Remove the Skull: Hemicraniectomy after Massive Strokes

Posted by Rena Xu • March 19th, 2014

Your seventy-year-old patient has just suffered a large stroke. The circumstances are not good: an extensive middle-cerebral-artery (MCA) infarction and massive brain edema, which mean an eighty-percent chance of mortality in the first week. For younger patients, a hemicraniectomy — the removal of half the skull — has been shown to help relieve pressure and prevent herniation as the brain expands. For a patient older than sixty years, though, it’s unclear whether such surgery is helpful or harmful. Time is precious, and you have to make a decision quickly.

A study by Juttler et al., reported in this week’s NEJM, sought to answer precisely this question: for patients sixty-one years of age or older, does hemicraniectomy improve outcomes? The Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY) II trial randomly assigned over a hundred patients who had suffered a malignant MCA infarction to either hemicraniectomy or conservative treatment in an intensive care unit. The primary outcome was survival without severe disability at six months, as measured by the modified Rankin scale (where 0 is no symptoms, and 6 is death; absence of severe disability means a score of 4 or lower).

The study found that a higher percentage of patients in the hemicraniectomy group survived without severe disability, as compared to the control group (38% vs. 18%; odds ratio 2.91, P=0.04). At one year, the survival rate was also higher for the hemicraniectomy group (57% vs. 24%). The trial was stopped early due to the demonstrated efficacy of hemicraniectomy relative to conservative management.

Although patients in the hemicraniectomy group did relatively better, it must be acknowledged that the survivors in both groups remained greatly disabled by their strokes.  No patients had a modified Rankin score of 0-2. As Allan Ropper, M.D., a neurologist at the Brigham and Women’s Hospital, points out in an accompanying editorial, half of the survivors a year later had a score of 4, meaning “unable to walk without assistance and unable to attend to own bodily needs without assistance,” while another third had a score of 5, meaning “bedridden, incontinent, and requiring constant nursing care and attention.” That was true for both groups. Hemicraniectomy helped, but the damage from the stroke was still devastating.

These findings raise broader questions about goals of care. Ropper writes: “In many ways, hemicraniectomy tests the fortitude of patients and their families who, in the moment, must make a decision about survival. Numerical values for the likelihood of severe disability have now been provided by the trial and may be discussed with the patient or a surrogate decision maker. However, the choice must be made early and quickly, just as the brain begins to swell, and advance directives typically do not cover these specific circumstances.”

NEJM Deputy Editor Mary Beth Hamel, M.D., M.P.H., states: “This trial provides valuable information for families who face difficult decisions about their loved ones who suffer these devastating events. The results also highlight the importance of advance care planning, to inform family and health care providers about patients’ preferences if they were to face this difficult choice.”

It’s time to make a decision about how to treat your seventy-year-old patient. You discuss the options with his care proxy and loved ones. They want whatever will keep him alive.  So you call a neurosurgeon — because based on the results of the DESTINY II study, the best chance of survival means a hemicraniectomy.

In your current practice, under what circumstances do you recommend hemicraniectomy?  To what extent does patient age factor into your treatment choice?  How will the findings of the DESTINY II study change your approach?


Management of Skin Abscesses

Posted by Sara Fazio • March 14th, 2014

The incidence of abscesses is increasing, and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has become common. A new review article explains the role of ultrasonography and provides guidance on the management of skin abscesses and the use of antibiotics.

Abscesses are one of the most common skin conditions managed by general practitioners and emergency physicians. The incidence of skin abscesses has increased, and this increase has coincided with the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA). In many parts of the world, MRSA infections are now the most common cause of skin abscesses.

Clinical Pearls

How does ultrasound enhance the diagnostic accuracy of physical exam in detection of an abscess?

Studies in adults and children suggest that soft-tissue ultrasonography enhances the diagnostic accuracy of abscess detection and alters plans for management that are based on physical examination alone. In a prospective study involving 126 adults with clinical cellulitis in whom an emergency physician believed an abscess was not obvious on physical examination but might be present, ultrasonography resulted in a change in projected management in 56% of the patients. Ultrasonographic images showed fluid collection that was consistent with an abscess in half these patients, and approximately 80% of patients who underwent additional diagnostic testing had pus or other fluid collections. Management was also altered in three quarters of patients in whom drainage had been thought to be required on the basis of physical examination alone (e.g., it was decided that drainage was not needed, that further imaging was required, or that the incision and drainage approach should be altered).

What are the general principles of incision and drainage of an abscess in the office setting?

