Shelia Hellman said on our Facebook page, “When I was an intern, it was a registered nurse in the ICU who calmly talked me through my first code blue and intubation. I was the only doctor in the house on nights, new to being a doctor, and had to words to adequately express my gratitude for that nurse’s knowledge and calm attitude.”

And Njemanze Ebubechukwu, M.D., said, in part, on our 200^th anniversary site,

“Humility was a watchword which the nurse on duty on my first day at work encouraged me to uphold despite any accolades or pitfalls I may encounter in my internship year.”

All physicians have learned important lessons from the nurses who share our role in caring for patients. We’re asking you to share your story. Read the responses received so far and submit your own.

(Image: A portrait of Florence Nightingale during the Crimean War, ministering to soldiers at Scutari. Credit: Public domain image via the History of Medicine, U.S. National Library of Medicine, NIH)

The development of cutaneous pain in a patient with a preexisting skin disorder should immediately raise the possibility of KVE, also known as dermatitis herpeticum or eczema herpeticum. In this disorder, a viral infection, usually caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), is superimposed on inflamed skin, typically atopic dermatitis, although other viruses may cause the same syndrome and other dermatoses may be infected.

Clinical Pearls

• What are the classic findings in KVE ?

The classic initial cutaneous manifestation of KVE is monomorphic vesicles that become pustular, often with a hemorrhagic and erosive component at later stages; erosions appear to be punched out or well demarcated, as seen in our patient. The erosive lesions tend to coalesce, creating large lesions with scalloped borders. Fever, malaise, and lymphadenopathy are often present. KVE can rapidly become fatal; in suspected cases, immediate treatment with intravenous acyclovir must be instituted.

Figure 1. Clinical Photographs of the Patient’s Skin.

• What viral infections are associated with the development of KVE?

Herpes simplex virus (HSV-1 and HSV-2) is most commonly associated with the development of KVE. However, infections with viruses other than HSV may be causative. The two most common are vaccinia virus and coxsackievirus A16. The U.S. military began a smallpox vaccination program in 2002 using the vaccinia virus; patients with atopic dermatitis are excluded from vaccination because of their risk of KVE. Despite this precaution, accidental exposures of persons with atopic dermatitis to recently vaccinated persons have occurred. Hand, foot, and mouth disease, caused by coxsackievirus A16, occurs most commonly in children. Disseminated skin disease after the initial distal vesicular eruption, with features characteristic of KVE, has been reported in a child with atopic dermatitis.

Morning Report Questions

Q: What are the predisposing skin conditions associated with the development of KVE?

A: The development of KVE is more likely in individuals with atopic dermatitis than in those with other inflammatory skin disorders. This predisposition is attributed both to abnormalities in the immune system and to defects in the barrier function of the epidermis that render such persons more susceptible to infection. Other conditions that have been described as substrates for the development of KVE include psoriasis, seborrheic dermatitis, rosacea, tinea cruris, Grover’s disease (transient acantholytic dermatosis), cutaneous T-cell lymphoma, pemphigus foliaceous, Darier’s disease (follicular keratosis), laser resurfacing, ichthyosis, pityriasis rubra pilaris, contact dermatitis, and burns.

Q: How is KVE diagnosed?

A: The diagnosis of KVE can be made by Tzanck testing of vesicular fluid, direct fluorescent antibody staining of vesicular fluid, or viral culture. Most rapid are the bedside Tzanck test and direct fluorescent antibody testing. In the erosive stage, culture of the vesicular fluid is most reliable for making a diagnosis, but this takes days. If the diagnosis of KVE is suspected, it is imperative to initiate treatment while awaiting culture results.

Certification to perform catheter-based interventions for coronary artery disease was originally limited to hospitals that had the capability to perform cardiac surgery on site. However, there has been a progressive worldwide trend to allow percutaneous coronary intervention (PCI) to be performed without on-site surgical backup.

Clinical Pearls

• Which factor had the greatest effect on decreasing the rate of emergency surgery resulting from angioplasty?

