Succinylcholine is a fast-acting muscle relaxant typically used when seconds count, for instance, when intubating trauma patients. Anesthesiologists also rely on it to reopen the vocal chords quickly and restore air flow in patients suffering from laryngospasm, a life-threatening complication that can occur when endotracheal breathing tubes are removed. Though it has been in use for 60 years, its unique combination of rapid onset and short duration has yet to be matched, making it the safest and most effective choice for many procedures.
But since late 2009, succinylcholine has been in short supply. In response, anesthesiologists and pharmacists at Emory University Hospital in Atlanta changed their protocol, says Arnold J. Berry, M.D., professor of anesthesiology at Emory's School of Medicine. Formerly, a syringe of succinylcholine was drawn for every intubation surgery case as a precaution. But usually it wasn't needed. "If we drew it up and didn't use it, it had to be discarded," Berry says. Now Emory anesthesiologists keep a sterile ampule of succinylcholine and a syringe on hand, but only draw it when needed.
This conservation strategy has helped Emory avoid adverse effects of the shortage, says Berry, who is also vice president of scientific affairs for the American Society of Anesthesiologists. In part Emory has coped because, as a large academic institution, it still is able to procure enough succinylcholine to meet its reduced need. But some smaller hospitals, surgery centers and physician offices haven't been as fortunate. "There have been reports from around the country where the unavailability of succinylcholine has led to adverse patient outcomes—sometimes even death," Berry says.
Succinylcholine is far from the only drug in short supply. In fact, reported drug shortages are at the highest level in more than a decade, says Erin Fox, manager of the Drug Information Service at the University of Utah, which provides comprehensive information on shortages to the American Society of Health-System Pharmacists. The service recorded 211 new drug shortages in 2010, up from 70 shortages in 2006 and 166 in 2009. In addition, there were at least 30 unresolved shortages that occurred prior to 2010.
Other observers believe current shortages are virtually unprecedented. "A lot of people say this is the worst shortage in 30 years," says Michael Alkire, president of Premier Purchasing Partners, which serves about 2,400 hospitals and 70,000 nonacute care providers nationwide. "I believe we are at a trigger point where something must be done."
The most common shortages are generic injectables, says Fox, who also is chair-elect of ASHP's clinical specialists and scientists section. They include some very common drugs such as propofol—a short-acting sedative-hypnotic—epinephrine, heparin and even morphine. Increasingly, they are drugs without effective substitutes, she adds. "We are used to dealing with shortages, but this year it is antibiotics and chemotherapy agents for which there are virtually no alternatives."
Patient Safety Concerns
Evidence is mounting that the shortages are affecting patient safety and care standards. More than 1,000 shortage-related "near misses," errors and adverse patient outcomes, including at least two deaths and several extended hospitalizations, were reported by 1,800 respondents to a survey conducted last summer by the Institute for Safe Medication Practices. "This was not a scientific study; we were just interested in getting a feel for what is going on out there," says ISMP President Michael Cohen. "We had no idea we would see so many errors due to shortages."
Often, mistakes occurred when substituting different medicines, or different preparations of the same medicine, for unavailable drugs. For example, hydromorphone, which is about seven times stronger than morphine, was accidently delivered at morphine-level dosages, resulting in two deaths and several cases in which naloxone injections were required to reverse its effects. Overdoses of morphine, and over- and underdoses of epinephrine and heparin were reported due to substitution of different strength agents for standard prepared doses and pre-loaded syringes.
In other cases, substitutions for unavailable drugs led to significant side effects. One patient died and another was readmitted when the antibiotic amikacin was unavailable to treat resistant organisms. Use of propofol substitutes for anesthesia resulted in phlebitis, prolonged nausea and vomiting, requiring extended hospitalization and difficulty weaning patients from breathing tubes, according to survey respondents.
Shortages of cancer drugs, including doxorubicin, cisplatin, etoposide and vincristine, are forcing oncologists to resort to unproven chemotherapy combinations, which often makes treatment more difficult and almost certainly compromises patient outcomes, says Michael Link, M.D., a pediatric oncologist at Lucile Packard Children's Hospital at Stanford University School of Medicine and president-elect of the American Society of Clinical Oncology.
They are also affecting clinical trials. For example, organizers of several ongoing trials involving doxorubicin have advised participants to substitute based on their own clinical judgment. "In addition to worrying about your patient being able to receive the drug, you also have to worry about whether all these changes to the original protocol will give you any kind of usable results when the trial ends," Link says.
Nearly four in five ISMP survey respondents also reported substantial drug shortage-related costs. These include time spent investigating and planning responses to shortages, locating alternative supplies or substitutes, preparing and administering alternatives and paying sharply higher prices to nonstandard suppliers. "In some cases it has created a 'gray market' where things that used to cost $10 now cost $100," Cohen says. Many respondents also reported indefinite postponement of elective surgical procedures, and some had to transfer patients to other facilities to receive needed drugs. Some oncology patients who could be treated as outpatients with the proper drugs were treated as inpatients with substitutes.
To top it off, in many cases there is little hope that supplies will return to normal any time soon. Consolidation in the drug industry is a big reason, Fox says. "With generics, products start out with five or six suppliers, but over time it dwindles to one or two. If there is a glitch with any one of them, there is a shortage and the other manufacturers can't take up the slack. The companies are all doing just-in-time inventory and lean manufacturing so there is little resiliency in the supply. It takes time to add capacity."
