From Medscape Neurology & Neurosurgery
From Medscape Medical News
Mediterranean Diet, Physical Activity Linked to Lower Alzheimer’s Risk
August 14, 2009 — Two new cohort studies come to slightly different conclusions about the merit of adherence to a Mediterranean-type diet on the risk for Alzheimer’s disease (AD).
In 1 study, researchers led by Nikolaos Scarmeas, MD, from Columbia University Medical Center in New York City, extend their previous findings, showing that both high adherence to the Mediterranean diet and higher levels of physical activity were independently associated with a lower risk for AD in a cohort of community-dwelling elders free of dementia at baseline.
In the other study, Catherine Féart, MD, from the Université Victor Ségalen Bordeaux 2 in Bordeaux, France, and colleagues, including Dr. Scarmeas, find that higher adherence to the Mediterranean diet was associated with slower cognitive decline when measured using the Mini-Mental State Examination (MMSE), but not when measured with other cognitive tests. No association was seen for adherence to the diet and the risk for incident dementia, although the researchers point out that the power to detect a difference was limited in this study.
Both reports are published in the August 12 issue of the Journal of the American Medical Association.
In an editorial accompanying the publications, David Knopman, MD, from the Mayo Clinic in Rochester, Minnesota, assesses these results cautiously and points out that the benefits of an inherent tendency to healthy food choices in free-living individuals are most likely accrued over a lifetime and in concert with other kinds of healthy choices.
“I see diet as part of a larger pattern of healthy behaviors, and I see this result as supporting the idea that risk reduction for dementia begins at least in midlife, if not earlier,” he told Medscape Neurology. “I really believe that changing one’s dietary habits at age 70 is probably a good thing incrementally, but the greater benefit accrues the earlier a change in diet is adopted.”
Lower AD Risk With Diet?
The Mediterranean diet features a high intake of vegetables, legumes, fruits, and cereals; a high intake of unsaturated fatty acids, mostly in the form of olive oil; a low intake of saturated fatty acids; a moderately high intake of fish; a low to moderate intake of dairy products, mostly as cheese or yogurt; a low intake of meat or poultry; and finally, a regular but moderate amount of alcohol, usually wine, generally taken with meals.
Previous research has shown that following a Mediterranean diet is protective against a variety of conditions, including hypertension, coronary heart disease, dyslipidemia, diabetes, obesity, and certain cancers, and is related to a reduction in all-cause mortality in the general population. Previous work by Dr. Scarmeas and colleagues has shown that higher adherence to the Mediterranean diet is associated with a lower risk for AD, as well as prolonged survival in AD (Ann Neurol. 2006;59:912–921; Neurology. 2007;69:1084–1093).
Another, earlier, report from the Washington Heights-Inwood Columbia Aging Project (WHICAP) by this group, published in the February issue of the Archives of Neurology and reported by Medscape Neurology at that time, suggested that elderly subjects who followed a Mediterranean diet were less likely to develop mild cognitive impairment and were also less likely to convert from mild cognitive impairment to AD (Arch Neurol. 2009;66:216–225).
The current report is an extension of these latter findings from WHICAP, this time looking at the relative contributions of physical exercise and the Mediterranean diet on the risk for AD.
Subjects in 2 cohorts totaling 1880 community-dwelling elderly people without dementia were followed up for a mean of 5.4 years, with standardized neurological and neuropsychological testing done every 1.5 years. Adherence to a Mediterranean-type diet and amount of physical activity were derived from questionnaires and divided into low, middle, and high adherence to the diet and no, some, or much physical activity; all models were adjusted for a variety of factors including ethnicity, education, and apolipoprotein E genotype.
During follow-up, 282 incident cases of AD occurred. Compared with those participants with low adherence to the Mediterranean diet, those individuals with high adherence had a significantly reduced risk for AD. Similarly, those reporting much physical activity at baseline had a significantly reduced risk for AD vs those reporting no physical activity.
Those reporting no physical activity and low adherence to a Mediterranean-type diet had an absolute risk for AD of 19%, whereas those reporting much physical activity and high adherence diet scores had an absolute risk for AD of 12%.
Risk for AD by Adherence to Mediterranean Diet and Amount of Physical Activity
| Measure | Hazard Ratio | 95% CI | P for Trend |
| Low Diet Score | Referent | — | — |
| Middle Diet Score | 0.98 | 0.72 – 1.33 | |
| High Diet Score | 0.60 | 0.72 – 0.80 | .08 |
| No Physical Activity | Referent | — | — |
| Some Physical Activity | 0.75 | 0.54 – 1.04 | .08 |
| Much Physical Activity | 0.67 | 0.47 – 0.95 | .03 |
| High Diet Score Plus Much Physical Activity vs Low Diet Score and No Physical Activity | 0.65 | 0.44 – 0.96 | .03 |
Their results “support the potentially independent and important role of both physical activity and dietary habits in relation to AD risk,” the researchers conclude. “These findings should be further evaluated in other populations.”
