Abstract

A loading dose is an initial dose of medication administered to rapidly achieve therapeutic levels. The determination of a loading dose can be complicated, involving calculations dependent upon patient characteristics. This, combined with the need to also administer maintenance doses, creates complexity and opportunities for errors. From June 2004 through May 2012, Pennsylvania facilities reported to the Pennsylvania Patient Safety Authority 580 events associated with the prescribing, dispensing, and administering of medication loading doses, 15 of which were harmful events. The most common types of events reported included “loading dose omitted or delayed,” “wrong loading dose given,” and “loading dose given multiple times.” The predominant medication associated with these reports was vancomycin (14.8%, n = 86). Phenytoin was the medication most frequently involved in harmful events (26.7%, n = 4). Strategies to prevent errors associated with loading doses include developing standardized clinical guidelines on how to prescribe, administer, and monitor loading and maintenance doses; standardizing electronic and paper order sets and protocols; and including a thorough review of current drug therapy during patient handoffs.

Introduction

A loading dose is an initial large dose of medication administered to rapidly achieve therapeutic levels in the body.^1,2,3 The clinical and therapeutic need for administration of a loading dose can vary based on the patient’s condition and the medication. For example, a therapeutic level of phenytoin may be needed quickly to stabilize a patient after a seizure.⁴ Other medications commonly administered with loading and maintenance doses include the antidote acetylcysteine, the cardiovascular agent digoxin, and the anticonvulsant fosphenytoin. Loading doses are typically followed by maintenance doses, which are given in lower doses to maintain therapeutic levels on a medium- to long-term basis. The combination of loading doses and maintenance doses creates complexity in prescribing, dispensing, and administering medications. This combination can lead to medication errors stemming from all nodes in the medication-use process.

There is scarce literature that addresses the problems and errors associated with loading dose regimens. A study by Hayes et al. demonstrated the complexity of acetylcysteine dosing regimens (which includes loading and maintenance doses) for the treatment of acetaminophen overdoses.⁵ This retrospective chart review of a regional poison control center’s records found a 33% error rate, which included medication errors in all phases of the medication-use process. The types of errors found included incorrect dose, incorrect infusion rate, and more than one hour of interruption in therapy. A case report by Cottington et al. described a fatality from a gross overdose administered for a loading dose test of methionine.⁶ Another study by Oudin et al. found prescribing problems with vancomycin loading doses.⁷ Of the 13 prescription errors the authors found, seven involved vancomycin loading doses, including five cases in which the loading dose was not prescribed, one case of a prescription delay, and one case of higher-than-intended dosing.

In November 2010, the National Patient Safety Agency (NPSA) in the United Kingdom published an alert regarding fatalities associated with loading dose errors and strategies to prevent their occurrence.^2,3 From January 2005 through April 2010, the NPSA’s National Reporting and Learning System received 1,165 reports related to loading doses, including 2 fatalities (both involving phenytoin), 4 cases of severe harm, and 102 cases of moderate harm. The cases that resulted in severe patient harm or death involved incorrect loading doses, omitted or delayed loading doses, or unintentional continuation of loading doses.²

Analyses of events involving loading doses of medications reported by Pennsylvania healthcare facilities to the Pennsylvania Patient Safety Authority have identified the most common types of events and medications associated with the prescribing, dispensing, and administering of medication loading doses in Pennsylvania.

Methodology

The term “loading” was used to query all event types in the Pennsylvania Patient Safety Reporting System (PA-PSRS) database reported from June 2004 through May 2012. The initial query yielded 905 reports. After eliminating reports that were not applicable (e.g., “patient bumped forehead while loading on wheelchair lift in van,” “continue offloading pressure on the heel”), 580 reports were analyzed in detail to identify trends and contributing factors.

Aggregate Analysis

From events reported from June 2004 through May 2012, analysts identified 580 events involving breakdowns in the prescribing, dispensing, and administration of medication loading doses. A breakdown of these events by harm score, which is adapted from the National Coordinating Council for Medication Error Reporting and Prevention’s harm index,⁸ shows that nearly 79% (n = 458) of the events reached the patient (harm score = C to I). Overall, 97.4% (n = 565) of the events were reported as Incidents (harm score = A to D) and 2.6% (n = 15) as Serious Events (harm score = E to I), including two events resulting in death.

