Interference or Patient Safety?

Benzocaine-Related Methemoglobinemia and Restrictions at the VA

In April 2006, after intensive research into benzocaine-related methemoglobinemia, federal Veterans Health Administration (VA) hospitals throughout the United States were required to remove benzocaine from their facilities and replace it with lidocaine. No exceptions were made.

The VA also completed a study of the safety of benzocaine in dental use, and determined that there was no need to phase out the use of benzocaine in dental facilities. However, the administration decided it did need to be eliminated from medical use.

In addition, although the Food and Drug Administration (FDA) was made aware of the VA’s actions, the federal agency decided there was no need to recall benzocaine from general use, and no need to introduce additional warnings in the labeling of benzocaine.

What led to the VA alert and the removal of benzocaine from the entire VA hospital system? Were the reasons behind the drug’s removal justified? Why did the FDA and VA system disagree?

In this article, EndoNurse will explore the background of methemoglobinemia, its causes, and how frequently this reaction actually occurs. And we will attempt to lay to rest any lingering questions about what led to this pharmaceutical decision in the spring of 2006.

Methemoglobinemia is a rare disorder that can be either inherited or acquired. It is so rare that most healthcare providers will never see a single case throughout their medical careers.

According to the National Institutes of Health (NIH), methemoglobinemia (MHB) is a blood disorder. In this disorder, “the body cannot recycle hemoglobin after it is damaged. Hemoglobin is the oxygen-carrying molecule found in red blood cells. In some cases of methemoglobinemia, the hemoglobin is unable to carry oxygen effectively to body tissues.”¹

Also known as hemoglobin M disease, erythrocyte reductase deficiency, or generalized reductase deficiency, MHB can be caused by exposure to some pharmaceutical agents, chemicals, or foods. It can also be inherited as an autosomal recessive condition. According to the NIH, this is related to a problem with the enzyme cytochrome b5 reductase.

“There are two subtypes of autosomal recessive methemoglobinemia — Type 1, also called erythrocyte reductase deficiency, occurs when red blood cells lack the enzyme; and Type 2, also called generalized reductase deficiency, occurs when the enzyme doesn’t work anywhere in the body,” according to the institutes. And hemoglobin M disease, an autosomal dominant condition, is related to problems in the hemoglobin molecule itself.

It is much more common to acquire MHB through exposure, rather than by inheritance. The more common causes of this reaction include anesthetics, which include benzocaine and Xylocaine; benzene; some antibiotics; and nitrites, which are sometimes used as food preservatives. “The condition may also occur in infants who are fed too many vegetables containing nitrates (such as beets),” the NIH observes.

Symptoms vary, and can include a bluish tinge of the skin and mucous membranes — this is related to Type 1 MHB. For those with Type 2, there may be more subtle symptoms such as failure to thrive or developmental delays; mental retardation and seizures are also associated with this type of MHB. And those with hemoglobin M disease may experience a bluish tinge of skin and mucous membranes, as well as a mild breakdown of red blood cells, according to information from the NIH.

However, when acquired MHB is the problem, in addition to the bluish tinge, patients may also complain of headache, fatigue, shortness of breath or lack of energy.

Typically, diagnosis is made via a blood test. Of note, if an infant is born with MHB, his arterial blood gases and pulse oximetry results will appear normal, observes the NIH.1 The standard treatment is methylene blue, but there are certain people who cannot use this medication. People with the blood disorder G6PD deficiency — or who are at risk for it — should not receive the drug. Other treatments may include ascorbic acid, which can reduce the level of methemoglobin; or hyperbaric oxygen therapy and exchange transfusions. “In most cases of mild acquired methemoglobinemia, no treatment is required, other than avoiding the medicine or chemical that caused the problem. However, treatment (such as a transfusion) may be needed in severe cases,” says the NIH.¹

According to the University of Michigan Health System’s Critical Care Unit, methemoglobin (metHb) is an abnormal form of hemoglobin — the iron molecule is in the ferric (3+) state rather than the normal ferrous (2+) state. “When iron in hemoglobin is switched to the ferric state, it is no longer capable of carrying oxygen or carbon dioxide. In addition, the oxy-hemoglobin dissociation curve is shifted to the left, impairing the delivery of oxygen at the tissue level.”

