Dying with Dignity in the Intensive Care Unit

Posted by Sara Fazio • June 27th, 2014

It is common for patients to have an expected death in an ICU. The final review in the Critical Care series covers issues related to the end of life in the absence of discordance between the patient’s family and caregivers.

The traditional goals of intensive care are to reduce the morbidity and mortality associated with critical illness, maintain organ function, and restore health. Despite technological advances, death in the intensive care unit (ICU) remains commonplace.

Clinical Pearls

According to the authors, what are the principles of “dying with dignity?”

The definition of “dying with dignity” recognizes the intrinsic,unconditional quality of human worth but also external qualities of physical comfort, autonomy, meaningfulness, preparedness, and interpersonal connection. Respect should be fostered by being mindful of the “ABCDs” of dignity-conserving care (attitudes, behaviors, compassion, and dialogue).

Table 1. Examples of the ABCDs of Dignity-Conserving Care.

How is palliative care defined by the World Health Organization?

The World Health Organization defines palliative care as “an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” Palliative care, which is essential regardless of whether a medical condition is acute or chronic and whether it is in an early or late stage, can also extend beyond the patient’s death to bereaved family members.

Figure 1. Curative and Palliative Approaches to Care throughout a Critical Illness.

Morning Report Questions

Q: How is family satisfaction in the ICU setting impacted by communication with clinicians?

A: Clear, candid communication is a determinant of family satisfaction with end-of-life care. Notably, measures of family satisfaction with respect to communication are higher among family members of patients who die in the ICU than among those of ICU patients who survive, perhaps reflecting the intensity of communication and the accompanying respect and compassion shown by clinicians for the families of dying patients. The power of effective communication also includes the power of silence. Family satisfaction with meetings about end-of-life care in the ICU is greater when physicians talk less and listen more.

Q: How many physicians in the ICU feel comfortable making recommendations to forgo the use of life-supporting technology, and how many report consistently doing so?

A: Physicians in the ICU sometimes make recommendations to forgo the use of life-support technology. In one study involving surrogates of 169 critically ill patients, 56% preferred to receive a physician’s recommendation on the use of life support, 42% preferred not to receive such a recommendation, and 2% stated that either approach was acceptable. A recent survey of ICU physicians showed that although more than 90% were comfortable making such recommendations and viewed them as appropriate, only 20% reported always providing recommendations to surrogates, and 10% reported rarely or never doing so. In this study, delivering such recommendations was associated with perceptions about the surrogate’s desire for, and agreement with, the physician’s recommendations. Other potential influences are uncertainty, personal values, and litigation concerns.

Prophylaxis against Venous Thromboembolism in Ambulatory Cancer Patients

Posted by Sara Fazio • June 27th, 2014

Patients with cancer are at increased risk for thrombosis, and those with thrombi have poorer overall survival rates than those without. In a new review article, Dr. Jean Connors from Brigham and Women’s Hospital and Dana Farber Cancer Institute summarizes available data and provides guidance for determining which patients might benefit from thromboprophylaxis.

The incidence of cancer-associated thrombosis is increasing, probably because of a combination of improved treatment outcomes resulting in longer patient survival, more aggressive and prothrombotic treatment regimens, an aging population, and increased detection owing to improvements in imaging technology and the frequency of imaging.

Clinical Pearls

What is the differential risk of venous thromboembolism among patients with cancer compared to patients without cancer?

The risk of venous thromboembolism is four to seven times as high among patients with cancer as among persons without this disease.  This risk is highest among patients with certain types of solid tumors and hematologic cancers and is increased among patients who are receiving chemotherapy or radiotherapy, who are undergoing operative procedures, who have metastatic disease, or who have inherited thrombophilias.

What are results in two recent trials of low-molecular-weight heparin preparations used for prophylaxis in cancer patients?

The PROTECHT [Prophylaxis of Thromboembolism during Chemotherapy] study randomly assigned 1150 ambulatory patients with cancer to receive prophylactic nadroparin or placebo. The nadroparin group, as compared with the placebo group, had a 50% reduction in composite venous and arterial events (2.0% vs. 3.9%, P=0.02). The SAVE-ONCO trial randomly assigned 3212 ambulatory patients receiving chemotherapy for locally advanced solid tumors or metastatic cancer to receive a prophylactic dose of semuloparin or placebo. The overall incidence of venous thromboembolism was 1.2% in the semuloparin group, as compared with 3.4% in the placebo group (hazard ratio, 0.36; 95% confidence interval, 0.21 to 0.60; P<0.001).

