Learning Objectives: After reading this article, the physician should be able to:
- Discuss the different classes of medications used in the treatment of type 2 diabetes mellitus and know their toxicities.
- Describe the best treatment for a sulfonylurea overdose.
- Explain the different physical exam skills used in determining if there are any meniscal or ligamentous injuries to the knee.
Release Date: January 2007
Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Toxicity, and Treatment
Harrigan RA, et al Ann Emerg Med 2001;38:68
This review article was published in 2001, and while it is an excellent review, some newer medications exist, some have virtually disappeared from use, and there is a slightly different classification used.
While diet, exercise, and weight loss are critical to the treatment of diabetes mellitus, pharmacologic therapy is often required. The oral medications used for treating diabetes can be categorized into hypoglycemic or antihyperglycemic agents. Most type 2 diabetics require more than one agent for adequate glycemic control.
The hypoglycemic agents (insulin secretagogues) can be divided into two subclasses: sulfonylureas and non-sulfonylureas. While they differ in the binding site and kinetics, the mechanism of action is similar. After binding a specific receptor, each drug inhibits an ATP-dependent potassium channel, resulting in membrane depolarization, calcium influx, and release of insulin from the pancreatic beta-cells. The non-sulfonylureas (repaglinide, a benzoic acid derivative, and nateglinide, a phenylalanine derivative) have a much more rapid onset, and short duration of action. Because of this, the non-sulfonylureas are to be taken three to four times daily, within 30 minutes of meals to better control postprandial hyperglycemia. Meanwhile, the sulfonylureas have a much longer half-life, making it the more important agent for emergency physicians to understand because it is much more likely to cause hypoglycemia for prolonged periods of time.
The major sulfonylureas in use today include glyburide, glipizide, and glimepride. Of these, glyburide and the extended-release glipizide are the most likely to cause hypoglycemia. When presented with a case of symptomatic hypoglycemia due to either accidental or intentional overdose of a sulfonylurea, or idiopathic hypoglycemia in patients with diabetes, first-line treatment is always intravenous dextrose. That said, dextrose itself is an insulin secretagogue, especially in patients on a sufonylurea, and while treating low blood glucose, it paradoxically contributes to rebound hypoglycemia through the stimulation of insulin release. Octreotide, a somatostatin analog, is an interesting antidote that suppresses numerous hormones secreted by the pancreas, including insulin. Experimental and clinical data appear to support the use of octreotide (intravenous or subcutaneous) in preventing further hypoglycemic episodes in these types of patients. And because no adverse effects can be attributed to octreotide therapy for sulfonylurea-induced hypoglycemia, it probably should be used in any patient who has rebound hypoglycemia more than once and in patients being admitted due to sulfonylurea-induced hypoglycemia.
The antihyperglycemic agents include the biguanides, thiazolidinediones, and alpha-glucosidase inhibitors. The only available biguanide is metformin. It works primarily by inhibiting hepatic glucose output, but secondarily decreases insulin resistance. It decreases the glucose levels of diabetic patients but does not in non-diabetic patients, and so is categorized as an antihyperglycemic. Side effects include nausea, vomiting, diarrhea, and abdominal discomfort. These side effects are usually mild, dose-related, and transiently seen at the initiation of therapy. Patients should be warned of these side effects when starting metformin.
The most serious toxicity, however, is lactic acidosis. Most cases of biguanide-induced lactic acidosis have been from phenformin at a rate of 60 cases per 100,000 patient-years. Because of this, phenformin was taken off the market in virtually every industrialized nation in 1976. The incidence of lactic acidosis with metformin is only about three cases per 100,000 patient-years and is more likely to occur in renal insufficiency, hepatic dysfunction, severe infection, alcoholism, and severe cardiovascular and pulmonary disease that result in decreased perfusion or hypoxia. Metformin should not be started in any male patient with a plasma creatinine level 1.5 mg/dl or higher or in any female patient whose level is 1.4 mg/dl or higher. Lactic acidosis also can occur in overdose, but can take several hours to present. It is recommended to observe for six to eight hours any patient who claims to have taken a large dose of metformin.