Many abscesses can be managed in the office setting by a general practitioner. Large, complex, or recalcitrant abscesses, especially those over sensitive areas (e.g., the hands or face), should prompt consideration of referral to a specialist or an emergency department, where additional resources can be brought to bear. The primary treatment for skin abscesses is incision and drainage. A single incision is made; the incision should be long enough to ensure complete drainage, allow lysis of loculations with a blunt instrument, and follow tension lines in order to minimize scarring. A common mistake is to make an incision that is not deep enough to reach and fully drain the abscess cavity. Particular care should be taken before incising the skin over critical structures, such as major vessels and nerves. A recent small study among adults suggested that many abscesses can be adequately drained through a short incision (median length, 1 cm).

Morning Report Questions

Q: According to the authors, when should primary closure of drained abscesses be considered?

A: Primary closure of drained abscesses should be considered for large incisions (i.e., >2 cm), especially over cosmetically important areas, and may warrant referral to a specialist. Primary closure should not be performed in patients with infected sebaceous cysts or lymph nodes or similar disease processes, patients in whom the adequacy of drainage is in doubt, and patients who have systemic infection or a strong risk factor for systemic infection (e.g., diabetes).

Figure 2. New Surgical Approaches to Abscess Treatment.

Q: When is antibiotic treatment recommended in addition to incision and drainage of an abscess, and in such cases, what is the appropriate antibiotic regimen?

A: The Infectious Diseases Society of America (IDSA) recommends systemic antibiotic treatment, in addition to incision and drainage, for patients with severe or extensive disease (e.g., multiple sites of infection) or with rapid disease progression and associated cellulitis, signs and symptoms of systemic illness, associated coexisting conditions or immunosuppression, very young age or advanced age, an abscess in an area difficult to drain (e.g., face, hands, or genitalia), associated septic phlebitis, or an abscess that does not respond to incision and drainage alone. Empirical antibiotic therapy, if prescribed, should have in vitro activity against community-associated MRSA. Most patients who have a minor abscess can be treated as outpatients with inexpensive oral antibiotics. TMP-SMX, clindamycin, and tetracycline have been shown to have in vitro activity against 94% to nearly 100% of more than 300 MRSA isolates tested in a 2008 U.S. emergency department-based surveillance study. Other antibiotics with anti-MRSA activity that have been approved by the Food and Drug Administration for the treatment of skin and soft-tissue infection include vancomycin, linezolid, daptomycin, telavancin, tigecycline, and ceftaroline.

29-Year-Old Man with Headache and Diplopia

Posted by Sara Fazio • March 14th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 29-year-old man was admitted to the hospital because of headache, vomiting, photophobia, diplopia, and stiff neck. He was born in Southeast Asia. Brain imaging showed diffuse leptomeningeal enhancement. Cultures were sterile. A diagnostic procedure was performed.

Chronic meningitis differs in important ways from acute meningitis. The symptoms of chronic meningitis are typically milder, and patients less often present with a complete meningitis syndrome. Over time, however, focal and diffuse neurologic deficits can accrue. Cases that involve prominent basal inflammation can be particularly severe, with cranial-nerve palsies, vasculopathy in the circle of Willis, and obstruction of CSF outflow leading to hydrocephalus.

Clinical Pearls

What are the most common infectious causes of chronic meningitis?

Historically, the most common infectious cause of chronic meningitis in case series has been Mycobacterium tuberculosis. Other organisms that cause chronic meningitis are Borrelia burgdorferi, Treponema pallidum, and Ehrlichia chaffeensis. Pyogenic bacteria rarely cause chronic meningitis but can do so in persons with a parameningeal focus, endocarditis, or partially treated acute bacterial meningitis. HIV is the most common viral cause of chronic meningitis, but HIV-related meningitis is rarely symptomatic. Fungal organisms are a typical cause of chronic meningitis in persons with immunocompromise. However, several fungi, especially cryptococcus, can cause meningitis in apparently normal hosts.

What are the noninfectious causes of chronic meningitis?

There is an extensive list of noninfectious causes of chronic meningitis. Several forms of vasculitis are associated with chronic meningitis, including primary central nervous system vasculitis, the Churg-Strauss syndrome, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), and Cogan’s syndrome. Connective-tissue diseases associated with meningitis include systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome. Several other systemic inflammatory processes have been associated with chronic meningitis, the most important of which is neurosarcoidosis. Chemical irritation can cause chronic meningitis in persons who have a dermoid cyst with intermittent release of cholesterol crystals, in those who have undergone a craniotomy, and in those who have received treatment with intravenous immunoglobulin or trimethoprim-sulfamethoxazole. Finally, neoplasms, most commonly breast carcinoma, lung carcinoma, melanoma, and leukemia, are relatively frequent causes of chronic meningitis.