Morning Report Questions

Q: At what platelet threshold should anticoagulant therapy be held in patients with cancer receiving chemotherapy and prophylactic anticoagulation?

A: Ambulatory patients with cancer who are receiving chemotherapy and prophylaxis against venous thromboembolism can be more closely monitored, and anticoagulation therapy can be withheld if there are changes in renal function or the platelet count that suggest an increased risk of bleeding. All guidelines suggest withholding any dose of anticoagulation drug if the platelet count is less than 50,000 per cubic millimeter; however, for very high-risk patients, the continued use of prophylactic anticoagulation therapy can be considered if the platelet count is more than 30,000 per cubic millimeter.

Q: What are current guidelines on the use of prophylactic anticoagulation against venous thromboembolism in ambulatory patients with cancer?

A: Current guidelines from the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) have subtle differences, but all advise against the use of routine prophylaxis against venous thromboembolism in most ambulatory patients with cancer. An exception is made for patients with multiple myeloma who have received either multiagent chemotherapy or thalidomide-lenalidomide regimens that include dexamethasone; among these patients, rates of venous thromboembolism of 23 to 75% have been reported.

Table 2. Comparison of Recommendations Regarding Prophylaxis against Venous Thromboembolism.

Atrial Fibrillation in Cryptogenic Stroke

Posted by Carla Rothaus • June 25th, 2014

Your 69-year-old patient has just had an ischemic stroke. Fortunately, he should make a good recovery. And yet, you feel unsettled. A standard post-stroke work up – 12-lead ECG, ambulatory 24-hour Holter ECG monitoring, brain and neurovascular imaging, and echocardiography – failed to reveal a cause for his stroke, putting it in the “cryptogenic” stroke category. You worry though, that he might have intermittent episodes of atrial fibrillation you simply have been unable to detect….

Patients who have had a stroke or transient ischemic attack (TIA) caused by atrial fibrillation are at significant risk for recurrent stroke, yet atrial fibrillation is often asymptomatic and intermittent (paroxysmal), and may escape detection with short periods of ECG monitoring. Distinguishing strokes caused by atrial fibrillation from those without identifiable cause has important therapeutic implications. While anti-platelet therapy is the recommended treatment for cryptogenic stroke, it is much less effective than anticoagulation in preventing recurrent stroke when the cause is atrial fibrillation. Multiple observational studies have suggested that prolonged ECG monitoring is superior to conventional 24-hour ECG monitoring in identifying atrial fibrillation in patients with stroke. Data from randomized clinical trials have been lacking however, and new practice guidelines have not been adopted.

This week’s NEJM includes the results of two studies designed to address this void. Gladstone et al. conducted a multicenter trial (EMBRACE) that randomized 572 patients to undergo ambulatory monitoring with either a 30-day event-triggered external loop recorder or one additional round of 24-hour Holter monitoring. Eligible patients were 55 years or older, had no history of atrial fibrillation, and had been given a diagnosis of cryptogenic stroke or TIA after standard work up was negative. The primary outcome was detection of one or more episodes of ECG-documented atrial fibrillation or flutter lasting 30 seconds or longer within 90 days after randomization. A multicenter randomized controlled trial performed by Sanna et al. (CRYSTAL AF) compared prolonged monitoring with an implantable loop recorder to conventional ECG monitoring in 441 patients 40 years or older with recent cryptogenic stroke or TIA.

Both studies showed that long-term monitoring in the intervention group resulted in a higher rate of detection of atrial fibrillation. In EMBRACE, atrial fibrillation was detected in about 1 out of 6 patients in the intervention group, as compared to about 1 out of 30 in the control group; the difference was significant at the P<0.001 level. In CRYSTAL AF, the rate of detection of atrial fibrillation was about 1 out of 11 among patients in the intervention group, as compared to less than 1 in 50 among patients in the control group; this difference was also significant (P<0.001).

