Join the conversation on the NEJM Group Open Forum

Posted by Karen Buckley • December 9th, 2014

Two active conversations await your participation on the NEJM Group Open Forum, powered by Medstro, a social professional network for physicians.

Dr. Julian Seifter, author of the recent Review Article, “Integration of Acid-Base and Electrolyte Disorders,” is on hand to answer your questions on this topic.

Meet “Fascinating Physician” Andrey Ostrovsky, a Pediatrics Senior Resident at Boston Children’s Hospital whose numerous accomplishments include founding three companies and working as Health Policy Fellow to a US Senator. Ask him how he manages it all.

The forum is publicly available for all to view, but in order to comment you must register with Medstro — a simple, one-minute process. Look for two new discussions on December 18.

D Is for Delay

Posted by Carla Rothaus • December 5th, 2014

In the latest Clinical Problem-Solving article, a 47-year-old homeless man presented to the emergency department with intermittent pain and a pins-and-needles sensation in his legs. One month earlier, paresthesias had developed in his toes, which spread gradually to his shins.

Pellagra (or “rough skin,” from the Italian pelle agra) is rare in the United States, but it remains an important problem in developing countries. This condition results from inadequate dietary intake of niacin and is characterized by “the four Ds”: diarrhea, dermatitis, dementia, and death.

Clinical Pearls

What causes pellagra?

Pellagra (or “rough skin,” from the Italian pelle agra) is rare in the United States, but it remains an important problem in developing countries. This condition results from inadequate dietary intake of niacin and is characterized by “the four Ds”: diarrhea, dermatitis, dementia, and death. The mechanism by which niacin deficiency leads to such severe multisystem failure is poorly understood. Pellagra develops in the context of malnutrition, including restricted diets and alcohol abuse.

Describe the dermatitis associated with pellagra.

The dermatitis of pellagra involves sun-exposed skin in a bilateral and symmetric pattern. The characteristic and prominent eruption can occur on the dorsum of the hands, the V-area of the neck, the face, and exposed skin on the legs and feet. The rash may resemble a sunburn with erythema, or it may be characterized by hyperpigmentation, thickening, dryness, and roughness. Pain may also develop owing to fissures and excessive dryness. One of the hallmark clinical signs is an eruption on the front of the neck extending into the region of cervical dermatomes C3 and C4, simulating a necklace (Casal’s necklace).

Morning Report Questions

Q: What are some additional clinical features of pellagra?

A: Patients with pellagra can have a wide range of neuropsychiatric manifestations, such as irritability, anxiety, delusions, hallucinations, apathy, spastic paresis, fatigue, depression, myelitis, and peripheral neuropathy of the upper and lower extremities. Approximately half the patients with pellagra have gastrointestinal manifestations. Diffuse inflammation and atrophy of the mucosal surface of the gastrointestinal tract results in diarrhea. Anorexia and malabsorptive diarrhea lead to malnutrition and eventual cachexia.

Q: Is pellagra easy to recognize?

A: Although pellagra is a prototypical nutritional deficiency with a well-defined tetrad of clinical manifestations, it is not always easily recognized. The classic symptoms and signs of niacin deficiency typically evolve at different intervals over time, rather than appearing simultaneously, making it harder for the clinician to see the pattern.

Conduct Disorder

Posted by Carla Rothaus • December 5th, 2014

Children with repetitive rule-breaking, aggression, and disregard for others are at increased risk for substance abuse, educational disruption, and criminal behavior. Progress is being made toward understanding the clinical and neurocognitive features of youth conduct disorders.  Read the new review article on this topic.

The term “conduct problems” refers to a pattern of repetitive rule-breaking behavior, aggression, and disregard for others. Youth conduct problems are predictive of an increased risk of substance abuse, criminal behavior, and educational disruption; they also incur a considerable societal burden from interpersonal suffering and financial costs.

Clinical Pearls

When does youth conduct disorder present clinically?