Three-City Study
The second report by Dr. Féart and colleagues used data from the Three-City study, a prospective cohort study examining vascular risk factors for dementia in 1410 adults living in Bordeaux who were 65 years of age or older in 2001 to 2002. Adherence to the Mediterranean diet was again assessed using a food questionnaire, and cognitive performance was measured using the MMSE, Isaacs Set Test (IST), Benton Visual Retention Test (BVRT), and Free and Cued Selective Reminding Test (FCSRT). Assessments were done at baseline and at least 1 other time during 5 years of follow-up.
A total of 99 new cases of dementia were validated by an independent expert committee of neurologists.
After adjustment for a variety of factors, the researchers found that a higher Mediterranean diet score was associated with fewer MMSE errors (β = .006; P = .04, for 1 point of the Mediterranean diet score), but not with performance on the other tests, particularly for those who remained free from dementia during 5 years.
However, adherence to the Mediterranean diet was not associated with the risk for incident dementia, although the researchers point out that their power to detect a difference on this endpoint was limited.
“The Mediterranean diet pattern probably does not fully explain the better health of persons who adhere to it, but it may contribute directly,” the authors speculate. “A Mediterranean diet also may indirectly constitute an indicator of a complex set of favorable social and lifestyle factors that contribute to better health. Further research is needed to allow the generalization of these results to other populations and to establish whether a Mediterranean diet slows cognitive decline or reduces incident dementia in addition to its cardiovascular benefits,” the authors conclude.
Findings to Be “Nibbled, Not Swallowed Whole”
In his editorial, Dr. Knopmen suggests that to say the Féart paper supports that of Scarmeas et al is “debatable,” pointing out that although the MMSE results in the Three-City study would seem to be in line with the WHICAP data, this was true only when it was considered as a continuous and not as a categorical variable.
“The lack of consistent association with the other cognitive measures, especially the FCSRT, is of concern if pre-AD pathology was the target of the Mediterranean-type diet,” he writes.
The studies reported in this issue, along with the earlier report by Scarmeas et al, provide only “moderately compelling evidence that adherence to the Mediterranean-type diet is linked to less late-life cognitive impairment,” Dr. Knopmen concludes. He cautions against the sort of “feeding frenzy” of media attention with these 2 studies that was seen after the initial report this year by Scarmeas et al, pointing out that the “nuanced science of these studies…should not be consumed so unabashedly.”
“The scientific value of these studies cannot be disputed, but whether or how they can or should be translated into recommendations for the public is the question,” Dr. Knopman writes. “For now, it is reasonable to nibble on these findings and savor them, but not to swallow them whole.”
The Washington Heights-Inwood Columbia Aging Project is supported by the National Institute on Aging. The authors have disclosed no relevant financial relationships. The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et del la Recherche Médicale (INSERM), the Institut de Santé Publique et Développement of the Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The authors have disclosed no relevant financial relationships. Dr. Knopman reports serving on a data and safety monitoring board for Sanofi-Aventis Pharmaceuticals (completed October 2008) and receiving personal compensation. Other disclosures appear in his editorial.
JAMA. 2009;302:627–637, 638–648, 686–687. Abstract
Clinical Context
The benefits of the Mediterranean diet on the reduction of cardiovascular disease, cancer, and overall mortality rate have been supported by numerous studies. The Mediterranean diet consists of plant foods (such as fruits, nuts, legumes, and cereals) and fish, with olive oil as the primary sources of monounsaturated fat and low to moderate intake of wine as well as low intake of red meat and poultry. In 2006, one study by Scarmeas and colleagues reported that adherence to the Mediterranean-type diet was also associated with a reduced incidence of AD; however, more studies are needed.
In this issue of the Journal of the American Medical Association, 2 articles report the results of studies designed to replicate and expand on the initial reports. In the study by Scarmeas and colleagues, the aim was to evaluate the association of the Mediterranean-type diet adherence and physical activity with the risk for incident AD. In another study by Féart and colleagues, it attempted to replicate the association of Mediterranean-type diet and cognitive decline as previously reported.
Study Highlights
- Scarmeas and colleagues
- 2 cohorts of 1880 elderly adults without dementia living in New York City were assessed for both diet and physical activity in relationship to AD risk.
- Standardized neurologic and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006.
- Participants were evaluated for adherence to a Mediterranean diet and physical activity, separately and combined, as the main predictors in Cox models.
- Models were adjusted for comorbid risk factors with the Charlson index.
- Main outcome measure was time to incident AD.
- 282 incident AD cases occurred at a mean (SD) of 5.4 (3.3) years of follow-up.
- Compared with individuals who were cognitively normal, characteristics of those who had AD were older, less educated, more likely to be Hispanic, less likely to be white, had a lower body mass index, reported slightly more leisure activities, and were less physically active.
- In both adjusted and unadjusted models, more physical activity was associated with lower risk for AD. Report of some physical activity was associated with a 29% to 41% lower risk for AD, whereas report of much physical activity was associated with a 37% to 50% lower risk.
- When considered simultaneously, both Mediterranean-type diet adherence and physical activity were associated with lower AD risk.
