Pioglitazone after Ischemic Stroke

Posted by Carla Rothaus • April 8th, 2016

2016-04-01_11-30-19The thiazolidinedione class of peroxisome proliferator–activated receptor γ (PPAR-γ) agonists are among the most potent insulin-sensitizing drugs available. One medication in this class, pioglitazone, may reduce the risk of cardiovascular events, including stroke, in patients with type 2 diabetes, for whom the drug is currently approved as a glucose-lowering agent. Kernan et al. designed the multicenter, double-blind Insulin Resistance Intervention after Stroke (IRIS) trial to test the hypothesis that pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or transient ischemic attack (TIA) in patients without diabetes who have insulin resistance.

In this trial in nondiabetic patients with insulin resistance and a recent ischemic stroke or transient ischemic attack, pioglitazone was associated with a lower risk of stroke and MI than was placebo but with a higher risk of weight gain, edema, and bone fracture. A new Original Article summarizes.

Clinical Pearl

• Insulin resistance is present in what percentage of patients without diabetes who have had an ischemic stroke or a TIA?

Insulin resistance is nearly universal in patients with type 2 diabetes but is also present in more than 50% of patients without diabetes who have had an ischemic stroke or a TIA. Treatment of insulin resistance represents a potential new preventive strategy that could be added to standard care after ischemic stroke or TIA.

Clinical Pearl

• Does pioglitazone reduce the rate of new stroke or myocardial infarction in patients without diabetes who have already had an ischemic stroke or TIA?

In the study by Kernan et al., the primary outcome was a first fatal or nonfatal stroke or fatal or nonfatal myocardial infarction. In the study, the rate of the primary outcome was lower among patients who received pioglitazone than among those who received placebo. The incidence of a new diagnosis of diabetes was also lower with pioglitazone.

Table 2. Primary and Secondary Outcomes.

Figure 1. Primary Outcome.

Morning Report Questions

Q: What adverse effects are associated with pioglitazone?

A: Weight gain with PPAR-γ agonists, such as pioglitazone, reflects an increase in adipose tissue mass and a tendency for fluid accumulation owing to renal sodium retention. Sodium retention, if unchecked, can also increase the risk of heart failure. In the IRIS trial, patients in the pioglitazone group had more weight gain, edema, and shortness of breath than did patients in the placebo group. However, the authors did not observe a greater incidence of heart failure in the pioglitazone group than in the placebo group, which was probably because the study excluded patients with a history of heart failure and used safety algorithms that triggered dose reduction for excessive weight gain or edema. Pioglitazone has also been associated with an increased risk of bone fracture. In the IRIS study, rates of serious bone fracture (i.e., requiring hospitalization or surgery) were higher in the pioglitazone group than in the placebo group, which were reported in 99 patients and 62 patients, respectively (5.1% vs. 3.2%, P=0.003).

Q: Did the study by Kernan et al. support a possible link between pioglitazone and an increased risk of bladder cancer?

A: Observational research conducted in 2011 and 2012 suggested that pioglitazone may increase the risk of bladder cancer. However, more recent studies showed no significant association for any dose or duration of therapy. Other research suggests that PPAR-γ agonists might prevent certain cancers. Although the study by Kernan et al. did not observe a significant effect of treatment on the incidence of total or any specific cancer, the study was not powered to address these questions.

Table 3. Adverse Events, According to Severity.

A Deficient Diagnosis

Posted by Carla Rothaus • April 8th, 2016

2016-04-01_11-21-46Humans, unlike most animals, require exogenous intake of ascorbic acid for the biosynthesis and hydroxylation of hormones, neurotransmitters, and mature collagen.

A previously healthy boy, 2 1/2 years old, presented with a 6-week history of progressive inability to bear weight on his right leg. His mother noted no recent trauma. His medical history was notable only for speech delay. A new Clinical Problem-Solving summarizes

Clinical Pearl

• Who is at risk for scurvy?

It is important that clinicians maintain a low threshold for considering scurvy in at-risk populations, including elderly persons, patients in psychiatric institutions, and persons with restrictive eating habits or alcohol use disorders. Scurvy is rare among children but has been described in children with autistic spectrum disorder, oral aversion, and global developmental delay. Although much attention has been devoted to the learning and behavioral challenges facing patients with autism spectrum disorder, their feeding difficulties and resulting nutritional deficiencies are still underrecognized by many physicians.

Clinical Pearl

• What imaging findings are characteristic of scurvy?

Findings on plain radiographs include a lucent transverse metaphyseal band with an adjacent dense sclerotic band, metaphyseal spurring, and nonspecific evidence of diffuse osteopenia and cortical thinning. MRI may reveal an abnormal bone marrow signal, periosteal elevation, and heterogeneous subperiosteal fluid consistent with hemorrhage.