Morning Report Questions

Q: What is the differential diagnosis for a low glucose level in the cerebrospinal fluid (CSF)?

A: Although there is an extensive differential diagnosis for causes of hypoglycorrhachia (a low CSF glucose level), the most prominent infectious causes are pyogenic bacteria, tuberculosis, and fungi, and the most important noninfectious causes are neoplasms, sarcoidosis, and subarachnoid blood; pyogenic bacteria and neoplasms tend to cause the lowest glucose levels.

Q: What are the characteristics of primary diffuse leptomeningeal gliomatosis?

A: Primary diffuse leptomeningeal gliomatosis is a distinct glioma syndrome, which is defined by diffuse infiltration of neoplastic glial cells in the leptomeninges without evidence of a primary intraparenchymal tumor. This is a rare diagnosis; there are approximately 50 autopsy-confirmed cases reported in the literature. This disease tends to affect relatively young people, and the prognosis is generally extremely poor, with a median survival time from diagnosis of 4 months in one review.

Have You Seen the Latest NEJM Quick Take?

Posted by Jennifer Zeis • March 13th, 2014

Our new Quick Take looks at a study on the care of children in Africa who have fever and a negative test for malaria. If a malaria test comes back negative, what might be the culprit? In less than three minutes, this Quick Take summarizes a new report on children in Tanzania.

Quick Takes are brief animations that summarize the key findings of an original research article and their broader implications, and are narrated by our Editor-in-Chief, Jeffrey Drazen.

And did you know we’ve published seven Quick Takes already? Check out all seven of the Quick Takes on this new page that collects them. Studies that received Quick Take treatment include reports on in-flight medical emergencies, radium-223 and prostate cancer, pulmonary nodules detected on CT, cesarean or vaginal delivery for twins, nut consumption and mortality, and distracted driving.

Idelalisib in Relapsed CLL and Indolent Lymphoma

Posted by Daniela Lamas • March 12th, 2014

It’s been five years since weakness and fatigue brought your patient, then seventy years old, to see his doctor. A routine blood test revealed an abnormally elevated white blood cell count. Doctors quickly diagnosed him with chronic lymphocytic leukemia. Soon afterward, he was started on his first of three treatment regimens that took him from rituximab to cyclophosphamide to fludarabine. But the leukemia had progressed. And while the drugs hadn’t suppressed his disease, they had wreaked havoc on his body. Now, he was ill and frail with platelets so low and kidney function so impaired that further chemotherapy simply wouldn’t make sense.

“Isn’t there anything else we can try?” he asks.

The answer now might be a cautious yes. Two studies in this week’s issue of NEJM describe promising results about a new oral drug called idelalisib. In one study, researchers show that idelalisib might help patients with CLL who aren’t candidates for further chemotherapy – like your patient – live longer. The other trial, published by a different team, demonstrates that the same drug might offer a benefit without a hefty side-effect profile for patients with non-Hodgkin’s lymphoma whose disease has progressed despite traditional therapies.

The results are driven by basic science studies into how signaling in B cells, the cells that go awry in both these disease, works. In the lab, scientists have learned that a specific set of cell signals becomes inappropriately hyperactive in malignancies like chronic lymphocytic leukemia. But attempts to inhibit individual pathways are often thwarted by side effects and resistance. Idelalisib represents an advance, because the drug targets a very specific pathway – the delta isoform of the phosphoinositide 3-kinase (PI3K) signal transduction pathway – and does so elegantly, without devastating adverse events.

Taken together, the two studies are striking. In one, Richard Furman and colleagues randomly assigned 220 patients with relapsed CLL to receive rituximab plus either idelalisib or placebo. These were all patients whose co-morbidities rendered them ineligible for further standard chemotherapy. The study was stopped early because the patients receiving idelalisib clearly did so much better. Those taking the study drug were less likely to see progression in their disease and more likely to be alive 12 months later.