For children with long-term behavioral problems, signs of conduct disorder often arise by early school age, but few children meet the full criteria for the disorder before 10 years of age. These early signs involve aggressive tendencies, impulsivity, and failure to comply with requests, which are features of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder. Prospective data show a trajectory of behavioral problems, with progression from ADHD  behavioral problems in early school years to oppositional-defiant disorder in subsequent years, followed by conduct disorder as children approach adolescence. Although this developmental pattern is common, it is not typical in children who have early behavioral problems — that is, conduct disorder does not develop in most children with ADHD or oppositional-defiant disorder, and successful treatment of these two conditions may reduce the risk of progression.

Figure 1. Overlap among Six Clinical Entities.

What are features of youth conduct disorder with associated callous-unemotional traits?

Callous-unemotional traits, which occur in fewer than half of young persons with conduct disorder, identify a subgroup with distinctive clinical features and neurocognitive perturbations. As compared with youth with conduct disorder who show remorse, empathy, and concern about school performance, those with callous-unemotional traits have a poorer prognosis and treatment response. Like ADHD and oppositional-defiant disorder, callous-unemotional traits are expressed early. Such traits have been identified in children as young as 2 years of age, and among young children with conduct problems, they predict a particularly early onset of a severe, persistent variant of conduct problems. In youth with conduct disorder, the presence of callous-unemotional traits predicts a poor response to typical socialization practices.

Morning Report Questions

Q: What is the prognosis of youth conduct disorder?

A: Once the diagnosis of conduct disorder is established, the prognosis is usually considered to be poor, though the outcome varies. Antisocial personality disorder, which has a particularly poor prognosis, develops in slightly less than 50% of patients with conduct disorder; however, youth with conduct disorder in whom antisocial personality disorder does not develop typically have other long-term problems. Thus, persistent psychopathology is the rule, though its nature can vary.

Q: Are there effective treatments for youth conduct disorder?

A: Currently available treatments target symptoms rather than underlying mechanisms, since the latter are, as yet, unknown. Most important, currently available treatments are only moderately effective. Two types of psychosocial intervention are effective in reducing conduct problems. One targets diverse behaviors with the use of multiple treatment components, including components that rely on principles from cognitive behavioral therapy to address anxiety and related emotional problems. The other form of effective psychosocial intervention facilitates proper child-rearing practices. Two pharmacologic interventions also show promise, but concerns about adverse effects should lead to judicious use. First, antipsychotic medications reduce irritability and aggression in children, although the usefulness of these drugs is limited by short-term adverse effects, such as sedation, and long-term adverse effects from disrupted metabolic and neurologic functions. Second, data also show benefits of psychostimulant medications. In general, psychostimulants are preferable to antipsychotic agents owing to fewer adverse effects. Nevertheless, stimulants can exacerbate anxiety and cause agitation.

Delirium Tremens

Posted by Carla Rothaus • November 28th, 2014

Alcohol withdrawal syndromes are underdiagnosed and understudied. Prevention and treatment involve supportive care and administration of benzodiazepines.  A new review article on this topic comes from Dr. Mark A Schuckit at the University of California, San Diego, School of Medicine.

About 50% of persons with alcohol-use disorders have symptoms of alcohol withdrawal when they reduce or discontinue their alcohol consumption; in 3 to 5% of these persons, grand mal convulsions, severe confusion (a delirium), or both develop. Approximately 1 to 4% of hospitalized patients who have withdrawal delirium die.

Clinical Pearls

How can the severity of alcohol withdrawal be assessed, and what are the diagnostic criteria for delirium tremens?

The revised Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) is a withdrawal rating instrument that is commonly used by trained clinicians. Scores on the CIWA-Ar range from 0 to 67; scores lower than 8 indicate mild withdrawal symptoms that rarely require the use of medications, scores from 8 to 15 indicate moderate withdrawal symptoms that are likely to respond to modest doses of benzodiazepines, and scores higher than 15 indicate severe syndromes that require close monitoring to avoid seizures and alcohol withdrawal delirium. A patient who meets the criteria for both alcohol withdrawal and delirium is considered to have delirium tremens.

Table 1. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised.

Table 2. DSM-5 Criteria for Withdrawal Delirium (Delirium Tremens). 

What factors are associated with the development of delirium tremens?