Figure 1. Radiograph and CT of the Femur.

Figure 2. MRI of Distal Femurs.

Morning Report Questions

Q: Describe some of the clinical manifestations of scurvy.

A: Generalized symptoms of scurvy include fatigue, mylagias, arthralgias, weakness, anorexia, weight loss, and irritability. Dermatologic manifestations include follicular hyperkeratosis with perifollicular hemorrhage surrounding twisted, brittle hairs (corkscrew hairs), ecchymoses, poor wound healing, and swelling in the legs. In dentulous patients, gingival swelling and hemorrhage may occur. Soft-tissue or subperiosteal hemorrhage, most commonly affecting the legs, may cause pain so severe that affected persons are unwilling to walk. Scurvy can also cause neurologic abnormalities, including irritability, developmental delay, and hypotonia, as well as anemia. Left untreated, scurvy may result in cardiorespiratory failure and death, the mechanisms of which are incompletely understood.

Q: How is scurvy generally diagnosed?

A: The diagnosis of scurvy depends on history, physical examination, and clinical improvement after the administration of ascorbic acid; however, serologic and radiologic studies may also be helpful. Although a low plasma vitamin C level is specific for the diagnosis of scurvy, plasma vitamin C levels quickly normalize with enteral intake of ascorbic acid and do no reflect tissue levels. In humans, leukocytes serve as a storage pool for ascorbic acid. The measurement of ascorbic acid levels in leukocytes may be considered, although such levels may not be easily obtainable and may also be affected by dietary intake.

Betamethasone for Women at Risk for Preterm Delivery

Posted by MaryAnn Wilbur, M.D. M.P.H. • April 6th, 2016

A term delivery occurs on or after 37 weeks gestation.  Any delivery prior is considered “preterm” and those   between 34 weeks, 0 days and 36 weeks, 6 days are often referred to as “late preterm.”  The standard of care has been to recommend antenatal glucocorticoids (typically, betamethasone 12.5mg IM q24 hours x 2 doses) to women who are anticipated to deliver a viable infant prior to 34 weeks, 0 days gestation.  However, this regimen has not been routinely given to women expected to deliver in the late preterm window.   This includes women suspected to be developing preterm labor and women with any condition requiring an iatrogenic preterm delivery.  For example, I recently developed preeclampsia at 36 weeks gestation and required an early delivery.  My OB and I never discussed betamethasone, because I was in the late preterm window.

I have also been the OB for many patients in this same situation and I likewise have not discussed glucocorticoids with those women expected to deliver a late preterm infant.  More than one medical student has asked about this.  They have noticed that we define all infants born prior to 37 weeks gestation as “preterm,” but only give glucocorticoids to those expected to deliver prior to 34 weeks gestation.  They ask, “Wouldn’t all preterm infants benefit?”  My short answer has always been that the data from prior trials supported glucocorticoids up until 34 weeks gestation, but the benefit for late preterm infants remained unclear.  The obstetric community has been awaiting the results from the Antenatal Late Preterm Study, which is published in this week’s NEJM.

In this multicenter randomized controlled trial, 2831 women with singleton pregnancies and at risk for a late preterm delivery were randomized to receive antenatal glucocorticoids (betamethasone x 2 doses) or placebo.  The primary outcome was a composite of newborn complications, largely related to the need for respiratory support.   The primary outcome occurred less often in the treatment group than in the placebo group, but newborns in the treatment group were more likely to have hypoglycemia shortly after birth.  The authors concluded that administration of betamethasone to women at risk for a late preterm delivery significantly reduced the rate of newborn respiratory complications.

These results provide support for extending the current guidelines such that women at risk for any preterm delivery receive glucocorticoids.  In fact, the American College of Obstetricians & Gyncologists (ACOG) released an updated Practice Advisory on April 4th.  They now say, “administration of betamethasone may be considered in women with a singleton pregnancy between 34 0/7 and 36 6/7 weeks gestation at imminent risk of preterm birth within 7 days.”  However, some experts suggest that guideline changes should reflect caution and should not necessarily be extended all the way up to a term gestational age, where the benefits of respiratory complications are likely to be less evident and the risk of hypoglycemia remains.  The decision of whether or not to give betamethasone will ultimately depend on clinical judgement.  Most OBs will probably employ a cautious discussion with each patient, considering the exact gestational age, likelihood of a late preterm delivery, and comorbidities of the individual patient (particularly diabetes) before moving on to a blanket change in practice.

Opioid Abuse in Chronic Pain

Posted by Carla Rothaus • April 1st, 2016

2016-03-28_10-50-55Chronic pain not caused by cancer is among the most prevalent and debilitating medical conditions but also among the most controversial and complex to manage. The urgency of patients’ needs, the demonstrated effectiveness of opioid analgesics for the management of acute pain, and the limited therapeutic alternatives for chronic pain have combined to produce an overreliance on opioid medications in the United States, with associated alarming increases in diversion, overdose, and addiction.