In the other study, Ajay Gopal and his team looked at whether idelalisib could benefit a group of patients with “indolent” non-Hodgkin’s lymphoma. This term refers to slow-growing but largely incurable lymphomas that had either not responded, or had come back after a course of treatment, and could lead to death. In this study, patients were not randomly assigned to the drug, or to placebo. Instead, 125 patients were given the drug – and monitored. What the researchers found was that the study drug was just as good as, and maybe better than, the other current treatment options. Importantly, toxicity of the drug was described as “acceptable,” with most common adverse events being diarrhea and elevation in liver function tests.

While the precise target population and long-term effects of this drug remain to be seen, its success in these two studies serves as an example of how science can move from bench to bedside, write biologists and cancer researchers David Fruman and Lewis Cantley in an accompanying editorial: “The emerging success of idelalisib illustrates the clinical translation of basic research studies of signaling pathways in malignant B cells into clinical advances in treatment of patients with B-cell malignancies.”

Wasting Away

Posted by Sara Fazio • March 7th, 2014

In the latest Clinical Problem-Solving article, a 40-year-old woman presented to the emergency department with pain, weakness, and poor oral intake. In the 3 months preceding presentation, she noted the gradual onset of bilateral diffuse flank pain that progressed to affect her lower back, abdomen, and both arms and legs.

On skeletal imaging, osteomalacia can present with pseudofractures, insufficiency fractures, and “hot spots” on bone scintigraphy that mimic metastatic cancer.

Clinical Pearls

What are the clinical manifestations of hypophosphatemia and at what phosphate level do they occur?

Clinical manifestations of hypophosphatemia are rarely apparent until levels are below 1 mg/dl. Common symptoms and signs include fatigue, proximal myopathy, dysphagia, ileus, and impaired cardiac contractility. There may be central nervous system involvement, with irritability, delirium, or coma. Hemolysis and impaired granulocyte function have also been described. Finally, chronically low serum phosphate levels lead to a reduction in bone-mineral deposition, presenting as rickets in childhood and osteomalacia in adulthood. Rickets is associated with stunted linear growth and bone deformities. In adulthood, bone deformities are rare, but widespread bone pain may occur.

What is the most common cause of hypophosphatemia?

Hypophosphatemia can rarely be caused by low dietary intake of phosphate, as in patients with alcohol abuse or prolonged starvation, especially in association with diarrhea, malabsorptive states, or high antacid intake, which inhibits phosphate absorption. A second mechanism for hypophosphatemia is redistribution of phosphate from the vascular compartment, either into cells (such as in acute leukemia, during treatment of diabetic ketoacidosis, or in refeeding after prolonged starvation) or into bone. Phosphate redistribution into bone occurs with “hungry bone” syndrome, in which case the decrease in parathyroid hormone levels following parathyroidectomy for primary hyperparathyroidism leads to rapid deposition of calcium and phosphate as hydroxyapatite into undermineralized bone within an expanded remodeling space. The most common cause of hypophosphatemia is urinary loss of phosphate. Urinary losses are most commonly caused by elevated levels of parathyroid hormone or fibroblast growth factor 23 (FGF-23), which reduce phosphate reabsorption, or proximal renal tubular dysfunction (Fanconi’s syndrome).

Morning Report Questions

Q: What is Fanconi’s syndrome?

A: Disorders of the proximal renal tubules lead to impaired phosphate reabsorption and hypophosphatemia, but typically also affect the other functions of the kidney tubules (renal Fanconi’s syndrome). Increased urinary losses of bicarbonate result in a non-anion gap metabolic acidosis (proximal renal tubular acidosis) and losses of potassium result in hypokalemia; there is also increased urinary loss of amino acids. Hypouricemia, glycosuria, proteinuria, and mild renal dysfunction are also consistent with this disorder. This syndrome may be genetic; occur as a complication of myeloma, amyloidosis, or Sjogren’s syndrome; or occur secondary to medications (e.g., acetazolamide, topiramate, ifosfamide, tenofovir) or heavy metal poisoning.

Q: How often is renal tubular dysfunction observed in patients taking tenofovir?

A: The full Fanconi’s syndrome is rare, reported in less than 0.1% of patients, but partial renal tubular dysfunction (defined by the presence of at least two of the following: glycosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria, or beta2-microglobulinuria) was noted in a fifth of patients taking tenofovir when assessed prospectively. Risk factors for renal dysfunction with tenofovir include increased age, low body weight, prior renal impairment, and concomitant use of other nephrotoxic drugs. In case reports and case series, Fanconi’s syndrome most often occurs in the first year of therapy and in patients with HIV infection, possibly due to higher levels from coadministration with ritonavir. Guidelines recommend that patients receiving tenofovir should undergo screening with calculation of estimated glomerular filtration rate, measurement of serum phosphate, and assessment for proteinuria and glycosuria every 6 months.