Delirium during alcohol withdrawal is predicted by the following: CIWA-Ar scores above 15 (especially in association with a systolic blood pressure >150 mm Hg or a pulse rate >100 beats per minute), recent withdrawal seizures (seen in 20% of persons with delirium), prior withdrawal delirium or seizures, older age, recent misuse of other depressant agents, and concomitant medical problems. The latter include electrolyte abnormalities (e.g., low levels of potassium, magnesium, or both), low platelet counts, and respiratory, cardiac, or gastrointestinal disease.

Morning Report Questions

Q: What are general guidelines for the management of withdrawal delirium?

A: The major treatment goals for withdrawal delirium are to control agitation, decrease the risk of seizures, and decrease the risk of injury and death; treatment is best carried out in a locked inpatient ward or an ICU [intensive care unit]. The approach to the management of withdrawal delirium includes a careful physical examination and appropriate blood tests to identify and treat medical problems that may have contributed to the severe withdrawal state. The same general types of support needed for any patient with delirium should be used for the patient with withdrawal delirium, including helping to reorient the patient to time, date, and place, evaluating and treating the patient in a well-lit room, providing reassurance, performing frequent monitoring of vital signs, and ensuring adequate hydration. Care should be taken when administering glucose to avoid precipitating Wernicke’s encephalopathy or thiamine-related cardiomyopathies and to circumvent overhydration in patients who have temporary, alcohol-related, compromised cardiac functioning.

Q: What is the mainstay of pharmacologic treatment for delirium tremens?

A: The mainstay of the pharmacologic treatment of withdrawal delirium is depressants such as benzodiazepines. No single drug of this class has been shown to be superior to another. The doses needed to control agitation and insomnia vary dramatically among patients and can be prodigious (e.g., >2000 mg of diazepam in the first 2 days in some patients); this underscores the advisability of providing treatment in a hospital, preferably in an ICU. Alternative depressant-like drugs have been proposed for uncomplicated withdrawal, but data are lacking regarding their use in persons who have withdrawal delirium.

Table 3. Suggested Treatment of Alcohol Withdrawal Delirium (Delirium Tremens).

Abdominal Aortic Aneurysms

Posted by Carla Rothaus • November 28th, 2014

Rupture of an abdominal aortic aneurysm is associated with a high risk of death. Endovascular repair results in lower perioperative morbidity and mortality than open repair, but the two methods have similar long-term mortality. The latest Clinical Practice review on this topic comes from Dr. K. Craig Kent at the University of Wisconsin School of Medicine and Public Health.

Rupture of an abdominal aortic aneurysm is often lethal; mortality is 85 to 90%. Of those persons who reach the hospital, only 50 to 70% survive. Thus, the goal is to identify and treat aneurysms before they rupture.

Clinical Pearls

What are the risk factors for abdominal aortic aneurysm?

Nonmodifiable risk factors for abdominal aortic aneurysm include older age, male sex, and a family history of the disorder. Starting at 50 years of age for men and 60 to 70 years of age for women, the incidence of aneurysms increases significantly with each decade. The risk of abdominal aortic aneurysm is approximately four times as high among men as among women and four times as high among people with a family history of the disorder as among those without a family history. Smoking is the strongest modifiable risk factor. Other, less prominent risk factors for abdominal aortic aneurysm include hypertension, an elevated cholesterol level, obesity, and preexisting atherosclerotic occlusive disease.

What are the recommendations for screening for abdominal aortic aneurysms?

Ultrasonography is the primary method used for screening and is highly sensitive (95%) and specific (100%). CT scanning and magnetic resonance imaging (MRI) are expensive, incur risks (radiation exposure from CT and risks associated with intravenous contrast material), and should not be used for screening but rather reserved for preinterventional planning. The current recommendations of the U.S. Preventive Services Task Force are a one-time screening in men 65 to 75 years of age who have ever smoked (grade B recommendation) and selective screening in men 65 to 75 years of age who have never smoked (grade C recommendation). Medicare also covers screening for patients with a family history of abdominal aortic aneurysm. Data from nonrandomized studies suggest that there may be subgroups of women who benefit from screening; however, this finding has not been prospectively validated.

Morning Report Questions

Q: What are the indications for surgical repair of an abdominal aortic aneurysm?