Increasing operator experience, improvements in technique, and major advances in technology and pharmacology contributed to steep reductions in the incidence of emergency surgery after PCI. Coronary stents had by far the greatest effect. Studies that were conducted after stents began to be used routinely showed an incidence of emergency surgery of 0.14% at the Cleveland Clinic and 0.3% at the Mayo Clinic. These figures represent decreases by a factor of 10 from historical results.

• How do outcomes compare for primary PCI in hospitals with and without the capability for on-site cardiac surgery?

Numerous studies have now shown that the safety outcomes (short-term mortality and need for emergency surgery) and efficacy outcomes (procedural success and longer-term rate of survival) of primary PCI are similar in hospitals with and those without the capability for on-site cardiac surgery. The risk (delayed access to emergency surgery for a small subgroup of patients) as compared with the substantial benefit (wider availability of timely reperfusion) appears to justify allowing primary PCI to be performed at centers that do not have the capability for cardiac surgery, at least when stringent structural and procedural requirements are met.

Morning Report Questions

Q: How do outcomes compare for elective PCI in hospitals with and without the capability for on-site cardiac surgery?

A: The overall feasibility and safety of elective PCI without on-site cardiac surgical backup have now been assessed in multiple observational studies, analysis of preliminary results from a recent randomized trial, and a large meta- analysis. These findings suggest that the results of nonemergency PCI are similar at sites with and at sites without on-site cardiac surgical backup, although more definitive, longer-term, randomized comparisons are forthcoming. The authors caution that despite the apparent safety and efficacy of nonemergency PCI performed at sites that do not have the capability for on-site surgery, this arrangement may result in less thorough consideration of alternative revascularization strategies than might be the case at sites that do have on-site cardiac surgery.

Q: What are current professional society guidelines with respect to PCI and the availability of on-site cardiac surgery?

A: Primary PCI without on-site surgical backup has carried a class IIb recommendation from the American College of Cardiology Foundation/American Heart Association and Society for Cardiovascular Angiography and Intervention for some time. The 2011 guidelines for the first time provided a class IIb (level of evidence B) recommendation for elective PCI in institutions without the capability for on-site cardiac surgery. These guidelines also mandate stringent criteria for such programs, including specific structural characteristics of the hospital and catheterization laboratory, the presence of experienced personnel, and the availability of PCI around the clock; volume standards; a formal relationship with a tertiary care center; regularly tested transfer protocols that ensure timely access of patients to the operating room when necessary; informed consent regarding the lack of on-site backup; explicit criteria regarding patient selection and the characteristics of the lesions; and participation in a local and national quality-monitoring program.

True randomization remains elusive, but in “Reproductive Technologies and the Risk of Birth Defects,” Davies et al of the Robinson Institute in Australia present data from the largest registry to-date, further untangling some of these complicated associations. In this population-wide cohort study, the authors compared over 6000 births from assisted reproductive technology with some 300,000 unassisted conceptions to assess associated rates of birth defects. The following types of births were compared: births from each mode of infertility treatment, births as a result of unassisted conception among women who required assisted reproductive technology previously, births to women with a history of infertility who had not received reproductive technology and births to women with neither a history of infertility nor treatment.

What did they find? The risk of a birth defect appeared significantly higher in pregnancies conceived using either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), as compared with unassisted births, with an adjusted odds ratio of 1.28. Various types of congenital defects were assessed for their association with assisted reproduction. Assisted conception was associated with an increased rate of any defect and multiple defects, as well as with cardiovascular, urogenital, gastrointestinal abnormalities, and cerebral palsy.  It should be noted that there were also differences, such as in age, race, and medical conditions including diabetes and pregnancy-induced hypertension, between mothers who required assisted reproduction and those who didn’t; after adjustment for such factors IVF was no longer associated with a higher rate of birth defects, although there was still an increased risk (albeit attenuated) associated with ICSI.