Global Supply of Health Professionals

Posted by Sara Fazio • March 7th, 2014

The world’s need for and supply of health professionals is in flux. The latest article in the Global Health Series reviews the supply of and demand for physicians and nurses around the world. An interactive graphic shows the density of health workers in each country.

There is a global crisis of severe shortages and marked maldistribution of health professionals that is exacerbated by three great global transitions — demographic changes, epidemiologic shifts, and redistribution of the disability burden.

Clinical Pearls

According to the World Health Organization, how large is the global shortage of doctors and nurses?

The World Health Organization has underscored the alarming global shortage of approximately 4.3 million doctors and nurses, which constitutes a shortfall of 15% of the total number of doctors and nurses worldwide. It is estimated that 57 poor countries are facing a severe crisis in that they have insufficient human resources to meet minimum needs. The shortage is worsened by a global imbalance between the availability of health workers and the burden of disease. Africa, with the lowest density of doctors and nurses, has the highest disease burden.

Figure 2. Global Health Workforce and Burden of Disease According to WHO Region.

According to the authors, what are the five forces that are shaping global supply and demand of health professionals?

The first are the major transitions — demographic and epidemiologic changes and shifts in disability burden — that are sweeping across many countries. Demographically, populations are aging and becoming more urbanized and more mobile. Epidemiologically, noncommunicable diseases are displacing the earlier infectious, nutrition-related, and maternity-related causes of death. Second, people today are better educated and more assertive and enjoy greater access to information. Professionals are no longer the sole source of medical or health knowledge. Third, the revolution in biosciences and information-communications technologies will continue to generate many new diagnostics, vaccines, and drugs. Expansion of the toolkit is likely to usher in greater professional specialization. Finally, market forces are intrinsically part of the health care system; individuals and consumers are linked to health markets, and there is a premium on the capability and willingness of health professionals with business and management skills to work in markets, devise incentives, control processes, and deliver outcomes to consumers in managed systems. There are also countervailing forces of social justice pushing for health equity as a basic human right. There is growing social demand for fairness in health, including universal health coverage.

Morning Report Questions

Q: How are new roles evolving among health care workers globally?

A: New roles are already evolving among different cadres of health workers. The demarcation of the responsibility and authority of different professions is not fixed. New technologies and practices  will enable some health workers — imaging technologists, nurse endoscopists, physician assistants, and the like — to take on work previously performed by those with higher qualifications. Much innovation in such roles is taking place in low-income and middle-income countries in which the scarcity of resources has prompted some remarkable innovations to flourish. Teamwork will be essential for the successful management of health care systems. A reasonable hypothesis is that insular training for individual professions does not sufficiently promote understanding, respect, and knowledge of allied professions in a health team. The current model of professional training — in which members of each health profession are trained in silos until they join the workplace, where they are expected to perform as teams — needs to be reexamined with the aim of inculcating cooperative and collaborative skills, through interprofessional and transprofessional education, as professionals are trained to be members of health teams.

Figure 3. Health Workforce in Five Countries, According to Type of Health Worker, 2011.

Q: What did the Independent Commission on Professional Education argue should be the third “educational stage”?

A: The Independent Commission on Professional Education argued for a third educational stage of “transformative learning.” The first, informative stage provides information and may be expected to create an expert. The second, formative stage inculcates values and behavior for producing members of a profession. Transformative learning, the third stage, promotes the development of leaders and change agents who are able to engage in the transformation of health care systems. It may be hypothesized that the blended learning process introduced by massive open online courses (MOOCs), involving flipped classrooms, peer interaction, individual mentoring, and interactive problem identification and problem solving, promises to help accelerate the transition of learning from informative and formative to transformative.

Surgery Versus Watchful Waiting for Localized Prostate Cancer: the 18-Year Debate

Posted by Joshua Allen-Dicker • March 5th, 2014

In 2013, over 238,000 men were diagnosed with prostate cancer in the United States.  Each of these patients and their physicians has undoubtedly been faced with a vexing series of decisions: What should I do next?  Will the treatment help, or will the cure be worse than the disease?  The publication of the 18-year follow-up of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) in this week’s NEJM attempts to provide some guidance to those diagnosed with and those treating localized prostate cancer.