A: Under most circumstances, aneurysms should not be prophylactically repaired unless they are at least 5.5 cm in diameter. Nevertheless, there are occasions when repair of small aneurysms should be considered. Symptomatic aneurysms should be immediately repaired. Pain in the abdomen, back, or flank is the most common symptom, but aneurysms can produce many other symptoms or signs (e.g., hematuria or gastrointestinal hemorrhage). The rate of growth is another important predictor of rupture; aneurysms that expand by more than 0.5 cm in diameter over a period of 6 months should be considered for repair regardless of the absolute size. The observations that aneurysms rupture at a smaller size in women than in men and that women have higher rupture-related mortality than men have led some experts to recommend a diameter of 5.0 cm as the threshold for elective intervention in women. Other factors that are associated with an increased risk of rupture and may prompt repair at a threshold of less than 5.5 cm include the presence of a saccular aneurysm (most aneurysms are fusiform) and a family history of abdominal aortic aneurysm.

Table 1. Annual Risk of Rupture of Abdominal Aortic Aneurysms.

Q: What surgical techniques are available for repair of an abdominal aortic aneurysm?

A: Two approaches to repairing aneurysms are currently available: open repair (performed since the 1950s) and endovascular repair (first performed in 1987). Endovascular repair, a less invasive approach, involves the intraluminal introduction of a covered stent through the femoral and iliac arteries; the stent functions as a sleeve that passes through the aneurysm sac, anchoring in the normal aorta above the aneurysm and in the iliac arteries below the aneurysm. To be eligible for endovascular repair, a patient must have appropriate anatomy, including iliac vessels that are of sufficient size to allow introduction of the graft and an aortic neck above the aneurysm that allows the proximal graft to be anchored without covering the renal arteries. Thus, with existing techniques, there are some infrarenal aneurysms that are not amenable to endovascular repair. The use of endovascular repair has grown steadily in the United States, and this procedure is currently performed in more than 75% of patients undergoing surgical intervention for abdominal aortic aneurysm, with a portion of the remaining patients having unsuitable anatomy. Endovascular repair confers an initial survival benefit; however, this benefit disappears over a period of 1 to 3 years. Endovascular repair and open repair are associated with similar mortality over the long term (8 to 10 years).

Figure 1. Techniques Available for Repair of Abdominal Aortic Aneurysms.

Figure 2. Annual Proportion of Elective Endovascular and Open Repairs for Abdominal Aortic Aneurysms in the United States, 2000-2012.

Atenolol versus Losartan in Children and Young Adults with Marfan’s Syndrome

Posted by Daniela Lamas • November 25th, 2014

When French pediatrician Antoine-Bernard Marfan first described the syndrome that would bear his name in 1896, doctors knew little about the management and prognosis of the connective tissue disorder.

In the century since that first description, what was once a fatal syndrome due to the risk of aortic dissection is now a condition that can be managed with proper care and follow-up. Two decades ago, a trial demonstrated that patients who were given beta blockade with propranolol had a lower rate of aortic enlargement than those given placebo, ushering in the beta blocker as a key component of therapy for those with Marfan’s.

More recently, basic science research into the pathogenesis of the disease has led to a new management strategy using angiotensin receptor blockade in lieu of beta blockade. Now, a study in this week’s issue of NEJM adds to this body of research, suggesting that one treatment modality might be no better than the other.

The science behind this trial dates back to the early 1990s, when researchers discovered that mutations in the gene encoding a protein called fibrillin-1 were responsible for Marfan’s syndrome. Fibrillin-1 is a structural component of elastic fibers in connective tissue, and also influences cell signaling activity through binding the protein TGF beta. Animal studies have provided evidence that excessive TGF beta signaling results in the clinical findings of Marfan’s, including aortic dilatation. This finding led to the question – could angiotensin receptor blockers (ARBs), which inhibit TGF beta signaling, reduce aortic dilatation in Marfan’s?

This hypothesis first led to mouse studies, which did in fact show a reduced rate of aortic enlargement in Marfan’s mice who received losartan, an ARB, compared to those who were given beta blockers or placebo. A small series of patients and then two clinical studies comparing a beta blocker-ARB combination to beta blockade alone came to similar conclusions.