In total, there were over 70 medications associated with loading doses involved in events reported to the Authority. Table 1 lists the top 20 medications involved in events related to loading dose issues. The antibiotic vancomycin was the most frequently reported medication (14.8%, n = 86); six anti-infective agents were in the top 20. In contrast, the United Kingdom’s NPSA incidents related to loading doses in its November 2010 Rapid Response Report identified warfarin as the most frequently reported medication involved.³ While 10 medications (i.e., amiodarone, caffeine citrate, clopidogrel, digoxin, gentamicin, heparin, magnesium sulfate, morphine, phenytoin, vancomycin) appear in the top 20 medications involved in events associated with loading doses in both Pennsylvania and the United Kingdom, only phenytoin appears in the top five medications for both. Other drugs in the top five in the United Kingdom include amiodarone and digoxin.

Authority analysts first categorized the types of events into two groups—those involving an error with the loading dose and those involving an error with the maintenance dose. Analysts then further categorized the reports into subtypes of these two general classifications. Table 3 lists the top event types. It should be noted that not enough information was provided to determine what occurred in roughly 20% (n = 117) of reports.

Focused Event Analysis

Loading Dose Omitted or Delayed

The goal of administering a loading dose of certain medications is to reach therapeutic drug concentrations or levels within the body as soon as possible. An omitted or missed loading dose may contribute to therapeutic failure and deterioration of the patient. Analysts identified “loading dose omitted or delayed” as the most frequently reported (25.5%, n = 148) type of event associated with the use of medications requiring loading doses. This is comparable to what the NPSA noted in its November 2010 Rapid Response Report.³ In that report, the NPSA found that omission or delayed administration of a loading dose occurred in 24% of incidents that were related to loading dose issues. This represented the second most frequently reported event in the NPSA data set.

In Pennsylvania, five medications, namely vancomycin (24.3%, n = 36), clopidogrel (12.2%, n = 18), phenytoin (11.5%, n = 17), morphine (5.4%, n = 8), and gentamicin (5.4%, n = 8) were involved in nearly 60% (n = 87) of omitted or delayed loading
dose events.

Transfer within and between facilities introduces vulnerability to the system,¹¹ making it easier for an error to occur and reach the patient. Breakdowns or interruptions when patients were transferred between units within a hospital or between hospitals was a leading contributor (16.2%, n = 24) to omitted loading doses. Often, this involved situations in which a loading dose was ordered in the emergency department (ED), but the patient was transferred prior to receiving the dose, as the following examples illustrate:

Orders written at 2200 in ED for IV [intravenous] Dilantin® loading dose. Patient presented to floor at approximately 0200. The Dilantin [loading dose] was not administered in ED. Patient admitted with diagnosis of new onset seizures.

Patient prescribed vancomycin protocol in ED. Loading dose for protocol sent to ED at approximately 9:30 to be administered at 10:00. Pharmacist spoke to nurse on unit about another patient when she learned that [the] loading dose was not administered to her patient. Protocol was then adjusted appropriately.

Wrong Loading Dose

Analysts identified wrong loading dose events as the second most frequently reported (15.2%, n = 88) events associated with the use of loading doses. This should not come as a surprise, as the determination of a loading dose can be complicated, involving calculations dependent upon patient characteristics such as weight or organ function and/or laboratory results. Comparatively, the NPSA found that the prescribing or administration of an incorrect loading dose was the most frequent (41%) event type related to loading dose issues.³

Once again, vancomycin was the drug most frequently involved (17%, n = 15) in these events. Other medications involved in wrong loading dose events included clopidogrel (10.2%, n = 9), HYDROmorphone (8%, n = 7), morphine (4.5%, n = 4), and acetylcysteine (4.5%, n = 4).

In 31.8% (n = 28) of wrong loading dose events, a maintenance dose was ordered or administered as the loading dose. As a result, a lower dose than clinically indicated was administered. While many of the event reports do not describe why this dose mix-up occurred, a number do indicate that the wrong dose was selected on the unit when pharmacy delivered the loading dose and maintenance dose(s) at the same time. For example, see the following:

Physician ordered tigecycline 100 mg IVPB [IV piggyback] stat followed by an order for tigecycline 50 mg IVPB every 12 hours. According to the pharmacy, the doses were dispensed, but the RN [registered nurse] administered tigecycline 50 mg IVPB as the initial stat loading dose instead of the 100 mg bag.