While the lifetime risk of being diagnosed with prostate cancer is around 17%, the risk of mortality from prostate cancer is substantially lower.  Historically, this discrepancy has spawned debates between those who believe localized prostate cancer represents a low risk for morbidity or mortality and should therefore only be monitored, and those who believe that surgical intervention represents a unique option to cure this potentially fatal disease as well as to prevent future complications.

The body of literature that guides this debate has been limited by study design and the indolent course of prostate cancer progression.  Most relevant trials have been retrospective cohorts criticized for their susceptibility to potential bias.  Those few randomized controlled trials examining management of localized prostate cancer are designed to detect outcomes over extended periods of time, introducing a significant lag time between intervention and recognition of meaningful results.

It should not be surprising then that SPCG-4 began enrolling patients in the distant past: 1989.  Between then and 1999, SPCG-4 randomized 695 men in Sweden, Finland and Iceland to either radical prostatectomy or watchful waiting.  All patients were subsequently followed at regular intervals.   The primary outcomes were all-cause mortality, prostate cancer specific mortality, and identification of disease metastatic to bone or outside of the pelvic area.

By December 31st, 2012, 294 of the 347 men randomized to receive radical prostatectomy underwent the procedure, and 294 of the 348 men randomized to watchful waiting had not undergone curative treatment.  The radical prostatectomy group had an overall mortality rate of 56.1% versus 68.9% in the watchful waiting group (RR 0.71, p<0.001). There was a similar significant difference in favor of radical prostatectomy with respect to prostate cancer-specific mortality (17.7% versus 28.7%, RR 0.56, p=0.001), and detection of distant metastases (26.1% versus 38.3%, RR 0.57, p<0.001).  In the subgroup analysis, an overall mortality benefit was restricted to men younger than 65 years at time of diagnosis as well as those with low or intermediate risk cancer at the time of study enrollment.  These results are consistent with the SPCG-4 twelve-year results, also published in NEJM.

These results, while impressive, also highlight a potential shortcoming of SPCG-4.  Between the time of the SPCG-4 patient enrollment and current day practice, prostate cancer diagnosis was revolutionized by the PSA test, which was first approved by the FDA in 1994 for use with digital rectal exams in screening for prostate cancer.  The ubiquity of the PSA screening test is especially apparent when one discovers that only 5.2% of SPCG-4 patients were diagnosed via use of the PSA test, compared to modern day, where a majority of cases are diagnosed via the PSA test.  It is possible that the PSA test, by allowing earlier detection of prostate cancer, places most of today’s newly diagnosed males in an even lower risk category than those studied by SPCG-4.

What to do with these lower risk patients is the focus of ongoing trials, including ProtecT (Prostate Testing for Cancer and Treatment trial) and PIVOT (Prostate Cancer Intervention versus Observation Trial), each begun during the era of PSA screening.  Of note, the 12-year follow-up of PIVOT, published in NEJM in 2012, did not show a significant mortality benefit for radical prostatectomy versus watchful waiting—additional data from longer periods of follow-up are being collected.

The 18-year follow-up of SPCG-4 is far from the final answer in the debate over management of localized prostate cancer.  In the meantime, SPCG-4 highlights an important lesson: for those clinicians and patients faced with decisions regarding newly diagnosed prostate cancer, treatment plans should always be considered within the context of the patient’s characteristics and disease severity.  As NEJM Deputy Editor Dan L. Longo notes, “The challenge facing the field is clear: more sophisticated measures are needed to distinguish potentially fatal from non-fatal disease early in the course.”

For clinicians and patients who favor watchful waiting in localized prostate cancer: does SPCG-4 make you more or less likely to consider radical prostatectomy?  For clinicians and patients who favor radical prostatectomy in localized prostate cancer: does SPCG-4 make you more or less likely to consider watchful waiting?

Global Health Author Q&A: University of Toronto’s Prabhat Jha

Posted by Jennifer Zeis • March 3rd, 2014

In a feature for Now@NEJM, we ask the authors of the Global Health review article series — all with different backgrounds, experiences, and perspectives — the same set of questions.

Answers from Prabhat Jha, M.D., D.Phil., of the Center for Global Health Research, St. Michael’s Hospital and Dalla Lana School of Public Health, University of Toronto

Dr. Jha is a co-author of the January 2, 2014, article, “Global Effects of Smoking, of Quitting, and of Taxing Tobacco.”

What do you regard as the most significant triumph in global health within the past decade?