“Red blood cells are continuously subjected to oxidative stressors that result in the formation of metHb. The erythrocytes have two mechanisms that work to keep the abnormal hemoglobin percent down to generally less than 1 percent. One reduces the oxidizing compounds before they can change the hemoglobin; the other changes the abnormal hemoglobin back into working hemoglobin by way of two enzyme pathways,” according to the unit’s Web site.

According to the university, ABG determination will show a normal PaO₂, with a SaO₂ lower than expected for the given PaO₂. Arterial blood will turn chocolate-brown.

“In the period of 2001-2007, we have received only four reports of methemoglobinemia. In that same period, it is estimated that 15,000,000 doses of our product Cetacaine® would have been administered,” says Stanley L. Wachman, president of Cetylite Industries, Inc. “Approximately 12 years ago, we were solicited by the American Association of Anesthesiologists to include in our package insert a warning regarding the possibility of our formula causing methemoglobinemia. We conferred with the FDA, which concluded that the condition was a ‘not unexpected adverse reaction’ but one that was not statistically significant in light of the hundreds of thousands of benzocainecontaining doses that were administered or consumed daily, and therefore did not warrant an insert warning. We, however, voluntarily added such a warning, since we have always been aware of a causal relationship between benzocaine and the condition, but not because our product was responsible for a substantial number of reported events.”

The manufacturers also point out that lidocaine has also been linked to MHB. “It might be worthwhile to find out the incidence of reported methemoglobinemia caused by lidocaine HCL,” Wachman observes.

Lidocaine has been linked to methemoglobinemia in multiple reports. Indeed, professional medical associations and hospitals alike list lidocaine among the medications that can cause MHB. One case study focuses on a patient who experienced two episodes of MHB — one each due to benzocaine and lidocaine.

To read this case study, visit http://archinte.ama-assn.org/cgi/content/abstract/140/11/1508.

In this case report published in the Archives of Internal Medicine (Vol. 140, No. 11, November 1, 1980, “Acute methemoglobinemia induced by topical benzocaine and lidocaine,” by W. J. O’Donohue, Jr., L. M. Moss and V. A. Angelillo), the authors note that “acute methemoglobinemia may result from the use of several local anesthetic agents.” In this instance, the two medications were given more than 20 hours apart, and resulted in two separate incidents of MHB.

“To our knowledge, the statement by the FDA regarding the proper use of benzocaine sprays contributing to the comfort of patients applies equally to lidocaine. As you can imagine, we in the benzocaine product community believe we have been unfairly targeted as purveyors of an inordinately dangerous drug,” Wachman adds. “Cetacaine’s 50-plus years of professional acceptance disproves this.”

“Methemoglobinemia is a condition that inhibits the body’s ability to effectively transport oxygen through the blood. Most of the literature suggests that the cause of this is related to incorrect usage or overdosing of benzocaine. In addition, there are specific populations that can be at higher risk, such as those with respiratory problems, very young children, and senior citizens,” says Tim Lorencovitz, MBA, product manager, infection control, for Sultan Healthcare Inc.

“In the years that we have sold our topical anesthetic, we are not aware of any specific instances of benzocaine-induced methemoglobinemia related to Topex. We feel part of that is the fact that our spray offers a metered dose, helping minimize the risk of overspray,” says Lorencovitz. “Unfortunately, none of the manufacturers can control how many sprays the administrator gives; we can only educate them on the correct number of sprays for optimal dosage. We feel the best way to approach this is to continually communicate within the healthcare community and educate them on what the risks are and about the steps to reduce the risk.”

Because methemoglobinemia is so rare, many healthcare workers have heard little about it since medical school or nursing school, and detailed information about it may be spotty. “It is difficult to comment on how well physicians and nurses are educated as to the chemicals that can cause methemoglobinemia,” Wachman points out. “We would suggest that most professionals are not aware of even a fraction of these chemicals causing the condition.”

Wachman observes that most crash carts contain methylene blue, and that personnel are aware of and trained in its use. “What is possible is that even with the cautionary statements on the products’ label, many professionals take liberties with the dosage, especially the spray forms. This applies to both metered and non-metered dispensers. While methemoglobinemia is not necessarily dose-related to a suspect drug, overdosing can not be completely discounted,” Wachman adds. “While we cannot speak to the education of the professional regarding the treatment of methemoglobinemia, what we can speak to is the training of our sales personnel, who are given training regarding our product’s possible cause and effect and to have at their disposal reference material to use while in the field if questioned by prospective customers.”