Loading Dose Given Multiple Times

A third subtype of loading dose error is “loading dose given multiple times.” Authority analysts identified this subtype as the third most frequently reported (7.1%, n = 41) loading dose event. The NPSA also noted that a loading dose was repeated in error in 7% of loading dose incidents in the United Kingdom.³ These events can result in supratherapeutic drug concentrations or levels within the body leading to adverse events. In Pennsylvania, 7.3% (n = 3) of these events resulted in harm, accounting for 20% of all harmful events associated with the prescribing, dispensing, and administering of medication loading doses.

Clopidogrel was the drug most frequently involved (24.4%, n = 10) in these events. Other drugs involved in “loading dose given multiple times” events include digoxin (9.8%, n = 4), phenytoin (7.3%, n = 3), and fosphenytoin (7.3%, n = 3).

Similar to “loading dose omitted or delayed” events, vulnerabilities introduced during the patient transfer process was the leading contributor (19.5%, n = 8) to events involving multiple administrations of a loading dose. For example, see the following:

Patient was admitted through the ED with seizures. In the ED, the patient was loaded with fosphenytoin along with benzodiazepines. The patient was admitted to the ICU [intensive care unit] and, in the ICU, continued to have seizure activity. The physician in the ICU ordered a loading dose of fosphenytoin. After the medication was administered, it was discovered that the patient had already received a loading dose in the ED. The patient received a total of 2,400 mg of fosphenytoin instead of 1,200 mg. Per the physician, it was reported to him that the patient only received “benzos” in ED. However, alerts did fire in the computer system for “duplicate therapy,” and the first dose was documented in the EMAR [electronic medication administration record].

Patient was admitted through the ED. Report was taken by charge nurse. The nurse in the ED did notify charge nurse that the patient had been given 1 mg loading dose of Dilaudid® prior to coming to the floor. Patient arrived to the floor, and there was a delay in patient getting put in the system by admissions. . . . Loading dose was administered a second time, as it was not marked off on floor orders. After being started on PCA [patient-controlled analgesia], patient was found to have low O₂ [oxygen] saturations and had to be placed 6 L NC [nasal cannula].

However, in 48.8% (n = 20) of “loading dose given multiple times” events, insufficient information was provided to determine what contributed to the event.

Risk Reduction Strategies

Healthcare facilities can strive to identify systems-based causes of the errors associated with the prescribing, dispensing, and administering of medication loading doses and implement effective risk reduction strategies to prevent harm to patients. Although many of the reports submitted to the Authority did not explicitly reveal all of the causes and contributing factors, healthcare facilities may consider the strategies described in this section, which are based on a review of events reported to the Authority, observations from the Institute for Safe Medication Practices, and recommendations in the literature.

• Review organizational processes associated with medications requiring loading doses in order to identify risks.
• Restrict and limit the physical availability of medications requiring loading doses, as appropriate.³
• Develop standardized clinical guidelines on how to prescribe, administer, and monitor loading and maintenance doses.³
• Standardize electronic and paper order sets and protocols. Ensure that these order sets are well designed. Well-designed order sets have the potential to
• coordinate care by communicating best practices across disciplines and lines of service,
• reduce variation and accidental oversight through standardized formatting and presentation,
• enhance workflow with instructions that are easily understood and intuitively organized, and
• reduce the risk for medication errors through integrated safety alerts and reminders.^12,13
• Establish guidelines for communication during patient transfers. Items to consider for inclusion are
• a brief overview of the patient’s status,
• essential patient information,
• physician orders that will be implemented pre-transport (e.g., loading dose, sedation, pain management),
• physician orders that will need to be implemented post-
  transport, and
• confirmation of patient arrival time.¹¹
• Provide clear documentation to ensure that all applicable patient information is available and communicated to the next level of care.¹⁴
• Include a thorough review of current drug therapy during handoffs in care. Such reports, particularly at a change of shift, can help with the timely discovery of instances when prescribed medications have been omitted by accident.¹⁵
• Explore having pharmacy dispense loading and maintenance doses separately, closer to the time when each one is to be administered, so they do not arrive on the patient care unit at the same time. This may help reduce the risk that both doses will be stored near each other on the patient care unit and confused for one another.
• Consider differentiating the packaging and labeling of loading doses and maintenance doses to reduce the risk that they may be confused for one another.