With this background, R.V. Lacro and colleagues set out to determine whether losartan is more effective than beta-blockers in slowing aortic-root enlargement in Marfan’s syndrome. The investigators enrolled just over 600 patients with Marfan’s whose ages ranged from 6 months to 25 years old. The study participants were randomly assigned to receive either atenolol or losartan. They were followed over a 3-year period for the primary outcome, which was the rate of aortic-root enlargement. Investigators also monitored rates of aortic-root surgery, aortic dissection and adverse events.

Their findings were surprising, given the strong rationale for treatment with an ARB in this population. In all of the endpoints studied, the investigators found that losartan performed no better than atenolol. There was no significant difference between groups in the rate of aortic-root enlargement, nor in rates of surgery, dissection or death.

What to take from this study?  In an accompanying editorial, Juan Bowen and Heidi Connelly discuss certain limitations of the study design that might have masked the true benefit of losartan for Marfan’s syndrome and urge physicians, instead of casting aside losartan as a therapeutic option, to “wait and see.” First, the editorialists note, the study did not have a placebo group and thus, cannot address the question of whether both beta-blockade and angiotensin-receptor blockade might be equally effective. The study also did not assign patients to a combined beta and angiotensin receptor blockade group, which could have demonstrated synergistic effects. Additionally, the losartan dose might not have been sufficient to meet its goal – suppressing TGF beta signaling. Finally, the enrolled patients had “advanced aortic disease” as gauged by their aortic root dilation scores at young ages. Perhaps, they note, blocking TGF beta could work more effectively at earlier disease stage.

Despite the study’s limitations, Bowen and Connelly write that they expect these results to stimulate debate and further research into how best to treat patients with Marfan’s. They conclude, “Each step forward gives hope to those living with Marfan’s syndrome as they strive to live healthier, longer, and more productive lives.”

Testicular Cancer

Posted by Carla Rothaus • November 21st, 2014

The treatment of testicular cancer is a success story in oncology. With available methods, 95% of men with this condition can be cured. Emphasis is shifting toward maintaining high cure rates and reducing or effectively managing late effects of treatment.  A new review article on this topic comes from Dr. Nasser Hanna and Lawrence Einhorn at the Indiana University School of Medicine.

Fifty years ago, a diagnosis of metastatic testicular cancer meant a 90% chance of death within 1 year. Today, a cure is expected in 95% of all patients who have received a diagnosis of testicular cancer and in 80% of patients with metastatic disease.

Clinical Pearls

Describe the epidemiology and clinical presentation of testicular cancer.

In the United States, the incidence of testicular cancer, which is highest among whites and lowest among blacks, has increased steadily over the past 20 years. In some parts of northern Europe, the incidence has doubled, and in Denmark and Norway, 1% of men will receive a diagnosis of testicular cancer during their lifetime. Genetic and environmental factors appear to play a role in this increase in incidence. The risk of testicular cancer is 8 to 10 times as high in a brother of a person with testicular cancer and 4 to 6 times as high in a son of a person with testicular cancer as in a brother or son of an unaffected family member. Genetic disorders, including Down’s syndrome and the testicular dysgenesis syndrome, are also associated with increased risks of testicular cancer. Cryptorchidism, which occurs in 2 to 5% of boys born at term, is the most well-characterized risk factor for testicular cancer. The timing of orchiopexy influences the future risk of testicular cancer. However, 90% of persons with testicular cancer do not have a history of cryptorchidism. Recent investigations have shed light on the malignant transformation of normal gonocytes into germ-cell tumors. Germ-cell tumors appear to develop as a result of a tumorigenic event in utero that leads to a precursor lesion classified as intratubular germ-cell neoplasia. Most patients with testicular cancer receive a diagnosis when the disease is in stage I and present with a testicular mass. Less frequently, patients report back pain (secondary to enlarged retroperitoneal lymph nodes) or symptoms of metastatic disease, including cough, hemoptysis, pain, and headaches.

Table 1. Staging and Risk Stratification of Germ-Cell Tumors.

What is the treatment for Stage I and Stage II seminoma?