What to make of these data? In the absence of randomization, these results must be interpreted with caution, as potential confounders remain. In this specific case, paternal data were unavailable, raising the question of whether the residual risk that remained was related to parental factors, rather than to the ICSI itself. Furthermore, an increased risk of birth defects was also found among women with prior infertility without assisted reproductive technology, again suggesting that parental factors may be contributing, as opposed to the technology. Moreover, it is important to note that the absolute magnitude of the risk increases seen with assisted reproductive technologies was modest. The risk of any birth defect was 8.3% for those who received assisted technology, versus 5.8% for those who conceived without assistance.

That said, patient counseling should likely note the presence of a persistent association between IVF and birth defects, despite controlling for maternal factors known to cause birth defects. More importantly, as far as identification of problems that are “actionable,” the possibility of a more elevated risk of ICSI warrants further investigation, as this may be an approach couples ultimately choose when clearly needed for conception.

Ultimately, these data don’t deliver answers that are as definitive as we would like. However, given the virtual impossibility of randomized trials with this particular cohort, these may be the best answers we will ever get.

In patients with low-risk thyroid cancer, it is unclear whether the administration of radioiodine provides any benefit after a complete surgical resection, and radioiodine is not recommended in patients with disease that is categorized as consisting of a tumor less than 1 cm in diameter and clinical stage N0. Therefore, radioiodine should be used with great care in order to minimize harm, administer the minimal amount of activity, and involve the best-tolerated methods.

Clinical Pearls

• Why is radioiodine administered to patients with thyroid cancer after total thyroidectomy?

Radioiodine (131I) is administered to patients with thyroid cancer after total thyroidectomy for three reasons: first, to eradicate normal-thyroid remnants (ablation) to obtain an undetectable serum thyroglobulin level; second, to irradiate any neoplastic focus to decrease the risk of recurrence; and third, to perform a 131I total-body scan to detect persistent carcinoma. Successful ablation is defined by the combination of undetectable serum thyroglobulin levels after thyrotropin stimulation and normal results on neck ultrasonography 6 to 12 months after 131I administration.

• What are the two methods used for thyrotropin stimulation prior to the administration of radioactive iodine for ablation?

The two methods used for thyrotropin stimulation are the use of recombinant human thyrotropin and thyroid hormone withdrawal. Each is administered after surgery and before radioiodine administration. The method used is a matter of debate. The use of recombinant human thyrotropin maintains quality of life, is cost-effective, and reduces the radiation dose delivered to the body as compared with the amount delivered with thyroid-hormone withdrawal. Recombinant human thyrotropin and thyroid-hormone withdrawal provide similar ablation rates when a radiation activity of 3.7 GBq is administered. Furthermore, whether the 3.7-GBq dose is necessary has been questioned.

Morning Report Questions

Q: What were the primary results of this study, which compared different doses of postoperative radioactive iodine in patients with low-risk thyroid cancer?

A: The primary outcome of this study was thyroid ablation. Ablation was assessed at a mean (+/-SD) of 8+/-2 months after radioiodine administration with the use of neck ultrasonography and determination of the level of recombinant human thyrotropin-stimulated serum thyroglobulin or a diagnostic 131I total-body scan in patients with detectable antithyroglobulin antibody. For the 684 patients who could be evaluated in this study, a follow-up study was performed between 6 and 10 months (average, 8.3+/-1.6 months) after 131I administration, and no significant difference was found between the 1.1-GBq group and the 3.7-GBq group.

Q: What were the findings in this study with respect to use of thyroid hormone withdrawal versus recombinant human thyrotropin prior to radioactive iodine?

A: The proportion of patients with symptoms of hypothyroidism was significantly higher in the groups undergoing thyroid-hormone withdrawal than in the groups receiving recombinant human thyrotropin. Thyroid-hormone withdrawal was associated with deterioration of the quality of life, as compared with recombinant human thyrotropin. Radioiodine may induce lacrimal and salivary-gland disturbances, depending on the amount of radioactivity administered. The incidence of salivary problems did not differ significantly between groups, but lacrimal dysfunction (runny eyes) was more frequent among patients undergoing thyroid-hormone withdrawal along with low (19%) or with a high (25%) 131I activity than among patients receiving recombinant human thyrotropin (10%).