The epidemic of opioid abuse is related in part to incomplete understanding of pain-relief management, opioid tolerance, and opioid addiction. Among the prevention strategies are more widespread sharing of data about opioid neuropharmacology and opioid-use patterns. A new Review Article summarizes.

Clinical Pearl

• How does opioid addiction differ from opioid tolerance and physical dependence?

There is lingering misunderstanding among some physicians about the important differences between physical dependence and addiction. The repeated administration of any opioid almost inevitably results in the development of tolerance and physical dependence. These predictable phenomena reflect counter-adaptations in opioid receptors and their intracellular signaling cascades. These short-term results of repeated opioid administration resolve rapidly after discontinuation of the opioid. In contrast, addiction will occur in only a small percentage of patients exposed to opioids. Addiction develops slowly, usually only after months of exposure, but once addiction develops, it is a separate, often chronic medical illness that will typically not remit simply with opioid discontinuation and will carry a high risk of relapse for years without proper treatment.

Clinical Pearl

• Does tolerance to the different effects of opioids develop at the same rate?

Tolerance leads to a decrease in opioid potency with repeated administration. Thus, prescribing opioids long-term for their analgesic effects will typically require increasingly higher doses in order to maintain the initial level of analgesia — up to 10 times the original dose. Some opioid effects show tolerance after a single dose, whereas for others, tolerance occurs more slowly. In particular, tolerance to the analgesic and euphoric effects of opioids develops quickly, whereas tolerance to respiratory depression develops more slowly, which explains why increases in dose by the prescriber or patient to maintain analgesia (or reward) can markedly increase the risk of overdose.

Morning Report Questions

Q: What are some of the risk factors for opioid overdose?

A: The contributing factors associated with overdose can be divided into those associated with the opioid itself (type, dose, potency, and duration of action) and those associated with critical features of the patient. Although the use of any opioid can lead to overdose, research suggests that exposure to higher doses of all opioids increases the risk of overdose. Opioid doses of more than 100 morphine milligram equivalents (MME, the conversion factor used to facilitate comparison of potency among opioids) are disproportionately associated with overdose-related hospital admissions and deaths. Several identifiable characteristics among patients have been reliably associated with an elevated risk of opioid overdose. Included among these factors are a history of overdose, a history of addiction to any substance (but particularly alcohol, benzodiazepines, or opioids), and health problems associated with respiratory depression or concurrent prescription of any medication that has a depressive effect on the respiratory system, such as benzodiazepines and sedative hypnotics. The presence of renal or hepatic dysfunction also increases the risk of overdose, since in patients with either of these conditions, the clearance of many opioid drugs is impaired, which leads to higher and longer-lasting drug levels in blood. Finally, because some cases of overdose may be purposeful suicide attempts, a history of suicidal thoughts or attempts and a diagnosis of major depression are also markers for an elevated risk of overdose.

Table 1. Misconceptions Regarding Opioids and Addiction.

Table 3. Factors Associated with the Risk of Opioid Overdose or Addiction.

Q: What strategies are recommended to reduce the risk of opioid overdose?

A: Recommended mitigation strategies include an overdose risk assessment and urine drug screening before prescription or represcription of opioids (to verify absence of drugs of abuse). The identification of these risks does not automatically rule out opioids as part of effective pain management. However, these risks do indicate the need for much greater education of the patient (and the patient’s family) about overdose risks, the use of an opioid treatment agreement, increased caution in prescribing high opioid doses or long-acting opioids, more frequent clinical follow-up, and, potentially, a prescription for and instruction in the use of naloxone, an opioid antagonist that can reverse an opioid-induced overdose. Indeed, expanding access to naloxone has been shown to significantly reduce the rate of death from opioid overdoses.

Table 4. Mitigation Strategies against Opioid Diversion and Misuse.

A Man with Sickle Cell Disease and Headache

Posted by Carla Rothaus • April 1st, 2016

26Approximately 17% of patients with sickle cell disease have cerebrovascular symptoms; 75% of those patients have cerebral infarction, 20% have either cerebral or subarachnoid hemorrhage, and a small percentage have cerebral sinovenous thrombosis.

A 22-year-old man with sickle cell disease presented with headache and difficulty speaking after smoking marijuana. He had anomia, apraxia, and alexia and was unable to perform arithmetic. Diagnostic tests were performed, and management decisions were made. A new Case Record summarizes.

Clinical Pearl

• What are the most common causes of stroke in young patients?

