Employ technology checks. When hanging a new infusion, require technology checks (e.g., barcoding) to verify the drug/solution, drug concentration, and patient.

Discontinue infusions. If the patient is stable for 2 hours after stopping a norepinephrine infusion, consider obtaining a discontinuation order from the prescriber. Once the infusion has been discontinued, immediately disconnect the infusion from the patient, remove it from the pump, and discard it to prevent inadvertent administration. Infusions paused for more than 2 hours should also be disconnected from the patient. 

Establish an extravasation protocol. Establish an extravasation protocol for the vesicant norepinephrine. Nurses should receive education about the protocol, including treatment with phentolamine mesylate and avoidance of applying cold compresses to the site, which may worsen the tissue damage.

General

Assess titration practices. Monitor staff compliance with the guidelines, protocols, and specific orders for norepinephrine infusions, as well as patient outcomes. Examples of measures include compliance with ordering the required titration parameters; delays in therapy; use of a smart pump with an enabled DERS (and interoperability); starting the infusion at the ordered rate; titrating according to the prescribed frequency and dosing parameters; frequency and type of smart pump alerts; documentation of the titration parameter (which should coincide with dose changes); and patient harm during therapy.