Knowledge of the condition is spreading, and, Lorencovitz says, “We have seen in recent years that the awareness of methemoglobinemia has increased. In my own experience, during the recent SGNA show, there were many nurses who were aware of it and were looking for answers from the manufacturers.”

But some benzocaine manufacturers feel that the VA neglected to get input from them before issuing its alert. “No one from our industry, to our knowledge, was contacted for comment prior to the posting of the alert. Dr. Bagian at the VA said that his staff attempted to reach people at Beutlich and as Cetylite. We have no record of such an attempt,” contends Erin E. Loeher, export manager for Beutlich LP — USA.

The VA’s action, she says, is supposed to focus on “'prevention, not punishment’ in order to reduce medical errors. But the statements made in the advisory are general, out of context and based on anecdotal case reports, not clinical evidence.”

And, she points out, the VA alert states that “Many cases of benzocaine-induced MHB have been reported in the medical literature that have resulted in injury or death.” However, she counters, “‘Many cases’ and ‘several’ are completely out of context, without the framework of how many dosages are actually given per year. We at Beutlich LP have no knowledge of any fatalities attributed to the use of HurriCaine Spray. According to FDA AERS, two fatalities have resulted from MHB following benzocaine topical anesthetic spray, but it is not certain whether benzocaine is the root cause. In fact, in the vast majority of instances, more than two substances that are known to cause MHB were introduced along with the benzocaine.”

Additionally, Loeher says, “There are well over 100 million applications of benzocaine administered annually in the healthcare setting. Assuming 100 uses per can, we sell an estimated annual average of 25 million doses of HurriCaine Spray per year. On average, we receive 13.4 reports of cases of MHB per year. That represents a 0.00005 percent chance of a patient getting MHB. The estimated number of incidences from one study said one in 7,000 bronchoscopies result in MHB. This would be 0.0001 percent — the highest estimated incidence rate we have seen in the literature anywhere.”

Lidocaine can still be problematic, Loeher points out — “Lidocaine toxicity is estimated to affect between 1 in 1,000 and 1 in 500 people,” she states. “And lidocaine is listed as the second most commonly overdosed drug in hospitals, next to heparin.”

Loeher references numerous studies on both benzocaine- and lidocaine-induced MHB, and concludes, “The VA Advisory may appear intimidating, but it is not based on clinical data.”

The center began investigating reports of MHB related to benzocaine. “It is a problem that can occur and has been well documented in the emergency medicine literature, GI literature, and anesthesiology literature, going back at least 10 or 15 years,” he says. “And basically, the recommendations were saying ‘People shouldn’t be using topical benzocaine-containing sprays, because of the risk of MHB.’”

One group of hospitals began placing MHB antidote kits in its endoscopy suites. “That’s one solution, but that’s going from the standpoint that you have to use benzocaine. Instead, why don’t you use an agent that will allow you not to have to worry about treating with an antidote? Also, we had a case of someone who was overdosed with methylene blue, which also gives you MHB, and then the treatment can become exchange transfusion. So you just trade one problem for another,” he adds.

Lidocaine is a better option, he says, especially because it does not cause MHB. “That’s a commonly held piece of information that is incorrect — that lidocaine is a clinically significant cause of MHB,” Bagian states. “When you read all the references in the VA paper that the pharmacy group put together, if you trace back the references that say lidocaine causes MHB, they all go back to one study a long time ago where MHB was associated with lidocaine. The study was using both lidocaine and benzocaine. So it was taken out of context and people said that lidocaine is associated with MHB. They didn’t add, ‘That’s when it was used with benzocaine.’ In subsequent papers, people didn’t reference their papers as well as they might have, and referenced another paper that referenced another paper that referenced another paper without looking at the source document. So the issue that lidocaine causes MHB is not really, from a clinical perspective, a relevant concern.”