Most patients with clinical stage I seminoma are cured with orchiectomy. Adjuvant radiation therapy was standard treatment for many years and was instrumental to the cure before the advent of effective chemotherapy. Over the past 20 years, the dose and field of radiation have been considerably reduced, and in many instances radiotherapy has been eliminated altogether. Most patients today are treated with active surveillance, although some still receive radiation therapy consisting of 20 Gy to the ipsilateral retroperitoneal lymph nodes (sometimes including the inguinal lymph nodes, depending on whether the patient had undergone prior surgery involving the inguinal, pelvic, or scrotal areas) or adjuvant carboplatin therapy. More relapses are associated with surveillance than with radiotherapy or chemotherapy (20% vs. 4%), but the long-term survival is nearly 100%, irrespective of the initial option chosen. For some patients with low-volume stage II seminoma (disease confined to the retroperitoneal lymph nodes, with the lymph nodes <3 cm in diameter), 30 to 36 Gy of radiation to the paraaortic and ipsilateral iliac lymph nodes remains a standard treatment. In other patients, the preferred treatment is chemotherapy with bleomycin, etoposide, and cisplatin (also known as BEP) for three cycles or etoposide and cisplatin for four cycles. Chemotherapy is preferred for patients with bulkier disease, since the rate of relapse is higher with radiotherapy alone. Cures are achieved in 98% of patients.

Table 2. Treatment Options for Stage I Seminoma.

Morning Report Questions

Q: How are the nonseminiferous germ-cell tumors managed?

A: Most patients with a nonseminomatous germ-cell tumor present with clinical stage I disease. Treatment options after orchiectomy include active surveillance, nerve-sparing retroperitoneal lymph-node dissection, and adjuvant BEP for one or two cycles; each of these options is associated with 99% long-term cure rates. Patients are characterized as high risk (relapse rates of 50% with surveillance) or low-risk (relapse rates of 15% with surveillance) according to the presence or absence of lymphovascular invasion. Patients with a low-volume stage II nonseminomatous germ-cell tumor (disease confined to the retroperitoneal lymph nodes, with the lymph nodes <3 cm in diameter) and normal beta-hCG [beta human chorionic gonadotropin] and AFP [alpha-fetoprotein] levels after orchiectomy are generally treated with retroperitoneal lymph-node dissection, although care must be individualized. Patients with higher-volume stage II disease or increasing levels of markers should receive chemotherapy (BEP for three cycles or etoposide and cisplatin for four cycles). Cures are achieved in 95 to 99% of patients.

Table 3. Treatment Options after Orchiectomy for Stage I Nonseminomatous Germ-Cell Tumor.

Q: What are long-term risks of treatment for a patient with testicular cancer?

A: Since most patients will survive after a diagnosis of testicular cancer, clinicians must be vigilant to reduce the long-term risks of therapy and limit unnecessary morbidity and early mortality. Therapeutic radiation has been recognized as a risk factor for secondary cancers. However, studies also implicate chemotherapy in the risk of cancers of the kidney, thyroid, soft tissue, bladder, stomach, and pancreas, as well as in the risk of lymphoma and leukemia. Survivors of testicular cancer are also at risk for later relapse of disease (defined as relapse >2 years after remission), as well as for the metabolic syndrome; cardiovascular disease; infertility; neurotoxic, nephrotoxic, and pulmonary toxic effects; Raynaud’s phenomenon; psychosocial disorders; and hypogonadism, which may confer a predisposition to sexual dysfunction, fatigue, depression, and osteoporosis. Retrograde ejaculation may develop postoperatively in men who have undergone retroperitoneal lymph-node dissection. The most comprehensive study to date is under way to understand the genetic susceptibility to the long-term toxic effects of platinum-based chemotherapy in survivors of testicular cancer.

Glycemic Control in Type 1 Diabetes

Posted by Carla Rothaus • November 21st, 2014

In a new study, patients with type 1 diabetes and a glycated hemoglobin level of 6.9% or lower (≤52 mmol per mole) were found to have a risk of death from any cause or from cardiovascular causes that was twice as high as that for matched controls.

The excess risks of death from any cause and from cardiovascular causes in patients with diabetes who have varying degrees of glycemic control, as compared with the risks in the general population, have not been evaluated. This study undertook an evaluation using the Swedish National Diabetes Register, which includes information on glycemic control for most adults with type 1 diabetes in Sweden.

Clinical Pearls

Why is glycemic control important for patients with type 1 diabetes?