It is important to consider a broad differential diagnosis for wheezing, especially when findings are atypical for asthma or when symptoms fail to subside as expected in response to conventional therapy. This case highlights the importance of measuring lung function both when attempting to confirm (or rule out) a diagnosis of asthma if it is suspected and when adjusting medications in patients with established asthma.

Clinical Pearls

• What is the differential diagnosis of a patient who presents with a cough and wheezing?

Recurrent episodes of shortness of breath, cough, and wheezing suggest a diagnosis of asthma. Nocturnal worsening of symptoms is consistent with this diagnosis. Atypical features, opening the possibility of alternative diagnoses, would be a late age at onset and the absence of identifiable triggers for the symptoms. Other potential causes include recurrent respiratory tract infections, gastroesophageal reflux with microaspiration of gastric contents, and congestive heart failure, including that resulting from valvular heart disease or diastolic dysfunction, which may cause “cardiac asthma.”

• How does aspirin-associated respiratory disease present?

Aspirin-exacerbated respiratory disease often presents in adulthood with a characteristic sequence of recurrent sinusitis, followed by the development of asthma and then the recognition of exacerbations of asthma precipitated by ingestion of aspirin or any other cyclooxygenase-1 inhibitor.

Morning Report Questions

Q: How does one make the diagnosis of tracheomalacia?

A: The diagnosis of tracheomalacia may be made with the use of fiberoptic bronchoscopy, but the speed of image collection on modern multidetector CT equipment makes chest CT a useful alternative means of diagnosis. Images should be obtained during inspiration and expiration and then compared. For images collected during expiration, the goal is to maximize the abnormal movement of the posterior tracheal wall (or any other malacic portion of the wall). The best time to obtain the image is near but not at the end of exhalation, when the pleural pressure is still positive. Precise criteria for radiographic diagnosis of tracheomalacia have not yet been defined, but many radiologists use a luminal narrowing of 50% on exhalation as a benchmark.

Q: What is the most common cause of tracheomalacia?

A: In adults, the most common cause of tracheomalacia is prolonged mechanical ventilation; high pressures in the endotracheal tube cuff may cause localized ischemic injury to the tracheal wall (the cartilage and the membranous sheath). Other causes of segmental tracheomalacia include prolonged external pressure on the tracheal wall, such as may be caused by a large substernal goiter or a congenital vascular sling (e.g., a right-sided aortic arch with an aberrant subclavian artery). More diffuse tracheomalacia is encountered in patients with the rare conditions of tracheobronchomegaly (Mounier-Kuhn syndrome) and relapsing polychondritis.

There are several compelling reasons, then, to use the lowest possible effective dose of radioiodine.  But currently there is no consensus on what that dose should be.

This week, NEJM publishes the results of two large prospective trials comparing the efficacy of low-dose and high-dose radioiodine ablation.  Both trials found no significant difference between the two doses in the rate of successful ablation achieved.  One study, by Mallick et al., was conducted in the U.K. and enrolled 438 patients with thyroid cancer of tumor stages T1 to T3, with possible lymph node involvement but no distant metastases.  Patients were randomized to receive either low-dose radioiodine (1.1 GBq [30 mCi]) or high-dose radioiodine (3.7 GBq [100 mCi]) following surgery.  The primary endpoint was the success rate of ablation, defined as a negative scan and thyroglobulin level of less than 2 ng/ml at 6 to 9 months.

