The UK National Patient Safety Agency has just issued a rapid response report on preventing fatalities from medication loading doses. This is a medication safety issue that has long flown under everyone’s radar. Problems with loading doses occur at every institution we have ever worked with, yet there is almost nothing in the literature highlighting this problem.
Loading doses are given when one wants to get the serum and/or tissue level of a drug up to achieve a therapeutic effect rapidly. Probably the best example is the loading dose of phenytoin in a patient with status epilepticus. In such cases there is an immediate urgent need to stop the patient’s seizures and prevent recurrence. It would take several days to get therapeutic levels of phenytoin if the patient were simply started on a typical oral maintenance dosage.
While the NPSA alert identified incidents in their databases involving loading doses of many medications, four medications (warfarin, amiodarone, digoxin, and phenytoin) really stuck out. These accounted for 36% of all incidents and 50% of all those causing moderate or severe harm.
In 41% of the incidents, the loading dose was either ordered or administered incorrectly. In another 24% it was either omitted or delayed. In a further 11% the loading dose was either repeated or continued incorrectly as the maintenance dose and in 8% the maintenance dose was prescribed at the wrong time (eg. too soon after the loading dose). They also noted that handovers and transitions of care were also vulnerable to missed communications regarding loading/maintenance doses.
The NPSA review included a literature search using keywords such as “loading” and “error” and had remarkably little success in finding published cases. We tried the same in a number of databases and different search terms and were similarly unsuccessful. In a case that received a lot of attention a few years ago, a patient died when inadvertently given 8000 mg. of IV Dilantin. An ER physician ordered a loading dose of 800 mg. IV for a patient with seizures but the nurse mistakenly thought it was 8000 mg. The nurse apparently had to use 32 vials of phenytoin to make up that amount! But not many other cases turned up.
However, coincidentally, the FDA just did a thorough review of both intravenous phenytoin and fosphenytoin last month and includes statistics about adverse effects and does cite cases of hypotension, bradycardia, cardiovascular collapse, and death. That panel was convened because of safety concerns surrounding IV phenytoin. However, the panel voted unanimously to keep IV phenytoin on the market, in part because of a current shortage of fosphenytoin and no good current alternative drugs for phenytoin’s indications.
One of the first questions we always ask when doing a root cause analysis of an event related to a procedure is “did the patient need the procedure in the first place?”. Well, in these cases we should ask “does the patient really need a loading dose?”
The answer for warfarin (coumadin) appears to be no. The evidence base was summarized recently in an ICSI Guideline: Venous Thromboembolism Diagnosis and Treatment and a systemic review (Heneghan 2010). Both conclude that there is no advantage to loading patients with a 10 mg. dose compared to starting with 5 mg. daily and they discourage use of the 10 mg. dose, particularly in elderly patients. The 10 mg. dose may or may not get the patient to a therapeutic INR faster (depending on which study you read) but may also be associated with early overanticoagulation and there is even some theoretical concern that the loading may actually promote the early hypercoagulability sometimes seen during warfarin initiation.
For phenytoin (Dilantin) the answer depends on the clinical circumstances. Obviously for true status epilepticus a loading dose is appropriately indicated. But for a patient who has had a single seizure (unless that seizure happens to occur during neurosurgery), a loading dose is probably not necessary. The gray zone would be in the patient who has had a flurry of several seizures but does not meet the definition of status epilepticus.
The rate of administration of IV phenytoin (and IV fosphenytoin) is the critical factor in producing hypotension, bradycardia or cardiovascular collapse. The rate is not to exceed 50 mg/min. in adults (1-3 mg/kg/minute in neonates) and should be by a slow IV push, not an infusion. That means that for a typical loading dose in an adult (1000-1500 mg), the physician would need to spend 20-30 minutes administering the drug. Over the years we’ve seen corners cut and either the rate would be accelerated or an IV infusion would be used. Some of that is because many neurologists have not seen significant cardiac side effects from IV phenytoin. But those of us who remember giving IV phenytoin to cardiac patients (once upon a time it was used more frequently as a second- or third-line antiarrhythmic agent) recall watching blood pressures bottom out as we increased rates of the IV push. The FDA review notes that the majority of cardiovascular deaths (for both IV phenytoin and fosphenytoin) occurred in adults and at recommended doses. Most had pre-existing cardiovascular disease.