The most common causes of stroke in young patients are cardioembolism, dissection, migraine, angiopathies of various types, and other causes, including coagulopathies associated with the use of oral contraceptives or with the presence of antiphospholipid antibodies.

Clinical Pearl

• What are the characteristics of strokes associated with cannabis use?

Cannabis use is often considered in cases of cerebral vasoconstriction, although the pathogenetic mechanism is unknown. In a review article, 59 reported cases of cannabis-related stroke were summarized. They tend to occur in men (at a 5:1 ratio), usually occur while the drug is being smoked or within a half hour after the last exposure, and are almost always ischemic, with only a single report of hemorrhagic stroke.

Morning Report Questions

Q: Describe some of the cardiovascular abnormalities associated with sickle cell disease.

A: Among patients with sickle cell disease, cerebral infarction tends to occur in patients who have frequent crises and to occur at the time of crisis. Numerous studies have showed that intravascular coagulation occurs in patients with sickle cell disease. In addition to the coagulopathy, a generalized vasculopathy affects all vessels in sickle cell disease. The vasculopathy may lead to carotid occlusion, dissection, or intracranial aneurysm formation. There have been numerous case reports of cerebral aneurysms in patients with sickle cell disease, including many cases involving multiple aneurysms (an average of three per patient), small aneurysms (3 to 7 mm in diameter), and those that preferentially affect the posterior circulation, especially in unusual locations.

Figure 1. Imaging Studies.

Figure 2. Peripheral-Blood Smear.

Q: Do the strokes associated with sickle cell disease tend to be ischemic or hemorrhagic?

A: Stroke in patients with sickle cell disease may be both ischemic and hemorrhagic, depending on the patient’s age. Ischemic stroke has a bimodal distribution, peaking in the first decade of life and again after 25 years of age. Hemorrhagic stroke peaks in the second and third decades of life. It is important to remember that patients with sickle cell disease and stroke have an estimated lifetime risk of a second stroke of 50%, and most second strokes occur within 3 years after the first.

Care in Crisis

Posted by Ken Bernard • March 31st, 2016

2016-03-30_13-06-55I initially envisioned this post as an upbeat piece of advice for graduating residents who will soon go out into the world as healers.  For me, this transition was both anxiety-provoking and rewarding, so I wanted to help residents avoid the pitfalls and enjoy the pearls.  Look for that piece next month because after the recent Senate hearings in early February highlighting the “horrifying and unacceptable” state of care delivered to the Native people of the Great Plains — my relatives — I felt compelled to reflect on this instead.

These health disparities and outcomes are predictable and, in many cases, avoidable.  The Senate committee, after hearing testimony from tribal leaders and patients who received care on reservations, noted systemic issues at the national level such as the chronic underfunding of the Indian Health Service (IHS) and provider vacancies, as well as local problems like antiquated facilities lacking equipment, untrained or under-trained medical staff, nepotism, and — in extreme cases — malpractice bordering on criminal negligence.  Of course, not all IHS sites are poorly performing; however, these issues should not be surprising to anyone who has come into contact with such IHS sites. Surely they are plainly apparent to the patients who have experienced substandard care over the past few decades.  In fact, there was a similar Senate hearing in 2010 which produced action plans to address these issues.  However, with high administrative turnover, varying needs and capabilities of each IHS facility, and a general lack of accountability at multiple levels, little progress was made.  These negative and disheartening stories overshadow all of the good work and excellent — even innovative and cutting-edge — care taking place at other IHS sites in Alaska, Wisconsin, and, fortunately, my hospital on the Northern Navajo Nation in Arizona.

My heart goes out to the dedicated staff and health care professionals who have taken up the duty to serve these communities and strive to improve the health of Native people in spite of all the obstacles, and to the patients and families who have been promised better, but were still delivered substandard care.

None of these disparities and deficiencies within the IHS are new problems.  Certain IHS sites seem to be in a state of perpetual crisis which has become routine and accepted, so care aberrations, resource constraints, and provider vacancies rarely reach the level of alarm which forces legislators or other key stakeholders to intervene.

Sadly, I think this lack of urgency is the result of mutual complacency.  On the one hand are the providers, who may feel like the health care game is rigged.  Without a strong economic infrastructure, secured basic necessities, and quality education, there is a fatalistic impression that there will always be disparities in health outcomes, no matter how hard they work.

Meanwhile, patients have been marginalized and disenfranchised for generations and seem to either be disillusioned or have forgotten that they deserve better. They do not demand that the rights and promises that have been made to them be kept, in ways that other U.S. citizens have come to demand and expect.

By this point, I hope you can see that the state of Native American health care on reservations is a multipronged series of problems. So the real question is how can we avoid getting bogged down in the current daily challenges established in the past, and what can we do to create a better future?