Can Future Crises Be Averted?
Recognizing the systemic nature of drug shortages, ASCO, ASA, ASHP and ISMP in November convened a summit to study the problem and come up with "an assertive action plan that reflects the recommendations and intent of stakeholders to work together to stop patient harm and disruptions in patient care caused by drug shortages," according to a joint press release. Manufacturers, wholesalers, distributors, group purchasers and the Food and Drug Administration and other regulators also attended. In January, summit conveners released recommendations for preventing drug shortages (see sidebar). The group will follow up by prioritizing interventions it believes will have the most impact.
Many summit attendees came away with a new appreciation of the complexity of pharmaceutical manufacturing and distribution—and the difficulty of addressing shortages. "One thing I learned was the complexity of the process in making injectable drugs," Berry says. Many current shortages result from delays in bringing production back online after recalls or shutdowns due to product contamination. The facilities not only must conduct extensive tests to ensure product safety, they also must pass FDA inspections.
Another issue is the quality of raw materials, many of which now come from China and other foreign countries, Premier's Alkire says. In some cases, they may be mishandled, improperly stored or even contaminated with counterfeit ingredients. "There needs to be strong oversight of raw goods," he says. These supplies also can be disrupted by political disputes or disasters beyond the control of manufacturers.
Product safety is also an issue at the distribution end of the supply chain, Alkire adds. When providers must go outside their usual distributors, not only are prices higher, it may also be difficult to trace supplies. "We have a big focus on making sure those products that are being produced offshore are not counterfeit." He advocates such measures as keeping records of products all the way back to the origin of the raw materials to ensure safety, and chemically marking lots to help ensure authenticity.
In the short term, better communication of impending shortages, their causes and likely duration is crucial, Fox says. This allows providers to conserve drugs and find alternatives when possible. "If you find out about a drug shortage while you still have a month's supply, it's a lot better than finding out when there is nothing." Alkire notes that many manufacturers are becoming more open with shortage information, but some distributors have been less cooperative.
When shortages develop, existing supplies sometimes may be conserved by testing expiring lots and extending expiration dates on those that are still stable, Link notes. Substitute drugs also may be available overseas, Berry adds. The ASA worked with the FDA to approve importation of a propofol product used in Europe that is nearly identical to the domestic product. But relying on overseas suppliers can introduce other problems. In January, Hospira withdrew from the market sodium thiopental, which is manufactured in Italy. The Italian government would not let the drug to be exported to the United States because it is used in many states for lethal injections.
Limited Production Capacity Stymies Solutions
Improving communication across the supply chain, removing barriers to suppliers and the FDA to minimize the impact of drug shortages, and clarifying the regulatory definition of "medically necessary," which could prompt earlier reporting of impending shortages to the FDA, are among the broad recommendations the summit group has released. Detailed public policy and other recommendations will be released in the next months.
Policymakers are responding. Sen. Amy Klobuchar (D-Minn.) said she will introduce legislation requiring manufacturers to provide the FDA with early notice of impending shortages, and to expedite importation of substitutes when necessary. The Obama administration is also launching a federal research institute to speed development of new drugs, though this will not address shortages of existing compounds.
However, the fundamental problem of limited production capacity remains, Alkire says. When a shortage of one drug develops, demand increases for alternate drugs, creating additional shortages. Obtaining supplies overseas creates worldwide shortages. And new clinical indications can raise demand for existing compounds. In addition to working with existing suppliers, Premier has approached investors about building new production facilities for generic drugs. Alkire believes that if a stable demand can be demonstrated, and long-term purchasing arrangements locked in, the business will provide enough return to attract the capital required. Premier currently collects information on about 310 million inpatient discharges annually, and is using the information to predict what drugs will be used when. The information can be used to order products in advance and allocate products on hand when shortages develop.
A similar predictive modeling effort is effective in allocating blood plasma products. "We already have a precedent," Alkire says. "We pool the supply and forecast demand on a monthly basis. If a provider uses more, we allocate more. If they use less, it goes back in the pool."
But adding production capacity will take years. In the meantime, Fox suggests that hospitals put a plan in place to identify shortages early and involve physicians, pharmacists and other hospital staff in developing specific coping strategies. "As soon as we think we might have a shortage, we give physicians the heads-up, so they can be proactive and think about how they use the medicine we have left."
For example, the University of Utah requires an ID approval for physicians to order some antibiotics in short supply. Information on shortages is targeted to specific physicians by e-mail, the hospital intranet, newsletters and staff meetings. Clinical pharmacists meet one-on-one with physicians. Drug-shortage discussions are a regular feature of physician staff meetings at Emory. Drug-shortage information can be placed in provider order entry and prescribing systems as well.
Cohen recommends monitoring the ASHP and FDA websites, which have information on the reasons and likely duration of shortages, as well as leads on alternative drugs. He recommends establishing a drug-shortage network with local providers. And, he suggests involving ethics committees and risk management to ensure drugs are distributed equitably. Shortage-associated adverse events should be monitored to assess the safety and efficacy of substitutions.
"This isn't like making peanut butter," Fox says. "When there isn't enough peanut butter, you can get by. When there aren't enough antibiotics or chemotherapy agents, it is a public health crisis and you have to respond."
Howard Larkin is a contributing editor to Hospitals & Health Networks magazine.
Sidebar - Policy Recommendations from the Drug Shortages Summit
Sidebar - How to Create a Response Plan