The right time frame for BIG changes in global health is not in years, but over 2-3 decades. Good news? Several:

First, in high-income countries, tobacco deaths in middle age have fallen by half or more. This in turn led to vascular mortality rates at ages 35-69 years in Canada falling by 75% since 1975. By contrast, tobacco deaths in low and middle-income countries are rising, mostly due to the lack of tax and non-tax interventions being used widely (Jha and Peto, Jan 2, 2014 NEJM).

Second, child mortality declines are impressive. Worldwide, the risk of dying before age 5 has fallen from 14% around 1970 to 9% around 1990 to about 5% in 2010.  Still that means about 7 million child deaths a year (of which 1.5 million occur in India alone). Moreover, the costs of saving a child’s life are getting cheaper (Hum, eLife, 2012). Give real credit to the late Jim Grant from UNICEF who in the 1980s really pushed simple effective interventions to save kids.

Third, widespread use of secondary treatments for infectious disease has substantially altered the trajectory of HIV/AIDS (Piot and Quinn, NEJM 2013) and the expansion of artesunate combination therapies for childhood malaria has had a huge impact.  The Affordable Medicines Facility–malaria (AmFm) is a novel financing mechanism to get good high quality drugs worldwide, and does so through a subsidy to private sector delivery (so as to crowd out fake drugs).  Sadly, the Obama’s administration did not support the extension of AmFM and this might die a slowly. It should be revived, and indeed used as a model for other drugs.

In the coming decade, which arena of global health do you feel warrants increased attention and awareness?

While its getting cheaper and cheaper to save a kid’s life, the opposite is happening for adult mortality (Hum, eLife 2012). This is in part due to the big tobacco and HIV epidemics, but more generally to the lack of appropriate investment to make adult survival also “cheaper, faster, better.”  Top of the list is of course tobacco, and Dean Jamison and Larry Summer’s (Lancet, 2013) recommended a big tax on tobacco as the top priority for global health — as did we (Jha and Peto, NEJM, 2014). Secondly, low cost secondary treatments for vascular disease are highly effective. A simple combination of blood pressure pills, aspirin and statins can reduce the risk of a middle aged person with existing vascular disease dropping dead from a heart attack or stroke or being hospitalized again from 1 in 2 over 10 years to 1 in 6.

Third, the world has started paying attention to direct measurement. Efforts such as the ongoing Indian Million Death Study (Westley, Nature, Dec 5, 2013) have shown the feasibility of low cost, direct evidence on the causes of death, risk factors, and the impact of interventions. This is a welcome alternative from indirect estimates such as the Global Burden of Disease, which rely on econometric models. GBD has actually estimates causes of death for 850 people based on one actual, representative death (Jha, BMC Med, 2014). This is bound to create serious errors. Thus direct measurement of the causes of death is needed.

How can we best harness the revolution in IT to improve health outcomes in the developing world?

IT is a means, not an end. The important things to think about are how low-cost, high impact public health prevention AND treatment approaches plus good measurement (the basic, historic recipe for good public health over the last 200 years) can be applied to a few BIG diseases. Then the use of IT should be thought to catalyze these public health strategies. It’s a mistake, as Bill Gates himself has pointed out to put too much stock in technology before the public health and clinical treatment strategies.

When American physicians think of global health, many are dissuaded from a global health career because they cannot spend a majority of their time abroad.  What are other ways for physicians to contribute to this discipline?

The main engine of global health improvements over the last century has been knowledge and technology (broadly defined as drugs, diagnostics, interventions, strategies, epidemiological studies, etc). As Harold Varmus and colleagues point out in the Institute of Medicine Report on global health — these technologies can be produced worldwide and shared worldwide. Thus the old model of “travel medicine” should be thrown out in favour of a shared research and knowledge model. This means that young doctors, epidemiologists, economists and other disciplines can invest in global health careers, and that western Universities should encourage them to do so. But they need to be unafraid to ask big questions and ask what will really make a difference.We are fortunate to be living during an extraordinary time of global health progress. We can envision that in our lifetimes (including a middle-aged hack like me), we might get premature mortality in LMICs to look like that in Canada. The tools to do so are knowledge (lots) and money (lots, but less important than knowledge).


Bleeding and Coagulopathies in Critical Care

Posted by Sara Fazio • February 28th, 2014

In the latest article in our Critical Care series, “Bleeding and Coagulopathies in Critical Care,” common abnormalities of blood coagulation leading to thrombosis or bleeding in the intensive care unit are reviewed.

The definition of a coagulopathy is “a condition in which the blood’s ability to clot is impaired.”