Conclusion

Loading doses are administered to rapidly achieve therapeutic levels in the body and are typically followed by maintenance doses to maintain therapeutic levels on a medium- to long-term basis. The combination of loading doses and maintenance doses creates complexity in the medication-use process and can lead to medication errors. In Pennsylvania, 580 medical error reports indicating the occurrence of an event associated with the prescribing, dispensing, and administering of medication loading doses were reported to the Authority from June 2004 through May 2012. The predominant types of events identified through analysis of event descriptions are “loading dose omitted or delayed,” “wrong loading dose given,” “loading dose given multiple times,” “maintenance dose missed,” “maintenance dose given at wrong time,” and “wrong maintenance dose given.” There are similarities in the types of events, frequency of the events, and medications involved in the events seen in Pennsylvania and the United Kingdom.³ Strategies to reduce the risk of errors include developing clinical guidelines and standardizing electronic and paper order forms and protocols to guide clinical practice, reduce variation, and improve drug information communication.

Notes

1. Merriam-Webster Dictionary [online], s.v. “loading dose.” [cited 2012 Jul 6]. http://www.merriam-webster.com/medical/loading%20dose.

2. National Patient Safety Agency. Rapid Response Report NPSA/2010/RRR018: preventing fatalities from medication loading doses [online]. 2010 Nov 25 [cited 2012 Jul 6]. http://www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=92307&type=full&servicetype=Attachment.

3. National Patient Safety Agency. Rapid Response Report NPSA/2010/RRR018: preventing fatalities from medication loading doses: supporting information [online]. 2010 Nov [cited 2012 Jul 6]. http://www.nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=92308&type=full&servicetype=Attachment.

4. Lamont T, Cousins D, Bischler A, et al. Safer loading doses of medicines: summary of a safety report from the National Patient Safety Agency. BMJ 2011 Jan 26;342(7792):332-4.

5. Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother 2008 Jun;42(6):766-70.

6. Cottington EM, LaMantia C, Stabler SP, et al. Adverse event associated with methionine loading test: a case report. Arterioscler Thromb Vasc Biol 2002 Jun 1;22(6):1046-50.

7. Oudin C, Vialet R, Boulamery A, et al. Vancomycin prescription in neonates and young infants: toward a simplified dosage. Arch Dis Child Fetal Neonatal Ed 2011 Sep;96(5):F365-70.

8. National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). NCC MERP index for categorizing medication errors [online]. 2001 Feb 20 [cited 2012 Jul 6]. http://www.nccmerp.org/medErrorCatIndex.html.

9. Institute for Safe Medication Practices. ISMP 2007 survey on high-alert medications: differences between nursing and pharmacy perspectives still prevalent. ISMP Med Saf Alert Acute Care 2007 May 17;12(10):1-3.

10. Institute for Safe Medication Practices. ISMP’s list of high-alert medications [online]. 2012 [cited 2012 Jul 2]. http://www.ismp.org/Tools/highAlertMedications.asp.

11. Continuous care throughout patient transfer. PA PSRS Patient Saf Advis [online] 2005 Dec [cited 2012 Jul 10]. http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2005/dec2(4)/Pages/20.aspx.

12. Institute for Safe Medication Practices. ISMP’s guidelines for standard order sets [online]. 2010 [cited 2012 Jul 5]. http://www.ismp.org/Tools/guidelines/StandardOrderSets.asp.

13. Institute for Safe Medication Practices. ISMP develops guidelines for standard order sets. ISMP Med Saf Alert Acute Care 2010 Mar 11;15(5):1-4.

14. Safe intrahospital transport of the non-ICU patient using standardized handoff communication. Pa Patient Saf Advis [online] 2009 Mar [cited 2012 Jul 11]. http://www.patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2009/Mar6(1)/Pages/16.aspx.