The thiazolidinediones, which currently include rosiglitazone and pioglitazone, are insulin-sensitizing drugs. They enhance the effect of insulin at the muscle, adipose, and hepatic tissue levels without increasing insulin secretion. They are quite effective agents with few side effects. They should be used with caution in patients with congestive heart failure because they increase circulating plasma volume, causing peripheral and pulmonary edema. They also can cause birth control pills to lose their contraceptive effect. The most worrisome side effect, serious and fatal hepatotoxicity, has rarely been seen and is more of a historical fact with the first thiazolidinedione, troglitazone. Troglitzone was withdrawn from the market in 2000. Because of these fears, however, primary care physicians will get baseline liver enzymes and follow them with time when patients take thiazolidinediones.
The alpha-glucosidase inhibitors include acarbose and miglitol. They are rarely used as monotherapy, and in fact are rarely used at all any more. They inhibit alpha-glucosidase, an intestinal brush border hydrolase enzyme, which normally converts carbohydrates to monosaccharides. The side effects are primarily gastrointestinal and include bloating, flatulence, diarrhea, and abdominal pain. One practical implication with this medicine is that if patients become hypoglycemic, feeding with complex carbohydrates is not an effective treatment.
Comment: Although beyond the scope of this review paper, emergency physicians are often called on to start the treatment for newly diagnosed type 2 diabetics. In this setting, a sulfonylurea or metformin is the appropriate initial therapy. Because most patients will eventually need these two agents together, which one is used first is not so important. That said, if not contraindicated, metformin, at a dose of 500 mg once or twice daily, is probably safest because it doesn't cause hypoglycemia by itself. The major reasons the thiazolidinediones are rarely first-line agents is that they are expensive and don't have the microvascular or macrovascular clinical outcome data that the sulfonylureas and metformin have.
Does This Patient Have a Torn Meniscus or Ligament of the Knee? Value of the Physical Examination
Solomon DH, et al JAMA 2001;286:1610
Overall, knee pain accounts for three to five percent of all visits to physicians, and a substantial proportion of these result in referrals for diagnostic imaging and specialty care. A thorough history and physical exam may aid the physician in assessing the likelihood of a torn meniscus, ligament, or other injury, and aid in deciding whether referral may be beneficial.
The anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL) limit the anterior and posterior displacement of the tibia or the femur, respectively. They also appear to aid in proprioception of the joint as well. The ACL is often injured during traumatic twisting injuries, in which the tibia moves forward with respect to the femur, often accompanied by valgus stress. The foot is usually planted, and the patient may experience a “popping” sensation. PCL injuries also usually occur from twisting with a planted foot when the force of the injury is directed posteriorly against the tibia with the knee flexed. The medial collateral ligament (MCL), which aids the ACL in preventing posterior motion of the femur, is injured when an abduction (valgus) and external rotation force is applied on a knee in an extended or slightly flexed position. Patients with ACL tears typically complain of the sensation that their knee is buckling or “giving out” especially during pivoting movements. They also may express a loss of confidence in the stability of their knee. Patients with isolated PCL tears may have no associated symptoms whatsoever.
The meniscal fibrocartilages are medial and lateral structures attached to the tibial plateau at the edge of the articulating surfaces of the femur and tibia. They provide a congruous surface for transmission of up to 50 percent of the axial forces across the knee joint, and also increase joint stability, facilitate nutrition, and provide lubrication and shock absorption for the articular cartilage. The medial meniscus is more firmly attached to the joint capsule and the MCL, and is relatively immobile. Because of this, the medial meniscus is more susceptible to injury. The menisci are without pain fibers, so it is the tearing and bleeding into the peripheral attachments as well as traction on the capsule that most likely produces the symptoms of pain after a meniscal injury. Patients with meniscal tears also may describe a “clicking” sensation, and complain of the knee locking in a flexed position.