First, Congress should fund the IHS to a level that is commensurate with its needs. Doing so would allow for the improvement and updating of facilities, competitive salaries to draw well-trained health care professionals, and investment in continued professional development for those who have committed to working in IHS facilities. Adequate funding would also allow programs such as telemedicine, medical homes, and mobile health units to expand, which would consequently allow health care professionals to widen their scope of practice while limiting demand on sub-specialists and decreasing the access-burden on patients.

Second, there needs to be a stronger link between academic medical centers and medical schools or other postgraduate training programs to allow for internships and learning opportunities as a  strategy for recruiting and retention. I myself am a product of one of these scholarship programs and I have seen my colleagues show interest but not clearly understand how to get involved or navigate the diverse offerings available through the Indian Health Service, the US Public Health Service Commission Core or the National Health Service Corps

Third, I see a tremendous amount of overlap between global health and the services and innovation needed in the resource-poor areas like IHS sites in our own country, and yet there is a much larger focus on global health tracks in medical schools and residency.  Can we alter this perception and offer more to encourage our best and brightest doctors, nurses, and medical professionals to seek out service opportunities at home? One bit of inspiration came as I was leaving Boston, when a global health fellowship started at Massachusetts General Hospital included a required rotation at an IHS site.  Similarly, for years Brigham and Women’s Hospital has been sending volunteers to IHS sites in Arizona and New Mexico that offer on-site clinical services and teaching.  These programs do exist, but would have a greater impact if expanded on a larger scale across many more institutions and supported by on-site staff in these resource-poor areas.  One of my early goals here at Tuba City Regional Healthcare is to create a more structured program for volunteers and trainees who want to come and serve and learn at our institution.  I think the experience is incredibly valuable, especially to residents who plan on community practice, and I look forward to making this a priority during my time here.  I hope others will do the same.

Fourth, we must identify, encourage, and fund young tribal members interested in public health, health care, technology, environmental sustainability, engineering, and business who make commitments to serve Native people and bring their talents back to the reservation.  I was an Indian Health Service Scholar who benefited from a loan repayment scholarship, which I would not have known about if my mother hadn’t received the same scholarship and encouraged me to apply.  I also ran the Four Directions Summer Research Program at Harvard Medical School, which brought Native college students from across the country together to work in labs and gain valuable real-world experience in various STEM fields. Perhaps more programs like these, where medical or other masters/doctorate level students can serve as mentors and advisors, could help open Native students’ eyes to the opportunities they have to grow personally and professionally while helping their people.

Fifth, we need a more holistic approach to health in these communities.  Access to high-quality health care is only part of the picture.  According to the World Health Organization, a strong economic and educational infrastructure and an ability to meet basic daily needs (food, water, shelter, and sanitation) are vital social determinants of health.  There are multiple opportunities for non-profit and for-profit organizations to create partnerships to close these gaps in areas like healthful and culturally appropriate food programs, renewable energy and sanitation, affordable and environmentally conscious housing, expansion of telecommunication and Internet services, and non-traditional educational offerings and cultural exchange.

Finally, we as members of these communities cannot wait for others to solve these issues for us.  Now is the time for collaboration and sharing of ideas and efforts to heal our own communities and people.  I would love to see a consortium of clinical directors, health professionals, and patients come together to pool our collective resources and social capital.  We are going to need each other as we try to create more adaptive and comprehensive health care systems.  This may be the most difficult step, because it takes courage, imagination, and, most importantly, trust and follow-through which have been damaged over the decades through broken promises and unfulfilled mandates. It will likely take years to earn this trust back. But we need to start doing this together in small steps if we are ever to create strong, sustainably healthy, and independent Native communities.  My dream is that rather than reading yet another report of the persistent shortcomings of the IHS, we can be examples of well-run, culturally competent centers of health care excellence.  Maybe soon we can all live out that same dream.

Therapy for Symptoms Attributed to Lyme Disease

Posted by Bhavna Seth, M.D. • March 30th, 2016


PLEASE, may we understand persistent symptoms attributable to Lyme disease?

There are few diseases that have created divisions between the medical establishment and some patients, or that have engaged political interest, as much as chronic Lyme disease has. In their recent NEJM article, Berende et al have provided evidence to guide the major controversy regarding the potential benefit of longer-term antibiotic therapy for Lyme disease, through a rigorous, randomized clinical trial, called Persistent Lyme Empiric Antibiotic Study Europe (PLEASE). In this double-blind, randomized, placebo-controlled study, patients were included with persistent symptoms attributed to Lyme disease, either temporally related to proven Lyme disease or accompanied by a positive B.burgdorferi IgG/IgM immunoblot. All patients received open-label ceftriaxone (2 weeks) followed by randomized blinded oral follow-up treatment of 12 weeks with doxycycline, clarithromycin with hydroxychloroquine, or placebo. The primary outcome was health related quality of life at End of Treatment (14 weeks), assessed using the RAND SF-36 physical component summary score.