In an accompanying editorial, Dr. Hooman Kamel (Weill Cornell Medical College) calls the study findings an “important advance,” and concludes that “prolonged monitoring of heart rhythm should now become part of the standard care of patients with cryptogenic stroke.” He notes however that prior studies establishing the benefit of antithrombotic therapy for paroxysmal atrial fibrillation included patients whose arrhythmia was detected with conventional monitoring; additional research is needed, he cautions, to assure that brief episodes of paroxysmal atrial fibrillation detected with prolonged monitoring present a similar stroke risk and merit similar treatment.

NEJM Executive Editor Dr. Gregory Curfman adds, “These studies support the application of prolonged ECG monitoring for the detection of paroxysmal atrial fibrillation in patients with stroke. This approach may allow more targeted use of anticoagulation for stroke prevention.”

Apply for NEJM Editorial Fellowship

Posted by Karen Buckley • June 23rd, 2014

The Journal invites applications for a one-year, full-time, paid editorial fellowship beginning in July 2015 from medical professionals at any career stage.  Applications are due by September 1, 2014.

The editorial fellow reviews and edits Images in Clinical Medicine submissions and organizes the Clinical Decisions series under the supervision of senior editors.  The fellow also moderates commenting at NEJM.org, does tagging for the Journal home page, writes Insights posts for the Now@NEJM blog, and contributes to other Journal work.

Participation in day-to-day editorial activities constitutes about 70% of the role.  For the remaining 30%, we expect fellows to undertake a project of their own choosing.

We are looking for candidates who have good medical judgment, can communicate that judgment in good written English, and can work independently.  Applicants do not need to be U. S. citizens, but successful candidates must reside in the Boston area for the duration of the fellowship.  Please send curriculum vitae and a description of the project you would like to pursue to Pam Miller, 10 Shattuck Street, Boston, MA 02115 or editorial@nejm.org by September 1, 2014.

For more insight on the NEJM fellowship experience, see the article by Dr. Terry Schraeder, a former NEJM fellow, “NEJM Fellowship: The Ultimate Journal Club,” in Science Editor, July – August 2005, Vol 28, No 4 , 141-142. Although written 10 years ago, it remains applicable to today’s fellowship.

Tofacitinib versus Methotrexate in Rheumatoid Arthritis

Posted by Sara Fazio • June 20th, 2014

In patients with rheumatoid arthritis, tofacitinib was associated with greater reductions in signs and symptoms than methotrexate. Herpes zoster infections and increases in creatinine and in LDL and HDL cholesterol levels were more common with tofacitinib.

Rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation and by joint destruction that leads to substantial disability. The predominant first-line treatment is methotrexate, a nonbiologic agent that is associated with acceptable clinical and functional improvements. Although methotrexate prevents progressive joint damage in some patients, concerns have been raised regarding its side effects and safety.

Clinical Pearls

What is tofacitinib, and what was the purpose of this study?

Tofacitinib is a new, oral, small-molecule Janus kinase (JAK) inhibitor that has been developed for the treatment of rheumatoid arthritis. In phase 3 studies, safety concerns about tofacitinib have included a risk of serious infection and changes in laboratory measurements. The authors report the clinical, structural, and safety outcomes of ORAL Start, a 24-month study of tofacitinib monotherapy as compared with methotrexate in patients with active moderate-to-severe rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate.

What was the radiographic progression in the tofacitinib groups compared to the methotrexate group?

Patients in both tofacitinib groups had significantly less radiographic progression from baseline, as reflected by the modified Sharp scores for erosion and joint-space narrowing, than patients in the methotrexate group at months 6, 12, and 24.

Morning Report Questions

Q: What were the clinical and patient-reported outcomes in the tofacitinib groups compared to the methotrexate group?

A: The mean (+/-SE) proportion of patients who had an American College of Rheumatology (ACR) 70 response (ACR 70 response indicates a 70% or greater reduction in the number of both tender and swollen joints) at month 6 (the coprimary end point) was 25.5+/-2.3% (94 of 369 patients) in the 5-mg tofacitinib group and 37.7+/-2.4% (148 of 393 patients) in the 10-mg tofacitinib group, as compared with 12.0+/-2.4% (22 of 184 patients) in the methotrexate group (P<0.001 for either dose vs. methotrexate). Greater reductions in arthritis pain and disease activity at month 6 were also reported by patients in both tofacitinib dose groups as compared with patients in the methotrexate group at month 6.