It’s easy to overdose on the benzocaine topical sprays, he adds. And the medication can be sprayed for too long; its delivery can be affected by the angle at which the bottle is held. “The question is, how do you design your system so it is tolerant of the way people use it? The manufacturers would say, ‘As long as you’re careful and don’t give an overdose, it’s not a problem.’ That’s a true statement, but it’s a ridiculous statement. Unfortunately, [overdose] happens all the time. When we started talked to practitioners, what we found was different from what we saw in our reporting system, where we had several reports of MHB secondary to benzocaine. When we polled places, virtually every place would regale us with numerous incidents they had. And because these incidents happened frequently, they said, ‘Well, we don’t need to report it, because everybody knows it’s just what happens. Why would I report that?’ That’s called normalization of deviance.”

The VA policy requires reporting of any problem that has caused harm to a patient, or that could cause harm to a patient. However, Bagian points out, “People don’t report everything, and we know that. The main reason we want people to report is not the count; it’s safety. We report to identify vulnerabilities. It’s up to us to then figure out the magnitude of that vulnerability. This was a very good case — while we had very few reports, when we got curious and delved more deeply into it, we found it happened very frequently. Here we had benzocaine, which is a drug that has bad or even lethal side effects, and we have monitoring techniques such as traditional pulse oximetry that are not generally accurate measuring the oxygenation when you have MHB.”

There are two options to addressing the problem — primary and secondary prevention. “Having an antidote is secondary prevention. Primary prevention is making it so it doesn’t happen. If you don’t have benzocaine, you can’t have benzocaine overdose,” Bagian points out. “What’s the utility or risk of going to another agent? It’s quite clear that topical lidocaine works just fine; we had a number of facilities that, for over 10 years, had banned benzocaine use [in their individual facilities].”

When the VA completed its research — comprised of literature reviews, risk assessments, and discussions with practitioners from GI, ENT, anesthesiology, and the emergency department — it went to the FDA and showed its results. The FDA determined that, as it had already given a warning about MHB, additional action was not necessary.

Two days after the VA alert was made public, the FDA issued another bulletin, restating the causes of MHB and the proper use of benzocaine-containing anesthetics.

Although the FDA has remained adamant about not removing benzocaine from the market, Bagian contends that the VA made the right decision, based on patient safety.

Many physicians, he says, do not know the proper dosage of benzocaine-containing sprays. “They tell me, ‘I can use as much as I need, until I get the anesthesia I want.’ But did you know that depending on which product you’re using, it’s a one-second spray or no more than two seconds? That’s what the product insert says. People don’t read the product inserts.”

Lidocaine is ultimately safer and harder to overdose than benzocaine, Bagian maintains. “The chance of giving enough lidocaine to get toxic effects is not going to happen. First of all, when you load your syringes, even the whole syringe is not a toxic dose. You can fill it all the way, and spray it, but with a 3cc syringe, you’re not going to have enough lidocaine to cause a problem.”

The facilities that switched to lidocaine before the VA alert are proof that the decision is a good thing, he says. “We have proven it in the clinical environment, showing that using lidocaine gave you every bit as good a pharmacologic effect to do what you need to do but does not have the side effects. It’s like buckling my seat belt — it doesn’t cost me anything, and it could save my life.”

Ultimately, he asserts, “We [determined] that this is a bad decision to leave in the hands of a clinician. Just because the physicians believe they’ve never had a problem, do we want to let them put the patient at risk?”

Instead of just recommending a switch, they removed benzocaine from the equation entirely. “When there is good evidence, and when to standardize reduces variation and you’re going to get better overall performance, then you should standardize,” Bagian says.

“We spoke with the pharmaceutical companies before we went out with this alert. Hundreds of man-hours went into the literature review, getting people together on panels, to make sure we know what we’re talking about. We know it has a huge impact on how we practice medicine, on the patient, and has economic impact on companies or shareholders. We take that very seriously. We don’t want to hurt any of those groups if it’s not to help the patient. If it helps the patient, if somebody invested in a company that is making something that isn’t particularly good, them’s the breaks,” he concludes.

In the end, it is up to each individual practitioner to determine what agent is the best for the patient and for the practice as a whole.

Editor’s note: We want to hear from our readers; what has your experience been with methemoglobinemia? Have you ever seen a case? Were you able to trace the cause to one specific agent, or were there multiple medications functioning as possible causes? How has the switch to lidocaine affected employees at VA facilities? Write to Kathy Dix at kdix@vpico.com to tell your story! A special follow-up section will be included in the next issue of EndoNurse.

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