15. Institute for Safe Medication Practices. Order scanning systems may pull multiple pages through the scanner at the same time, leading to drug omissions. ISMP Med Saf Alert Acute Care 2009 Nov 5;14(22):1-3.

Supplemental Material

Self-Assessment Questions

Learning Objectives

• Recognize the most frequently reported event types involving the prescribing, dispensing, and administering of medication loading doses.
• Recall causes and contributing factors associated with the predominant types of events involving the prescribing, dispensing, and administering of medication loading doses.
• Identify the most frequently reported medications involved in events associated with the prescribing, dispensing, and administering of medication loading doses.
• Distinguish between effective and ineffective strategies to reduce the risk of events involving the prescribing, dispensing, and administering of medication loading doses.

Questions

The following questions about this article may be useful for internal education and assessment. You may use the following examples or develop your own questions.

1. Which of the following is the most frequently reported type of event associated with the prescribing, dispensing, and administering of medication loading doses?
   1. Loading dose administered at the wrong rate.
   2. Loading dose given multiple times.
   3. Loading dose omitted or delayed.
   4. Maintenance dose missed.
   5. Wrong loading dose given.
2. Which of the following is a leading factor in omitted or delayed loading dose events in Pennsylvania facilities?
   1. Pharmacy delivery of the loading dose and maintenance dose(s) to the unit at the same time.
   2. Breakdowns when patients were transferred between units within a hospital.
   3. Failure to follow protocol guidance when prescribing, dispensing, or administering a loading dose.
   4. Omission of an independent double check.
   5. Limited physical availability of medications requiring loading doses
3. The top four medications involved in events associated with the prescribing, dispensing, and administering of medication loading doses include all of the following EXCEPT:
1. Acetylcysteine
2. Clopidogrel
3. HYDROmorphone
4. Phenytoin
5. Vancomycin

The patient was admitted through the emergency department (ED) with seizures. In the ED, the patient received a loading dose of fosphenytoin. The patient was admitted to the intensive care unit (ICU) and, in the ICU, continued to have seizure activity. The physician in the ICU ordered a loading dose of fosphenytoin. After the medication was administered, it was discovered that the patient had already received a loading dose in the ED. The patient received a total of 2,400 mg of fosphenytoin instead of 1,200 mg. Per the physician, it was reported to him that the patient had only received benzodiazepines in the ED. However, alerts did fire in the computer system for “duplicate therapy,” and the first dose was documented in the electronic medication administration record.

4. Select the most appropriate strategy to help prevent this event from reoccurring.
   1. Differentiate the packaging and labeling of loading doses and maintenance doses to reduce the risk that they may be confused for one another.
   2. Restrict and limit the physical availability of medications requiring loading doses, as appropriate.
   3. Standardize electronic and paper order sets and protocols.
   4. Establish a protocol to guide communication during patient transfers that includes the physician orders implemented pre-transport and those that still need to be executed.
   5. Develop standardized clinical guidelines on how to prescribe, administer, and monitor loading and maintenance doses.

   A physician ordered tigecycline 100 mg intravenous (IV) piggyback statim (stat) followed by an order for tigecycline 50 mg IV piggyback every 12 hours. According to the pharmacy, the loading and maintenance doses were dispensed and delivered to the unit. The nurse inadvertently administered the tigecycline 50 mg IV bag as the initial stat loading dose instead of the tigecycline 100 mg IV bag.

5. Which of the following factors may have contributed to this wrong loading dose event?
1. Communication during handoff failed.
2. The patient’s loading dose was miscalculated.
3. A loading dose of the medication was not required for this patient.
4. Tigecycline was available as a floor stock item.
5. Pharmacy delivered both the loading dose and maintenance dose to the unit at the same time.
6. Which of the following strategies would be most effective in reducing the risk of this wrong loading dose event?
1. Store loading and maintenance doses apart from one another in pharmacy and patient care areas.
2. Dispense loading and maintenance doses from pharmacy separately, closer to the time when each one is to be administered.
3. Differentiate the package type and design of loading doses and maintenance doses.
4. Restrict and limit the physical availability of medications requiring loading doses.
5. Develop standardized clinical guidelines on how to prescribe, administer, and monitor loading maintenance doses.