Prior to examining the knee, the physician should first inspect the patient's gait, if he is able to walk. Next, inspect for asymmetry. An early sign of an effusion is the loss of the peripatellar groove on either side of the patella. After inspection, palpation can begin with checking for differences in temperature, which suggest inflammation. The knees should then be palpated, searching for an effusion. Ballottement of the patella is one useful technique for detecting smaller effusions. In this test, the examiner quickly pushes down on the patella. In the normal knee, nothing happens, but in the knee with an effusion (i.e., a “floating” patella), ballottement causes the patella to tap against the femoral condyle. The sensation of tapping felt by the examiner is a positive ballottement test for a knee effusion.
The three functional tests that may help in examining the integrity of the ACL are the Lachman test, the anterior drawer test, and the lateral pivot shift test. The Lachman and anterior drawer tests are performed similarly. The main difference is that during the Lachman test, the patient is supine with the knee flexed 20 to 30 degrees, while in the anterior drawer test, the patient is supine with the knee flexed 90 degrees. During both tests, the lower leg is given a brisk forward tug and a discrete endpoint should be felt in a normal knee. A positive test is one in which there is no abrupt stop (discrete endpoint). It is often useful to perform this test on the uninjured knee to compare.
PCL stability is generally assessed using the posterior drawer test. This is performed with the patient supine and the knee flexed to 90 degrees. The alignment of the knee is then inspected. If the tibia of the affected knee is subluxed posteriorly (a posterior “sag”), and applying anterior pressure corrects the sag, it is considered a positive posterior drawer sign. Additionally if posterior force on the tibia encounters no discrete endpoint, then the test is positive as well for a likely PCL tear. The abduction (or valgus) stress test is a special technique to assess if the PCL is injured along with the MCL.
Meniscal integrity is assessed by checking for joint-line tenderness and performing the McMurray, Apley compression, and/or the medial-lateral grind tests.
Comment: In reviewing this article, I purposefully left out a lot of data because I felt it was questionable at best and likely not applicable to the emergency department. One problem with the data was the wide confidence intervals. In analyzing the usefulness of the anterior drawer test, for example, the specificity from various studies ranged from 23% to 100% and the sensitivity from 9% to 93%. Solomon et al then attempted to calculate summary likelihoods from these types of data, which in my mind probably should not have been done. None of the studies included patients in the truly acute phase (right after injury) either. The “acute” patients described in this study were those seen within three months of injury. All of the exams were done by orthopedic surgeons, and the reproducibility was rarely reported in any study. While the existing data are so poor, it is difficult to draw any real conclusions to the applicability of the clinical examination of the knee, especially in the emergency department.
As emergency physicians, it is prudent to maintain an even broader differential than described in this paper. Other easily missed but potentially dangerous knee injuries include quadriceps or patellar tendon rupture and knee dislocation. When searching for a quadriceps or patellar tendon rupture, all patients should be asked to extend a flexed knee against mild resistance and keep the knee extended while lifting the leg off of the bed. If unable to do so, the diagnosis is likely. Meanwhile, in the correct setting, a knee that is severely unstable in multiple directions is suspicious for a spontaneously reduced knee dislocation. A high level of suspicion should be maintained for this type of injury because of the possibility of associated arterial and nerve injuries. Anyone with a suspected knee dislocation or quadriceps/patellar tendon rupture requires emergent orthopedic consultation in the emergency department.
About the LLSA
As part of its continuous certification program, the American Board of Emergency Medicine has developed the Lifelong Learning and Self-Assessment (LLSA) program to promote continuous education of diplomates. Each year, beginning in 2004, 16 to 20 articles are chosen based on the Emergency Medicine Model. A list of these articles can be found on the ABEM web site, www.abem.org.
ABEM is not authorized to confer CME credit for the successful completion of the LLSA test, but it has no objection to physicians participating in such activities. EMN's CME activity, Learning to Live with the LLSA, is not affiliated with ABEM's LLSA program, and reading this article and completing the quiz does not count toward ABEM certification. Rather, participants may earn 1 CME credit from the Lippincott Continuing Medical Education Institute, Inc., for each completed EMN quiz.