Type 1 diabetes is associated with a substantially increased risk of premature death as compared with that in the general population. Among persons with diabetes who are younger than 30 years of age, excess mortality is largely explained by acute complications of diabetes, including diabetic ketoacidosis and hypoglycemia; cardiovascular disease is the main cause of death later in life. Improving glycemic control in patients with type 1 diabetes substantially reduces their risk of microvascular complications and cardiovascular disease. Accordingly, diabetes treatment guidelines emphasize good glycemic control, which is indicated by the glycated hemoglobin level, a measure of the mean glycemic level recorded during the preceding 2 to 3 months. Although a target level of less than 7.0% (53 mmol per mole) is generally recommended and is considered to be associated with a lower risk of diabetic complications, as compared with higher levels, in two national registries, only 13 to 15% of patients with type 1 diabetes met this target, whereas more than 20% had very poor glycemic control (i.e., a glycated hemoglobin level >8.8%, or greater than or equal to 73 mmol per mole).

What is the risk of all-cause and cardiovascular mortality at different levels of HbA1c?

This nationwide Swedish study of 33,915 patients with type 1 diabetes and 169,249 controls matched for age and sex shows that for patients with type 1 diabetes who had on-target glycemic control, the risk of death from any cause and the risk of death from cardiovascular causes were still more than twice the risks in the general population. Analyses of outcomes within the group of patients with diabetes showed that the risk of death from any cause and the risk of death from cardiovascular causes increased incrementally with higher updated mean glycated hemoglobin levels. The hazard ratio for death from any cause among patients with diabetes was 2.36 (95% CI, 1.97 to 2.83) at an updated mean glycated hemoglobin level of 6.9% or lower and increased to 8.51 (95% CI, 7.24 to 10.01) for a level of 9.7% or higher (greater than or equal to 83 mmol per mole). For death from cardiovascular causes, the corresponding hazard ratios ranged from 2.92 (95% CI, 2.07 to 4.13) to 10.46 (95% CI, 7.62 to 14.37).

Table 2. Mortality among Patients with Type 1 Diabetes as Compared with Controls According to Baseline Level of Glycated Hemoglobin.

Table 3. Adjusted Hazard Ratios for Death from Any Cause and Death from Cardiovascular Causes among Patients with Type 1 Diabetes versus Controls, According to Time-Updated Mean Glycated Hemoglobin Level and Renal Disease Status, Model 3.

Morning Report Questions

Q: How does the risk of all-cause or cardiovascular mortality differ by gender or change over time?

A: As compared with men, women with type 1 diabetes had a significantly greater excess risk of death from cardiovascular disease but not of death from any cause. The excess risk of death associated with diabetes did not diminish over time, with increases during the last 7 calendar years of the study (2005 through 2011) that were similar to those during the first 7 years (1998 through 2004).

Figure 1. Hazard Ratios for Death from Any Cause and for Death from Cardiovascular Causes According to Age and Sex among Patients with Type 1 Diabetes versus Controls.

Q: Is there an explanation for the increased risk of all-cause and cardiovascular mortality in type 1 diabetes patients with HbA1c less than or equal to 6.9%?

A: Unlike patients with type 2 diabetes, those with type 1 diabetes generally do not have excess rates of obesity, hypertension, or hypercholesterolemia; thus, the increased risks of death from any cause and of death from cardiovascular causes among patients with type 1 diabetes who have good glycemic control is unexplained. In this study, beginning with the year 2005, patients with type 1 diabetes were four to five times as likely as controls to receive a prescription for statins or renin-angiotensin-aldosterone system inhibitors. Thus, the omission of currently recommended cardioprotective treatment cannot explain the remaining excess risk of death; determination of the underlying reasons will require further research.

Ask the Authors: Ebola in Well-Resourced Settings

Posted by Karen Buckley • November 20th, 2014

The physicians who treated patients with Ebola in Atlanta and Hamburg are now answering your questions on the NEJM Group Open Forum.