Table 2. Coprimary and Secondary Efficacy End Points.

Q: What adverse events were associated with tofacitinib in this study?

A: The most common adverse events were infections and gastrointestinal disorders. Herpes zoster infections occurred in 13 of 373 patients (3.5%) in the 5-mg tofacitinib group and in 18 of 397 patients (4.5%) in the 10-mg tofacitinib group — a total of 31 of 770 patients (4.0%) in the combined tofacitinib groups — as compared with 2 of 186 patients in the methotrexate group (1.1%). A total of 106 patients discontinued the study drug because of adverse events, 105 patients (11.0%) had serious adverse events, and 24 patients (2.5%) had serious infections. Six confirmed cases of cancer were reported: two (non-Hodgkin’s lymphoma and chronic lymphocytic leukemia) in the 5-mg tofacitinib group, three (prostate cancer, Burkitt’s B-cell lymphoma, and colon cancer) in the 10-mg tofacitinib group, and one (gastric cancer) in the methotrexate group. At 24 months, decreases in mean absolute neutrophil counts and increases in mean serum creatinine levels were seen in all groups. Serum creatinine levels increased from baseline by 33% or more in 37 of 373 patients who received 5 mg of tofacitinib (9.9%) and in 38 of 397 patients who received 10 mg of tofacitinib (9.6%), as compared with 5 of 186 patients who received methotrexate (2.7%).

Table 3. Safety Data from Months 0 to 24.

19-Year-Old Woman with Headache, Fever, Stiff Neck, and Mental-Status Changes

Posted by Sara Fazio • June 20th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 19-year-old woman was admitted to the pediatric ICU because of a headache, fever, photophobia, neck stiffness, and mental-status changes. She was drowsy and disoriented with respect to year. She had truncal ataxia and rotatory nystagmus, and her face and right arm were numb.

In a 2010 study, M. pneumoniae was detected at autopsy in brain tissue of 3 patients (2 with encephalitis and 1 with acute disseminated encephalomyelitis) and in the CSF in approximately 50 patients, with the use of either culture or PCS; these findings suggest the possibility of a direct M. pneumoniae infection of the central nervous system. In addition, anti-galactocerebroside (GalC) antibodies have been detected in the blood, the CSF, or both (with the use of ELISA) in some patients with M. pneumoniae-associated encephalitis, particularly those with evidence of demyelination on MRI.

Clinical Pearls

What were the results of the California Encephalitis Project in 2006 regarding causes of encephalitis?

In the California Encephalitis Project, of the 1570 patients who participated in the study that was published in 2006, a confirmed or probable cause of encephalitis was identified in 24% (the cause was infectious in 16% and noninfectious in 8%), a possible infectious cause was identified in 13%, and no cause was identified in the remaining 63%. The most commonly identified cause was M. pneumoniae; it was considered a possible cause and not a confirmed or probable one in nearly all cases. The following viral causes were each identified in at least 1% of patients: enterovirus, herpes simplex virus, varicella-zoster virus, West Nile virus, and Epstein-Barr virus.

What is neuromyelitis optica?

Neuromyelitis optica is an inflammatory disorder typically characterized by a bilateral optic neuropathy and cervical myelopathy. Patients with neuromyelitis optica can present with longitudinally extensive myelitis without optic neuritis, and cerebral involvement with encephalopathy can be present, particularly in younger patients. Also, patients with neuromyelitis optica are more likely than patients with other demyelinating disorders to have eosinophils in the CSF. Extensive leptomeningeal enhancement is rarely described with neuromyelitis optica.

Morning Report Questions

Q: What limitations are there when interpreting serologic testing for M. pneumoniae?

A: The interpretation of serologic tests for M. pneumoniae is complicated both by the persistence of antibodies against M. pneumoniae after infection and by the imperfect sensitivity and specificity of available assays. The IgM antibody response peaks approximately 3 weeks after infection and then begins to decline, but it may persist for several months. Since tests for IgM antibodies against M. pneumoniae can have both false negative and false positive results, the serologic diagnosis is most reliable when the IgG antibody titer in convalescent-phase serum specimens is four times as high as the IgG antibody titer in acute-phase serum specimen.