Although all the groups showed significant improvement over time (p=0.001), there was no statistically significant difference across treatment arms (p=0.69). It is possible that the initial two week therapy with ceftriaxone administered to all groups accounted for some of the improvement observed in all groups. What this study does strongly suggest is that longer term antimicrobial therapy is not an efficacious approach to treating persistent symptoms attributed to Lyme. Unfortunately, despite the improvement over time, the patients still had a health related quality of life which was worse than that expected in the general population.

An interesting aspect of the study is that about 1200 patients had to be screened for recruiting the 284 study participants. One of the most important causes for excluding potential participants was negative serology combined with unproven or temporally unrelated Lyme disease. This highlights the constellation of possible diagnoses, aside from Lyme disease, that can give rise to these symptoms.

In an accompanying editorial, Melia and Auwaerter propose that it is time to abandon the longer term antibiotic therapy strategy to treat long-standing symptoms ascribed to Lyme disease. In this editorial they also point out that over two-thirds (185 of 281) of the participating patients did not present with obvious clinical manifestations suggestive of Lyme disease (i.e. temporally related symptomatic Lyme disease or erythema migrans); they were diagnosed with the the disease based on B. burgdorferi IgG or IgM antibodies confirmed on immunoblot.

The protean presentation of Lyme disease makes it a difficult diagnosis, and often, a difficult condition to live with. Patients with chronic, debilitating symptoms which they ascribe to long standing Lyme disease, thus, feel betrayed when evidence based medicine does not support their diagnosis. This uncertainty, combined with the devitalizing course of the disease, makes for a counter-narrative to the evidence.

NEJM Deputy Editor Dr. Lindsey R. Baden notes, “It is important that rigorous evidence guide medical practice as all medications including antimicrobials have side effects, including engendering antimicrobial resistant organisms. Furthermore, using ineffective treatments means that effective treatments are not pursued and developed. Well done trials, such as this one, provide important evidence to guide the community to focus efforts in other directions to try and provide relief to these patients.”

This study by Berende et al provides convincing evidence against longer term use of antibiotics.  Though the human side of the story is immensely disheartening, there needs to be a closer scrutiny into the etiology of the symptoms that are being attributed to Lyme disease.

On one side of the schism stands the evidence, which grows stronger by the day, that persistent symptoms attributed to Lyme disease are not amenable to longer antibiotic therapy; and on the other, there is a multitude of patients suffering from debiliating neurologic, cognitive, musculoskeletal or even multisystemic symptoms. Standing witness at the tug of war between these two sides, we still do not have an answer. We know that longer term antibiotics do not work; but we do not know what works, or sometimes, even what causes these devastating collection of symptoms.

Don’t miss the NEJM Quick Take video summary on this study: 

A Man with Dyspnea and Chest Pain

Posted by Carla Rothaus • March 25th, 2016

2016-03-18_14-12-45In every patient with a large pulmonary embolus, one may consider the possibility that the embolus is caused by a benign cardiac tumor, primary cardiac cancer, or a metastasis to the heart.

A 29-year-old man presented with severe dyspnea and chest pain on the right side. Computed tomographic angiography revealed a filling defect in the main and right pulmonary arteries that was consistent with pulmonary embolism. Diagnostic procedures were performed. A new Case Record summarizes.

Clinical Pearl

• What is the most common cause of pulmonary embolism?

The most common cause of pulmonary embolism is venous thromboembolism, in which a thrombus forms in the deep veins of the legs or pelvis and then the clot breaks free and migrates to the pulmonary arteries through the inferior vena cava, right atrium, and right ventricle. Occasionally, the migrating thrombus can be visualized while it is moving in the right atrium or right ventricle and tethered to the right ventricular trabeculae or eustachian valve. Clots associated with venous thromboembolism are often heterogeneous, containing both acute and chronic elements. Thrombi associated with venous thromboembolism usually have a solid or sausagelike appearance that represents a cast of the vessel from which the thrombi were derived.

Clinical Pearl

• Is there a laboratory or imaging test that can provide prognostic information in a patient with pulmonary embolism?

Unfortunately, no single examination or imaging study accurately predicts the likelihood of decompensation from suspected pulmonary embolism. Many patients appear to be well but in reality are extremely ill. In patients with pulmonary embolism, clinical instinct alone can fool the clinician, especially in young patients who may compensate very well but then precipitously decline. Patients with pulmonary embolism can be stable one moment and near death the next. An elevated level of troponin in a patient with pulmonary embolism suggests right ventricular myocardial injury, and an elevated level of N-terminal pro–B-type natriuretic peptide (NT-proBNP) suggests right ventricular strain. Other laboratory results, such as an elevated d-dimer level and leukocytosis, are not prognostically specific. Right ventricular failure is most likely the main factor that causes death from pulmonary embolism, and thus findings of right ventricular dysfunction and dilatation are prognostically important and help to define the urgency of therapy for patients who otherwise appear to be stable. Many investigators have tried to develop scoring systems that are based on clot burden, but these systems have not necessarily been predictive of outcome.