Clinical Pearls

• What are possible adverse events associated with the use of fresh frozen plasma?

Retrospective studies of military and civilian casualties showing improved survival with transfusion of 1 U of fresh-frozen plasma for each unit of red cells have resulted in earlier administration of an increased number of units of fresh-frozen plasma. However, these studies have been criticized, particularly for methodologic flaws that include survival bias and heterogeneity between studies. Despite the lack of evidence that bleeding after surgery and gastrointestinal or obstetric hemorrhage are associated with hemostatic changes similar to those in acute traumatic coagulopathy, the early use of a transfusion ratio of fresh-frozen plasma to red cells of 1:1 or 1:2 has become widespread. This increased use of plasma is not risk-free, since the incidence of transfusion-related acute lung injury is increased, as may be the risk of the acute respiratory distress syndrome (ARDS). In one study involving trauma patients requiring a nonmassive transfusion (<10 U of packed red cells within 12 hours after admission), the administration of more than 6 units of fresh-frozen plasma, as compared with no transfusion, was associated with an increase by a factor of 12 in the rate of ARDS and an increase by a factor of 6 in the multiple organ dysfunction syndrome.

• What is the utility of tranexamic acid in the setting of acute bleeding?

Tranexamic acid is a synthetic lysine amino acid derivative that functions to diminish the breakdown of fibrin by plasmin (i.e., a fibrinolytic agent). Tranexamic acid should be administered to all patients with major bleeding after trauma. This recommendation is supported by a large, randomized, controlled trial, the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) study, in which 20,000 trauma patients with bleeding or at risk for major bleeding were randomly assigned to receive either tranexamic acid or placebo. Patients received tranexamic acid within 3 hours after injury had a one-third reduction in deaths from bleeding. The drug ceased to confer benefit and appeared to be associated with increased mortality if it was administered more than 3 hours after injury. The incidence of thrombosis after trauma was not increased in the study patients. Strong evidence that tranexamic acid reduced the need for blood transfusion in surgery has been available for years, although the effect of tranexamic acid on thromboembolic events and mortality in such patients remains uncertain.

Morning Report Questions

Q: What is the pathogenesis, presentation, and appropriate treatment for disseminated intravascular coagulation (DIC)?

A: DIC typically originates in the microvasculature and can cause damage of such severity that it leads to organ dysfunction. DIC usually presents as hemorrhage, with only 5 to 10% of cases presenting with microthrombi (e.g., digital ischemia) alone. Sepsis is the most common cause of DIC in critical care. The consumption of the coagulation proteins and platelets produces a bleeding tendency, with thrombocytopenia, a prolonged prothrombin time and activated partial-thromboplastin time, hypofibrinogenemia, and elevated levels of fibrin degradation products, such as d-dimers. The physiologic anticoagulants are also consumed in the process of inhibiting the many activated coagulation factors. In fulminant DIC, the consumption and exhaustion of platelets and coagulation proteins usually results in oozing at vascular access sites and wounds but occasionally causes profuse hemorrhage. The cornerstone for managing this condition remains the management of the underlying cause (e.g., sepsis). Guidelines for management are based mainly on expert opinion, which suggests replacement of coagulation proteins and platelets in patients who are bleeding. The use of antifibrinolytic agents is contraindicated in the management of DIC, since the fibrinolytic system is required in recovery to ensure the dissolution of the widespread fibrin.

Figure 2.Pathogenesis of Disseminated Intravascular Coagulation in Sepsis.

Table 2. Diagnostic Scoring System for Disseminated Intravascular Coagulation (DIC).

Q: What is the pathogenesis, presentation and appropriate treatment for thrombotic thrombocytopenic purpura (TTP)?

A: TTP is a microangiopathic hemolytic anemia causing red-cell fragmentation. The majority of cases of TTP are due to a deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13), a disorder that may be hereditary or caused by autoimmune destruction. The rate of death in untreated cases is nearly 95%, but with early plasmapheresis, the survival rate is 80 to 90%. The use of rituximab, a chimeric monoclonal antibody against the surface B-cell protein CD20, which leads to destruction of those cells, has been shown to reduce the rate of recurrence of the acquired form of this disorder from 57% to 10%. Thrombotic thrombocytopenic purpura is a medical emergency and in untreated cases is associated with a rate of death of 90%, usually from myocardial infarction due to platelet thrombi in the coronary arteries. An active diagnosis of this disorder or failure to rule it out should lead to urgent plasmapheresis.