Q: How reliable is PCR testing of cerebrospinal fluid for M. pneumoniae?

A: The results of PCR testing of CSF for M. pneumoniae have been reportedly inconsistent among patients with central nervous system disease that is attributed to mycoplasma infection, even when the testing is performed early in the clinical course. CSF PCR testing for M. pneumoniae is not widely available, although assays that have not been approved by the FDA are offered at some institutions and reference laboratories. The performance characteristics of these assays vary, and the reference standard to which they should be compared is unknown. PCR assays detected M. pneumoniae in the CSF in only 2% of the 111 patients in the California Encephalitis Project who received a diagnosis of encephalitis associated with M. pneumoniae.

Vote Now on Clinical Decisions: Genetic Testing

Posted by Karen Buckley • June 19th, 2014

A 45-year-old health conscious patient who has been with your primary care practice for several years mentions at a regular visit his three relatives with cancers of the breast, ovary, and prostate. He wants to know about genetic testing and any preventive measures he can take.

Do you think he should receive genetic screening? If so, should he be referred for whole-genome sequencing or sequencing of cancer genes only?

Read more about the patient, and arguments for each approach from two experts in the field, in the new Clinical Decisions. Then vote and comment at NEJM.org. Voting is open until July 3.

Naloxegol for Opioid-Induced Constipation

Posted by John Staples • June 18th, 2014

Did opioid-induced constipation contribute to Elvis Presley’s death? Would he still be making music today if he’d won the battle with his bowels? Though many disagree, Elvis’ former personal physician thinks that a cure for the King’s constipation might have spared his life.

If this kind of conjecture from suspicious minds leaves you all shook up (or at least wishing for a little less conversation), simply consider this: Opioid-induced constipation adversely affects quality of life for millions of Americans annually. Many of these individuals obtain little relief from lifestyle changes and laxatives. Peripherally acting m-opioid receptor antagonists mitigate the effect of opioids on the gastrointestinal tract, yet neither of the currently available agents are approved by the FDA for use in outpatients with chronic noncancer pain. Are there any other options on the horizon?

In this week’s NEJM,  Dr. William D. Chey (University of Michigan Health System, Ann Arbor, MI) and his KODIAC colleagues present two identically-designed multicenter randomized phase III trials of a new peripherally acting m-opioid receptor antagonist. The two trials randomized a total of 1352 adult outpatients with noncancer pain and opioid-induced constipation to one of three groups: Higher-dose naloxegol (25mg daily), lower-dose naloxegol (12.5mg daily), or placebo. Laxative and other bowel regimens were stopped, and patients recorded bowel movements and pain levels in a daily diary for the duration of the trial.

After 12 weeks of treatment, patients in the higher-dose naloxegol groups were more likely to respond than were placebo-treated patients (40% vs 29% and 44% vs 29%; p<0.025 for both). Adverse events such as abdominal pain and diarrhea were significantly more common in the higher-dose naloxegol groups than among the placebo groups (61% vs 47% and 69% vs 59%; p<0.01 for both). Lower-dose naloxegol was superior to placebo in only one of the two trials. Serious adverse events, pain scores, and daily opioid doses were similar across all groups.

“Constipation is a major concern for many patients taking opioids,” says primary-care provider and NEJM Deputy Editor Dr. Mary Beth Hamel. “These studies did not compare naloxegol to other available treatments for constipation, and the observed benefits over placebo were not large. Nevertheless, peripheral m-opioid receptor antagonists may be one more option for patients and clinicians to try.”

Test Your Skills with a New Interactive Medical Case

Posted by Karen Buckley • June 16th, 2014

The latest Interactive Medical Case presents a 64-year-old man with gait instability, visual changes, diffuse weakness, headaches, and worsening shortness of breath with activity. Test your diagnostic and therapeutic skills at NEJM.org.

Interactive Medical Cases are online simulations based on a real patient’s experience of illness. You follow interactive steps through an evolving patient’s history, diagnosis, and management, from presentation to outcome. During the presentation of the case, you access videos, lab results and brief commentary that explain concepts important for diagnosis and treatment.