The authors found that ablation was similarly successful in the two groups (85% in the low-dose group versus 88.9% in the high-dose group; P=0.24). There was a significant difference, however, in the duration of hospital isolation.  Nearly 40% of patients in the low-dose group only required one day of hospital isolation, as compared to 7.1% of those in the high-dose group; conversely, more than 36% of patients in the high-dose group had to remain hospitalized for three or more days, as compared to 13% of those in the low-dose group (P<0.001 for both comparisons).  Length of hospital stay was based on an assessment of radiation risk and clinical condition.

In addition to a shorter isolation period, treatment with the low dose resulted in a lower rates of adverse events such as neck pain and nausea as compared to treatment with the high dose (21% versus 33%; P=0.007).

Schlumberger et al. report similar results from a study conducted in France.  More than 750 patients with stage T1 or T2 tumors were randomized to receive treatment with either low- or high-dose radioiodine, and ablation success rates were assessed at 8 months.  Again, there was no notable difference in success rates between the two groups.

These studies also examined various ways to stimulate radioiodine uptake in preparation for ablation.  Both studies found no difference between withdrawing thyroid suppression and using thyrotropin stimulation.

In an accompanying editorial, Drs. Erik K. Alexander and P. Reed Larsen of the Division of Endocrinology at Brigham and Women’s Hospital raise the question of whether radioiodine ablation should be used at all for low-risk patients.  “Using ¹³¹I to achieve effective ablation…must be weighed against increasing the risk of second primary cancers and the expense and logistics of ¹³¹I administration,” they observe; “many would argue that persistent local or metastatic disease would likely be identified by elevations in serum [thyroglobulin] during initial assessment and/or subsequent follow-up, allowing for treatment modification.”

For the cases in which radioiodine ablation is indicated, however, the results of these two studies promise to change standard practice.  And by reducing the dose of radioiodine – and therefore the physical, psychological, and financial costs associated with its use – such a change may be an important step toward more discriminating treatment of an increasingly common disease.

In your current practice, how do you assess the tradeoffs of radioiodine ablation for patients of different risk profiles?  How will the findings of these studies affect your approach to treating thyroid cancer?

When NEJM was founded in 1812, medical knowledge was limited. We had no understanding of infectious disease. Surgery was unsanitary and performed without anesthesia. Cancer was unrecognized, in part because so few people lived long enough to develop it.

The first part of the film, “From Rough to Refined: The Rise of Surgery,” takes the viewer from the first public demonstration of ether anesthesia in 1846 to a modern-day operating room, where Dr. Atul Gawande performs a thyroidectomy.

With the global prevalence of type 2 diabetes now expected to hit nearly 10 percent of the world’s population by 2030, the need for new strategies to help patients achieve glycemic control has never been greater. Diabetes has traditionally been perceived as a medical disease, managed with insulin and oral hypoglycemics. However, two studies published in this week’s issue of NEJM report that bariatric surgery – pioneered as a last-ditch effort for weight loss in obese patients – may improve glycemic control more successfully than medication alone.

Both single-center studies compared methods of bariatric surgery to intensive medical therapy for glycemic control in obese patients with poorly controlled diabetes.

In one study, reported by Philip Schauer and colleagues, 150 patients were randomly assigned to either intensive medical therapy for diabetes or medication plus either a Roux-en-Y gastric bypass or sleeve gastrectomy. These were mainly obese patients, with a BMI between 27 to 43 and an average HgbA1C level of 9.2%. While all three groups showed improved glycemic control, those who were randomly assigned to surgery were much more likely to have reached the target HgbA1C goal of 6% or less by 12 months of follow-up. Only 12% of those receiving medical treatment reached this goal, compared to 42% in the gastric-bypass group, and 37% in the sleeve gastrectomy group.

Not surprisingly, weight loss was greater in the surgical than the medical therapy group. However, those who received a bariatric intervention were also less likely to need diabetic medications, lipid-lowering agents, or anti-hypertensive meds by the study’s end.

Four patients in the surgical group suffered complications requiring reoperation, though there were no deaths or complications that were considered life-threatening.

Interestingly, this striking effect of bariatric surgery on glucose control appeared to go beyond the benefits of weight loss itself, according to the authors of an accompanying study.