Another key issue with phenytoin is use of the wrong dilution technique. It is supposed to be given in normal saline, not glucose solutions. Note also that intravenous phenytoin has been associated with the “purple glove syndrome” (FDA 2010), a rare but serious condition. That was actually the primary reason for the recent FDA safety review.
Amiodarone is now a widely used antiarrhythmic drug that has peculiar volume of distribution and pharmacokinetics. Thus, it is typically given in high doses for the first week or so, then tapered down to much lower maintenance doses. Of course, the other problem is that it has a very long half-life and remains in the body for a long time after discontinuation. The NPSA alert describes a patient who died after taking a loading dose of amiodarone for 12 months rather than what should have been a much lower maintenance dose. While amiodarone is typically initiated in-hospital, the relatively long duration of the “loading” period means that most patients are discharged from the hospital before the transition to the maintenance dose takes place. Hence, the potential for errors during the handoffs from one venue to another become another challenge.
Digoxin toxicity is, fortunately, much less common today primarily because we use so little digoxin. Whereas previously it was used in CHF patients for its inotropic actions, its primary use today is for its chronotropic effects (mainly to slow the heart rate in atrial tachyarrhythmias). But it is for that chronotropic effect that the loading dose is most often necessary. Digoxin has one of the narrowest therapeutic ranges of all the drugs we use and is extremely susceptible to development of toxic manifestations based on renal function and electrolyte disturbances.
Loading doses may be especially problematic when staff are unfamiliar with the drug involved. ISMP described a case in 2000 where the glycoprotein IIb/IIIa inhibitor Integrilin was given inadvertently in too high a loading dose in a patient forced to stay in a surgical ICU because the CCU was full. Unfamiliarity of the staff in that unit with the nuances of Integrilin use played a role. It is important to ensure that all staff (nursing, pharmacy, and physicians) be provided adequate information about various medications, especially those considered to be high risk ones. This case illustrates a point we have made several times: while we typically develop order sets for those conditions we most commonly encounter, sometimes it makes sense to also develop order sets for those that are rarely encountered but could be problematic to those unfamiliar with the condition.
Technological solutions are obvious potential means to avoid such errors. But does CPOE actually reduce the chance of errors with loading doses or could it paradoxically increase that risk? We’ve seen some pretty “clunky” IT systems that are not particularly user-friendly when it comes to ordering medications. That is especially so when the order is a complex one in which different doses of a drug are being given on different days, as is the case with loading doses followed by maintenance doses. Considerable confusion may occur when entering such orders, whether directly entered by the physician or entered by a nurse or pharmacist. We have seen instances where the loading dose of a drug gets continued every day or ones where the patient gets both the loading dose and maintenance dose on the same days. Theoretically, use of standardized order sets or protocols (whether paper or electronic) may help avoid such errors but such have not specifically been studied for drugs with loading doses.
The other problem, of course, is that clinical decision support tools that can make CPOE and pharmacy computer systems safer are still suboptimally used. Many current systems do not provide dose range alerts that would flag a relatively high dose of a medication for verification. Also, most current systems do not require an indication field be filled out for each drug. A good system would require input of the indication, with a check box or drop down list where “loading dose” could be indicated (and the system programmed to not continue loading doses beyond the specified time period).
We concur with the NPSA recommendations that each facility should:
Loading doses are an error-prone facet of the medication process that have been underrecognized but have the potential to cause significant patient harm. You should consider adding an initiative on loading doses to your medication safety program.
NPSA (UK). Rapid Response Report. Preventing Fatalities from medication loading doses. November 2010
Rapid Response Report
Patient died from 8GMs of Dilantin
Allnurses.com Jan 25, 2007 10:03 PM written by CraigBSN02
FDA. Joint Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. November 3, 2010
ICSI (Institute for Clinical Systems Improvement). Health Care Guideline: Venous Thromboembolism Diagnosis and Treatment. February 2010
Heneghan C, Tyndel S, Bankhead C, et al. Optimal loading dose for the initiation of warfarin: a systematic review. BMC Cardiovascular Disorders 2010; 10:18
ISMP (Institute for Safe Medication Practices). Admitting "overflow" patients to units without proper expertise is a setup for errors. ISMP Medication Safety Alert Acute Care Edition 2000; October 4, 2000