Two recent NEJM Brief Reports provide detailed clinical information about three patients with Ebola virus disease who were transferred from West Africa to the United States or Germany in the midst of their illness. While most cases occur in areas where tragically few resources are available to care for affected patients, these reports afford us the opportunity to observe the course of illness in a well-resourced health care setting. The cases highlight the importance of intensive fluid management during the course of the illness. Authors of both reports are answering questions about what this means for treating patients as the epidemic continues and more cases present to well-resourced settings.

The NEJM Group Open Forum is publicly available for all to view, but in order to comment you must register with Medstro and be a physician. This discussion is open until Wednesday, November 26.

Join the discussion now!

Mortality in Type 1 Diabetes

Posted by Joshua Allen-Dicker • November 19th, 2014

There are moments during every physician’s day when she or he gives medical advice based on well-established evidence– “The data show that starting medication A for this disease will reduce the risk of death by 20%.”   There are also moments when she or he may give advice just because it seems like the right thing to do, though evidence may be lacking– “It makes sense that using medication B might help in the treatment of this disease.” Sometimes advice based on common sense or medical tradition turns out to be misguided (e.g., bed rest for back pain, niacin for atherosclerotic vascular disease). And sometimes advice that makes sense is spot-on correct, as shown by a paper published in this week’s issue of NEJM, “Glycemic Control and Excess Mortality in Type 1 Diabetes Mellitus, “ by Lind and colleagues.

According to a recent Centers for Disease Control and Prevention report, each year over 18,000 people in the United States are diagnosed with type 1 diabetes (T1D). People with T1D are at increased risk for both microvascular complications (e.g., neuropathy, nephropathy) and macrovascular complications (e.g., coronary disease, stroke), as well as morbidity associated with these conditions. As above, it might make sense that better glycemic control, as measured by a lower hemoglobin A1c level, would be associated with improved outcomes for these disease states. However, unlike prior research that has demonstrated a clear association between lower HbA1c levels and improved outcomes from microvascular complications, the relation between mortality and glycemic control has remained less well defined.

Lind and colleagues describe a prospective cohort study of patients with T1D who were enrolled in Sweden’s National Diabetes Registry. For each person with diabetes enrolled in the study, the study also included 5 matched controls from Sweden’s general population. Participants were followed from enrollment until death or study completion. Outcome data collected for all participants included date of death (if it occurred) and relevant associated diagnoses. Data collected specifically for participants with T1D included albuminuria status, kidney function, and updated mean HbA1c level. Cox regression models were used to compare outcomes between persons with T1D and the matched controls.

Between 1996 and the end of 2011, 33,915 patients with T1D and 169,249 controls were enrolled in the study. In their subsequent analyses of these populations, Lind et al. found that persons with poor glycemic control (HbA1c ≥9.7%) had 8-10 times the risk of mortality compared to the control population, and significantly higher mortality than persons with T1D who had appropriate glycemic control.

At first glance, the results of Lind et al. are no surprise—better glycemic control can improve outcomes in T1D.  However, Lind also provides us with humbling data. First, while the risk of mortality in T1D appears to be modifiable and dependent on adequate glycemic control, our progress in improving T1D outcomes may have stalled over the last two decades.  In comparing study time periods (1998-2004 cf. 2005-2011), there was no significant improvement in excess mortality risk for the T1D population.  Additionally, the authors found that even when the glycemic control of persons with T1D was appropriate (updated mean HbA1c ≤ 6.9%), they still had twice the risk of mortality as compared to the control population.

As clinicians these results may leave us wondering: what can we do to help improve outcomes in T1D?  We know there has been an historical gap between guidelines and the actual quality of care patients receive–only 13-15% of persons with T1D reach their HbA1c goal.  Similar data exist for other diabetes quality metrics.  Innovation in patient engagement, quality improvement projects around guideline adherence and identification of additional outcomes metrics may be appropriate starting places for our collective efforts.

On top of this we should ask, if appropriately controlled T1D still carries an increased risk of mortality, what are we missing?  Continued research on insulin replacement strategies (e.g. the bionic pancreas) and mitigation of the end-organ effects of diabetes is needed.

After reading Lind et al., we may feel inclined to congratulate ourselves–our clinical intuition was correct after all.  However, by strengthening the known association between glycemic control and mortality, Lind and colleagues have sounded an important warning: clinicians and researchers still have much progress to make in improving our understanding of T1D and the quality of care we provide each day.