Morning Report Questions

Q: List some benign tumors that can involve the heart.

A: Benign tumors include cardiac myxomas, which represent about 25% of all cardiac tumors; these are usually tethered to the interatrial septum, but 80% are located in the left atrium and only 20% are located in the right atrium. Papillary fibroelastoma is the most common valvular tumor; the appearance is often likened to a sea anemone. Lipomas and fibromas are generally not mobile. Rhabdomyomas are most commonly seen in children. Leiomyomas, hemangiomas, and teratomas are rare; teratomas are generally of pericardial origin.

Q: Is a malignant tumor involving the heart more likely to be a primary tumor or a metastasis?

A: Malignant primary cardiac tumors are extremely rare; they are predominantly manifested by sarcomatous tumors and occasionally by lymphoma. Several types of cancer can migrate to the heart and establish an intracardiac metastatic focus of disease, although this is a rare occurrence. These types include lung, breast, renal, hepatic, adrenal, and germ-cell tumors, as well as melanoma, sarcoma, lymphoma, squamous-cell carcinoma, and thyroid carcinoma. Some extracardiac tumors, most commonly renal-cell or hepatocellular carcinoma, invade the heart and pulmonary arteries through the inferior vena cava. The majority of malignant cardiac tumors are secondary metastases.

Figure 1. Imaging Studies of the Chest.

Figure 2. Echocardiographic Images.

Chronic Stable Angina

Posted by Carla Rothaus • March 25th, 2016

2016-03-18_14-15-33Angina is the initial manifestation in approximately half of all patients who present with coronary artery disease. The presence of chronic angina approximately doubles the risk of major cardiovascular events.

Management of angina includes lifestyle changes and pharmacologic treatment to reduce cardiovascular risks, antianginal therapies (beta-blockers, long-acting nitrates, calcium-channel blockers, and — recently in the United States — ranolazine), and revascularization. A new Clinical Practice article summarizes.

Clinical Pearl

• Do diagnostic tests for coronary artery disease also provide prognostic information?

Several tests that are used to diagnose coronary artery disease can also provide prognostic information. The standard exercise ECG stress test is the least sensitive test for coronary artery disease and cannot define its extent, but the duration of exercise, presence of ST-segment changes, and occurrence of angina confer prognostic information. As compared with the routine exercise ECG stress test, stress tests that involve imaging typically have a superior ability to detect coronary artery disease without an appreciable loss of specificity. The exercise ejection fraction is one of the most important prognostic variables in patients with coronary artery disease. Imaging stress tests allow evaluation of left ventricular performance and assessment of the extent of ischemia during stress.

Table 1. Tests to Diagnose and Assess the Prognosis of Clinically Significant Coronary Disease.

Clinical Pearl

• What are some of the general guidelines for the management of suspected chronic angina?

Establishing a diagnosis of chronic angina should be pursued in parallel with managing symptoms and initiating preventive therapies. In patients in whom stable angina is suspected, preventive therapies, including aspirin, should be started immediately if they are not already in use. Blood pressure should be reduced to below 120/85 mm Hg if possible, and a moderate-to-high-intensity statin (that reduces low-density lipoprotein [LDL] cholesterol levels by >30% from pretreatment levels) should be used. Changes in lifestyle behaviors should also be recommended. These changes include weight loss in overweight or obese patients, dietary changes to reduce fat and sugar intake, and smoking cessation. Antianginal therapy should be initiated as soon as the diagnosis is suspected. In patients with stable angina, beta-blockers, calcium-channel blockers, and long-acting nitrates reduce angina similarly and appear to have a similar safety profile (except for short-acting calcium-channel blockers).

Morning Report Questions

Q: What are some of the newer medical therapies for chronic angina?

A: Ranolazine is a metabolic antianginal agent that is approved for the treatment of chronic angina. It diminishes myocardial ischemia by reducing calcium overload caused by inhibition of the late sodium current. It does not affect heart rate or blood pressure and thus may be considered as a first-line agent for patients with slow heart rate or low blood pressure. It has been evaluated in two studies of outcomes in patients with angina, with mixed results. Ranolazine prolongs the QT interval in a dose-dependent manner; however, no increase in significant arrhythmias has been observed with its use in multiple safety studies. Still, caution is warranted regarding prescription of other drugs that cause QT-interval prolongation, as well as regarding other drug–drug interactions. Ivabradine is a selective heart-rate–lowering (physiological) agent that inhibits the If current in the pacemaker cells in the sino-atrial node. It is approved for treatment of heart failure with a goal of preventing hospitalization in patients who have an increased heart rate despite adequate beta-blocker therapy. It has also been reported to be effective in improving exercise duration in patients with chronic angina who are not receiving background therapy. However, the results of a large randomized trial involving patients who had both stable coronary artery disease without heart failure and a resting heart rate of 70 beats per minute or more have aroused concern about the use of ivabradine for chronic angina. Ivabradine should not be used to treat angina in the absence of heart failure.