Browse the list of previous Interactive Medical Cases. Try one or all 30 cases and earn CME credit or MOC points now!

The Child or Adolescent with Elevated Blood Pressure

Posted by Sara Fazio • June 13th, 2014

Evaluation of children and adolescents with hypertension can detect evidence of the secondary systemic effects of hypertension (in particular, renal disease). Initial therapy is usually nonpharmacologic, but pharmacotherapy is used if other methods fail, hypertension is severe, or there are coexisting conditions such as diabetes mellitus.  NEJM Deputy Editor and Massachusetts General Hospital pediatrician Dr. Julie Ingelfinger is the author of this new Clinical Practice review article.

The prevalence of elevated blood pressure among children and adolescents has been increasing worldwide in concert with the marked increase in the prevalence of obesity among the young.

Clinical Pearls

How is hypertension defined in a child or adolescent?

Hypertension is diagnosed in a young person if the mean systolic blood pressure or diastolic blood pressure is above the 95th percentile for sex, age, and height on three or more occasions. Stage 1 hypertension is defined as blood pressure between the 95th and 99th percentile plus 5 mm Hg, and stage 2 hypertension is defined as blood pressure above the 99th percentile plus 5 mm Hg. Prehypertension is defined as a mean systolic or diastolic blood pressure at or above the 90th percentile but below the 95th percentile or blood pressure of 120/80 mm Hg or greater, even if the blood pressure is at or below the 90th percentile (and up to the 95th percentile).

Table 2. Classifications of Blood Pressure and Therapeutic Approaches.

In addition to a history and physical examination, what evaluation is recommended in children or adolescents with hypertension?

Evaluation of hypertension in children and adolescents is generally phased. In addition to a careful history taking and physical examination, a phase 1 evaluation to identify common secondary causes is recommended in patients with blood pressure that is persistently at or above the 95th percentile and in patients with diabetes, cardiac disease, and other chronic conditions if the blood pressure is above the 90th percentile. This evaluation includes basic laboratory tests (measurement of levels of blood urea nitrogen, creatinine, and electrolytes; a complete blood count; and a urinalysis and urine culture) and renal ultrasonography to assess for renal scarring, disparate kidney size, and congenital anomalies. About 80% of cases of secondary hypertension in children are attributed to renal disease, and another 10% are attributed to renovascular disease. Left ventricular mass should also be assessed; the interpretation must consider the patient’s height, body-surface area, and level of fitness.

Table 3. Continued Evaluation for Pediatric Hypertension.

Morning Report Questions

Q: What are the principles of nonpharmacologic therapy in childhood hypertension?

A: Lifestyle changes are recommended for children with prehypertension or stage 1 hypertension. These approaches include a program of dynamic exercise (i.e., exercise that involves substantial and recurrent body movement, such as bicycling or running); a balanced diet with a high intake of fruits, vegetables, and low-fat dairy products, as well as a reduction in dietary sodium; a weight-reduction program in patients who are overweight; and reinforcement of adherence to these practices. Several studies involving children and adolescents have suggested that successful weight loss is effective in decreasing blood-pressure levels. However, effecting such changes is often difficult. The inclusion of family participation appears to be useful, if not essential, particularly if the child needs to lose weight.

Q: When should medication be started in a child with hypertension and what is the best choice of agent?

A: If blood pressure does not improve with lifestyle changes, or if concerted efforts to encourage lifestyle modification are not successful, medication may be indicated. Medication should be initiated if there are symptoms or coexisting conditions or if there is an identified secondary cause of hypertension or evidence of end-organ damage in children or adolescents with stage 1 hypertension. In addition, drug therapy should be initiated routinely in young people with stage 2 hypertension. There is no consensus regarding the best initial therapy for hypertension in children and adolescents; comparative trials are lacking in the pediatric population. A survey of pediatric nephrologists indicated that 47% considered ACE inhibitors to be first-line therapy, 37% chose calcium-channel blockers, 15.3% chose diuretics, and 6.6% chose beta-blockers (some chose more than one medication as a first-line agent).

Table 4. Selected Oral Medications for Hypertension in Children and Adolescents.