Geltrude Mingrone and colleagues randomized 60 patients with a BMI greater than 35 and poorly controlled diabetes to receive either conventional medical therapy, a Roux-en-Y gastric bypass, or biliopancreatic diversion. Their endpoint was “diabetes remission,” defined as fasting plasma glucose less than 100 mg per deciliter and a HgbA1C of less than 6.5% without active pharmacologic therapy. Seventy-five percent of patients in the gastric-bypass group and 95% of those with a biliopancreatic diversion reached this goal.  None of the patients assigned to medical therapy met this endpoint of diabetes remission.

Weight loss appears not to be the only mechanism by which diabetes improves in this population. In fact, the authors found no correlation between normalization of fasting glucose and the weight loss achieved after the surgical intervention.  This suggests, Mingrone and colleagues write, that the surgery itself may be affecting insulin sensitivity beyond the changes in weight.

Will these studies usher in bariatric surgery as part of the regimen for diabetes?

In an accompanying editorial Paul Zimmet from Melbourne and K. George Alberti  from London note that  the International Diabetes Federation has  issued a position statement recognizing bariatric surgery as a treatment for obese patients with hard-to-control diabetes.   But important questions still remain: How long do the positive effects of bariatric surgery last? Are there unforeseen side-effects of the surgical procedures? And, finally, when should physicians start considering bariatric surgery for their diabetic patients?

The growing incidence of obesity and type 2 diabetes mellitus globally is widely recognized as one of the most challenging contemporary threats to public health. Uncontrolled diabetes leads to macrovascular and microvascular complications, including myocardial infarction, stroke, blindness, neuropathy, and renal failure in many patients. Despite improvements in pharmacotherapy, fewer than 50% of patients with moderate-to-severe type 2 diabetes actually achieve and maintain therapeutic thresholds, particularly for glycemic control.

Clinical Pearls

• What was the goal of intensive medical therapy in this study?

The goal of medical management was modification of diabetes medications until the patient reached the therapeutic goal of a glycated hemoglobin level of 6.0% or less or became intolerant to the medical treatment. All patients were treated with lipid-lowering and antihypertensive medications, according to American Diabetes Association guidelines, with the following targets: systolic blood pressure, 130 mm Hg or less; diastolic blood pressure, 80 mm Hg or less; and low-density lipoprotein cholesterol, 100 mg per deciliter (2.6 mmol per liter) or less.

• What were the primary results of this study, which compared intensive medical therapy to surgical therapy to achieve control of diabetes?

At 12 months, mean levels of glycated hemoglobin and fasting plasma glucose were significantly lower in the two surgical groups (gastric bypass and sleeve gastrectomy) than in the medical-therapy group (P<0.001 for both comparisons).

Morning Report Questions

Q: What differences were noted between the two surgical groups?

A: The target glycated hemoglobin level of 6.0% or less at 12 months occurred in 21 of 50 patients (42%) in the gastric- bypass group (P=0.002) and 18 of 49 patients (37%) in the sleeve-gastrectomy group (P=0.008). There were no significant differences in the primary end point between the two surgical groups (P=0.59). However, all patients in the gastric-bypass group who achieved the target glycated hemoglobin level did so without medications, whereas 5 of 18 patients (28%) in the sleeve-gastrectomy group required the use of one or more glucose-lowering drugs.

Q: How did adverse events compare between the three groups?

A: Additional surgical interventions were required in four patients, including laparoscopic procedures for blood-clot evacuation, assessment of nausea and vomiting, and cholecystectomy after gastric bypass and jejunostomy for feeding access to treat a gastric leak after sleeve gastrectomy. There were no deaths, episodes of serious hypoglycemia requiring intervention, malnutrition, or excessive weight loss among the three groups. Adverse events requiring hospitalization occurred in 11 (22%) of the gastric bypass patients, 4 (8%) of the sleeve-gastrectomy patients and 4 (8%) of the intensive medical-therapy group.