Table 2. Antianginal Agents.

Q: When would you consider revascularization for a patient with chronic stable angina?

A: The decision regarding whether and how to revascularize (with percutaneous coronary intervention [PCI] or coronary-artery bypass grafting [CABG]) or whether to continue medical therapy should ideally involve a heart-team approach incorporating input from interventional cardiologists and cardiothoracic surgeons. The decision should take into account clinical risk factors, characteristics of the lesion, and hemodynamic factors, and it may be informed by the use of validated risk scores to refine the selection of patients for PCI versus CABG. Randomized trials involving patients who were eligible for either medical therapy or revascularization have shown that PCI is effective in reducing angina in patients with chronic angina, but it does not result in a lower risk of death or myocardial infarction than that with medical therapy. These observations suggest that medical therapy alone is a reasonable starting point if it has an acceptable side-effect profile. Revascularization should be considered for patients who have ongoing angina despite adequate medical therapy; this group includes as many as 50% of patients with chronic angina.

Early versus Late Parenteral Nutrition in Critically Ill Children

Posted by Ravi Parikh, M.D., M.P.P. • March 23rd, 2016

16During our intensive care unit rotations as residents, patient nutrition is a daily talking point. While it is easy to get lost in the details of the critical illnesses that bring patients to the ICU, we are regularly asked by attendings, nurses, and others, “how are we going to feed this patient?” Indeed, nutrient deficiencies are associated with poor outcomes such as infection, prolonged intubation, and delayed recovery. Our natural inclination is to start feeding early – delaying nutrition can only be bad, right? In adults, this question was addressed in a 2011 randomized controlled trial published in NEJM. That study showed that patients receiving late parenteral (IV) nutrition had faster recovery while in the ICU and fewer complications when compared to those receiving early parenteral nutrition, without a difference in mortality. Based on that trial, early nutrition in critically ill adults may not be such a good thing. But does the same effect hold in children, who are growing and whose nutritional requirements per kilogram are greater than those of adults?

In this week’s issue of NEJM, Fivez et al., the same group that published the 2011 trial, report the results of a multi-center randomized controlled trial that attempts to answer this question. Investigators enrolled children admitted to a participating pediatric ICU (PICU) and deemed at risk for nutritional deficiency according to the STRONGKids nutritional screening tool and whose expected PICU stay was  >24 hours. Children who had been readmitted or who were premature newborns were excluded. From 2012-2015, 1440 of 7519 children screened were randomized to receive either early parenteral nutrition (the standard of care), initiated within 24 hours after PICU admission or late parenteral nutrition, starting on day 8 of PICU admission. In both groups, enteral nutrition – generally via nasogastric tube – was initiated early per local guidelines.

The investigators found that children (median age 1.2 years old) receiving early parenteral nutrition had nearly 8% more new infections (p<0.001) – usually bloodstream or airway infections – and a 2.7-day longer PICU length of stay (p=0.002) than children receiving late parenteral nutrition. These effects were more pronounced among children at higher risk of nutritional deficiency on admission. In an analysis of secondary outcomes, death, readmission within 48 hours, and serious adverse events rates were similar in the two groups. Interestingly, late parental nutrition reduced the length of mechanical ventilation and the odds of renal replacement therapy – two markers of poor prognostic outcomes in ICU patients. Importantly, the impact of late parenteral nutrition was consistent across diagnoses, illness severity, centers, and age of the child.

Thus, the findings reported by Fivez et al. provide evidence against the use of early parenteral nutrition in critically ill children admitted to the PICU. These results are likely to change practice regarding the timing of initiation of parenteral nutrition in children. However, the study doesn’t tell us whether early enteral nutrition is harmful, and additional studies should investigate this question. In the accompanying editorial, Nilesh Mehta, Director of Critical Care Nutrition at Boston Children’s Hospital, rightly notes that “the presupposition that a uniform approach would apply to all [children] is too simplistic.” While the results of the Fivez et al. study may lead to recalibration of when parenteral nutrition is initiated, prescription of nutrition in children must be individualized to their condition, expected nutritional deficiency, and other important variables.

Don’t miss the NEJM Quick Take video summary on this study: