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Question: Norepinephrine is a high-availability drug that is administered intravenously (IV) as a continuous infusion. It is a vasopressor that is commonly titrated to maintain adequate blood pressure and target organ perfusion in critically ill adults and children with severe hypotension or shock that persists despite adequate fluid rehydration. Even minor errors in titration or dose, as well as delays in treatment, can lead to dangerous side effects. The Multicenter Health System recently sent the ISMP the results of a common cause analysis (CCA) for 106 norepinephrine errors that occurred in 2020 and 2021. Exploring multiple events with CCA allows organizations to collect common root causes and system vulnerabilities. Data from the organization’s reporting program and smart infusion pumps was used to identify potential errors.
ISMP received 16 noradrenaline-related reports in 2020 and 2021 through the ISMP National Medication Error Reporting Program (ISMP MERP). About a third of these reports dealt with dangers associated with similar names, labels, or packaging, but no errors were actually reported. We have published reports of seven norepinephrine patient errors: four dosing errors (April 16, 2020; August 26, 2021; February 24, 2022); one error of incorrect concentration; one error of incorrect titration of the drug; accidental interruption of norepinephrine infusion. All 16 ISMP reports were added to the CCA multicenter health system (n=106) and the pooled results (N=122) for each step in the drug use process are shown below. The reported error is included to provide an example of some common causes.
Prescribe. We have identified several causative factors associated with prescribing errors, including unnecessary use of oral commands, prescribing norepinephrine without the use of command sets, and unclear or uncertain targets and/or titration parameters (especially if command sets are not used). Sometimes the prescribed titration parameters are too strict or impractical (eg, the prescribed increments are too large), making it difficult for nurses to comply when monitoring a patient’s blood pressure. In other cases, doctors may prescribe weight-based or non-weight-based doses, but this is sometimes confused. This out-of-the-box prescribing increases the likelihood of downstream physicians making mistakes, including pump programming errors, since two dosing options are available in the pump library. In addition, delays were reported requiring order clarification when prescribing orders included weight-based and non-weight-based dosing instructions.
A doctor asks a nurse to write a prescription for norepinephrine for a patient with unstable blood pressure. The nurse entered the order exactly as the doctor orally ordered: 0.05 mcg/kg/min IV titrated to a target mean arterial pressure (MAP) above 65 mmHg. But the doctor’s dosage instructions mix non-weight-based dose escalation with a weight-based maximum dose: titrate at a rate of 5 mcg/min every 5 minutes to a maximum dose of 1.5 mcg/kg/min. The organization’s smart infusion pump was unable to titrate the mcg/min dose to the maximum weight-based dose, mcg/kg/min. Pharmacists had to check instructions with doctors, which led to delays in providing care.
Prepare and distribute. Many preparation and dosing errors are due to excessive pharmacy workload, exacerbated by pharmacy staff requiring maximum concentration norepinephrine infusions (32 mg/250 ml) (available at 503B formulation pharmacies but not available in all locations). lead to multitasking and fatigue. Other common causes of dispensing errors include noradrenaline labels hidden in light-tight bags and a lack of understanding by pharmacy staff of the urgency of dispensing.
A co-infusion of norepinephrine and nicardipine in a dark amber bag went wrong. For dark infusions, the dosing system printed two labels, one on the infusion bag itself and another on the outside of the amber bag. Norepinephrine infusions were inadvertently placed in amber packets labeled “nicardipine” prior to distribution of the product for use by different patients and vice versa. Errors were not noticed prior to dispensing or dosing. The patient treated with nicardipine was given norepinephrine but did not cause long-term harm.
administrative. Common errors include incorrect dose or concentration error, incorrect rate error, and incorrect drug error. Most of these errors are due to incorrect programming of the smart infusion pump, in part due to the presence of dose selection in the drug library, both by weight and without it; storage errors; connection and reconnection of interrupted or suspended infusions to the patient started the wrong infusion or did not mark the lines and did not follow them when starting or resuming the infusion. Something went wrong in the emergency rooms and operating rooms, and smart pump compatibility with electronic health records (EHR) was not available. Extravasation leading to tissue damage has also been reported.
The nurse administered norepinephrine as directed at a rate of 0.1 µg/kg/min. Instead of programming the pump to deliver 0.1 mcg/kg/min, the nurse programmed the pump to deliver 0.1 mcg/min. As a result, the patient received 80 times less norepinephrine than prescribed. When the infusion was gradually titrated and reached a rate of 1.5 µg/min, the nurse judged that she had reached the prescribed maximum limit of 1.5 µg/kg/min. Because the patient’s mean arterial pressure was still abnormal, a second vasopressor was added.
Inventory and storage. Most errors occur when filling automatic dispense cabinets (ADCs) or changing norepinephrine vials in coded carts. The main reason for these inventory errors is the same labeling and packaging. However, other common causes have also been identified, such as low standard levels of norepinephrine infusions at the ADC that were insufficient to meet the needs of the patient care unit, leading to treatment delays if pharmacies had to make up infusions due to shortages. Failure to scan the barcode of each norepinephrine product while storing ADC is another common source of error.
The pharmacist mistakenly refilled the ADC with pharmacy-prepared 32 mg/250 ml norepinephrine solution in the manufacturer’s 4 mg/250 ml premix drawer. The nurse encountered an error while trying to receive a 4 mg/250 ml norepinephrine infusion from the ADC. The barcode on each individual infusion was not scanned before being placed in the ADC. When the nurse realized that there was only a 32 mg/250 ml bag in the ADC (should be in the refrigerated part of the ADC), she asked for the correct concentration. Norepinephrine 4mg/250mL infusion solutions are not available in pharmacies due to the manufacturer’s lack of premixed 4mg/250mL packs, resulting in delays in mixing infusion assistance.
monitor. Incorrect monitoring of patients, titration of norepinephrine infusions outside order parameters, and not anticipating when the next infusion bag is needed are the most common causes of monitoring errors.
A dying patient with orders to “do not resuscitate” is injected with norepinephrine to last long enough for her family to say goodbye. The norepinephrine infusion ended, and there was no spare bag in the ADC. The nurse immediately called the pharmacy and demanded a new bag. The pharmacy did not have time to prepare the medicine before the patient passed away and said goodbye to her family.
Danger. All hazards that did not result in an error are reported to the ISMP and include similar labeling or drug names. Most reports indicate that the packaging and labeling of the various concentrations of norepinephrine infusions dispensed by 503B outsourcers appear to be nearly identical.
Recommendations for safe practice. Consider the following recommendations when developing or revising your facility’s strategy to reduce errors in the safe use of norepinephrine (and other vasopressor) infusions:
limit concentration. Standardized for a limited number of concentrations for the treatment of pediatric and/or adult patients. Specify the weight limit for the most concentrated infusion to be reserved for patients with fluid restriction or requiring higher doses of norepinephrine (to minimize bag changes).
Choose a single dosing method. Standardize norepinephrine infusion prescriptions as based on body weight (mcg/kg/min) or without it (mcg/min) to reduce the risk of error. The American Society of Health System Pharmacists (ASHP) Safety Standards Initiative4 recommends the use of norepinephrine dosage units in micrograms/kg/minute. Some hospitals may standardize dosage to micrograms per minute depending on physician preference – both are acceptable, but two dosing options are not allowed.
Requires prescribing according to the standard order template. Requires a norepinephrine infusion prescription using a standard ordering template with required fields for desired concentration, measurable titration target (eg, SBP, systolic blood pressure), titration parameters (eg, starting dose, dose range, unit of increase, and dosing frequency) up or down ), the route of administration and the maximum dose that must not be exceeded and / or the attending physician should be called. The default turnaround time should be “stat” for these orders to take precedence in the pharmacy’s queue.
Limit verbal orders. Limit verbal orders to real emergencies or when the doctor is physically unable to enter or write an order electronically. Physicians must make their own arrangements unless there are extenuating circumstances.
Buy ready-made solutions when they are available. Use concentrations of premixed norepinephrine solutions from manufacturers and/or solutions prepared by third party vendors (such as 503B) to reduce pharmacy preparation time, reduce treatment delays, and avoid pharmacy formulation errors.
differential concentration. Distinguish different concentrations by making them visually distinct before dosing.
Provide adequate ADC rate levels. Stock up on ADC and provide adequate norepinephrine infusions to meet patient needs. Monitor usage and adjust standard levels as needed.
Create processes for batch processing and/or compounding on demand. Because it can take time to mix the unredeemed maximum concentration, pharmacies can use a variety of strategies to prioritize timely preparation and delivery, including dosing and/or compressing when containers are empty within hours, prompted by point of care or email notifications need to be prepared.
Each package/vial is scanned. To avoid errors during preparation, distribution, or storage, scan the barcode on each norepinephrine infusion bag or vial for verification prior to preparation, distribution, or storage in the ADC. Barcodes can only be used on labels that are affixed directly to the package.
Check the label on the bag. If a light-tight bag is used during a routine dosing check, the norepinephrine infusion should be temporarily removed from the bag for testing. Alternatively, put a light protection bag over the infusion prior to testing and place it in the bag immediately after testing.
Create guidelines. Establish guidelines (or protocol) for infusion titration of norepinephrine (or other titrated drug), including standard concentrations, safe dose ranges, typical titration dose increments, titration frequency (minutes), maximum dose/rate, baseline, and monitoring required. If possible, link recommendations to the titration order in the Medicines Regulatory Record (MAR).
Use a smart pump. All norepinephrine infusions are infused and titrated using a smart infusion pump with Dose Error Reduction System (DERS) enabled so that DERS can alert healthcare professionals to potential prescribing, calculation, or programming errors.
Enable Compatibility. Where possible, enable a bi-directional smart infusion pump that is compatible with electronic health records. Interoperability allows pumps to be prefilled with verified infusion settings prescribed by the physician (at least at the start of titration) and also increases pharmacy awareness of how much is left in titrated infusions.
Mark the lines and trace the pipes. Label each infusion line above the pump and near the patient access point. In addition, before starting or changing the norepinephrine bag or infusion rate, manually route the tubing from the solution container to the pump and patient to verify that the pump/channel and route of administration are correct.
Accept inspection. When a new infusion is suspended, a technical inspection (eg barcode) is required to verify the drug/solution, drug concentration and patient.
Stop the infusion. If the patient is stable within 2 hours of discontinuing the norepinephrine infusion, consider obtaining a discontinuation order from the treating physician. Once the infusion is stopped, immediately disconnect the infusion from the patient, remove it from the pump, and discard to avoid accidental administration. The infusion must also be disconnected from the patient if the infusion is interrupted for more than 2 hours.
Set up an extravasation protocol. Set up an extravasation protocol for frothing norepinephrine. Nurses should be informed about this regimen, including treatment with phentolamine mesylate and avoidance of cold compresses on the affected area, which can aggravate tissue damage.
Evaluate titration practice. Monitor staff compliance with recommendations for norepinephrine infusion, protocols and specific physician prescriptions, as well as patient outcomes. Examples of measures include compliance with the titration parameters required for the order; delay in treatment; use of smart pumps with DERS enabled (and interoperability); start infusion at a predetermined rate; titration according to the prescribed frequency and dosing parameters; the smart pump alerts you to the frequency and type of dose, documentation of titration parameters (should match dose changes) and patient harm during treatment.