- The middle diet adherence tertile was associated with a 2% to 14% risk reduction, whereas the highest diet adherence tertile was associated with a 32% to 40% reduced risk.
- Similarly, compared with individuals with no physical activity, individuals reporting some physical activity had a 25% to 38% lower risk for AD, whereas individuals reporting much physical activity had a 33% to 48% lower risk for AD.
- Compared with individuals neither adhering to the diet nor participating in physical activity, those both adhering to the diet and participating in physical activity had a lower risk for AD (hazard ratio, 0.65; P = .03 for trend).
- Overall, the association of physical activity and Mediterranean-type diet was independent of each other.
- Féart and colleagues
- 1410 adults (≥ 65 years) from Bordeaux, France, included in the Three-City cohort in 2001 to 2002, were evaluated for whether adherence to a Mediterranean diet was associated with change in cognitive performance and lower risk for all-cause dementia or AD.
- Adherence to a Mediterranean diet (score 0 – 9) was computed from a food frequency questionnaire and 24-hour recall (median score 4.36 [SD, 1.66]).
- Main outcome measure was the cognitive performance assessed on 4 neuropsychological tests: the MMSE, IST, BVRT, and FCSRT.
- Incident cases of dementia (n = 99) were validated by an independent expert committee of neurologists.
- After adjusting for cardiovascular risk factors and stroke, higher Mediterranean diet score was associated with fewer MMSE errors (β = −0.006; P = .04 for 1 point of Mediterranean diet score).
- Overall performance on the IST, BVRT, or FCSRT with time was not significantly associated with Mediterranean diet adherence.
- Greater adherence as a categorical variable (score 6 – 9) was not significantly associated with fewer MMSE errors and better FCSRT scores in the entire cohort, but in individuals who were free from dementia for 5 years, the association for the highest vs the lowest group was significant (adjusted for all factors, for MMSE: β = −0.03; P = .04; for FCSRT: β = 0.21; P = .04).
- Mediterranean diet adherence was not associated with risk for incident dementia (fully adjusted model: hazard ratio, 1.12; P = .72), although this study was underpowered for this outcome.
Clinical Implications
- In the study by Scarmeas and colleagues, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with a reduced risk for AD.
- In the study by Féart and colleagues, higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline; however, higher adherence was not associated with the risk for incident dementia.
New Guidelines Address Treatment of Hospitalized Patients With High Blood Glucose Levels
News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP
CME/CE Released: 05/11/2009; Valid for credit through 05/11/2010
May 11, 2009 — A consensus statement of the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) issues clinical recommendations on the proper treatment of hospitalized patients with high blood glucose levels.
The new guidelines, which target healthcare professionals, supporting staff, hospital administrators, and others involved in improved management of hyperglycemia in inpatient settings, are published in the May/June issue of Endocrine Practice and in the May issue of Diabetes Care.
“Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients,” write Etie S. Moghissi, MD, FACP, FACE, from the University of California in Los Angeles, and colleagues. “There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) suggested that intensive treatment of hyperglycemia improved hospital outcomes.”
In 2004, the American College of Endocrinology (ACE) and the AACE, in collaboration with the ADA and other medical organizations, developed recommendations for treatment of inpatient hyperglycemia. These guidelines generally endorsed tight glycemic control in critical care units. In 2005, the ADA annual Standards of Medical Care included recommendations for treatment of inpatient hyperglycemia. In 2006, the ACE and ADA collaborated on a joint “Call to Action” for inpatient glycemic control, highlighting several barriers to systematic implementation in hospitals.
Questions to Be Considered
The main objectives of the AACE and ADA in preparing this updated consensus statement were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. After extensive review of the most current literature, members of the consensus panel considered the following questions:
1. Does improving glycemic control for inpatients with hyperglycemia improve clinical outcomes?
2. What glycemic targets should be recommended for different patient populations?
3. In specific clinical situations, which available treatment options can safely and effectively achieve optimal glycemic targets?
4. What safety issues are associated with inpatient management of hyperglycemia?
5. What systems need to be in place to implement these recommendations?
6. Is it cost-effective to treat hyperglycemia in hospitalized patients?
7. What are the best strategies to shift management of hyperglycemia to outpatient care?
8. What additional research is needed?
Recommendations for Critically Ill Patients
Specific clinical recommendations for critically ill patients are as follows:
• For treatment of persistent hyperglycemia, beginning at a threshold of no greater than 180 mg/dL (10.0 mmol/L), insulin therapy should be started.
• For most critically ill patients, a glucose range of 140 to 180 mg/dL (7.8 – 10.0 mmol/L) is recommended once insulin therapy has been started.
• To achieve and maintain glycemic control in critically ill patients, the preferred method is intravenous insulin infusions.
• Validated insulin infusion protocols that are shown to be safe and effective and to have low rates of hypoglycemia are recommended.
• To reduce hypoglycemia and to achieve optimal glucose control, frequent glucose monitoring is essential in patients receiving intravenous insulin.
Recommendations for Patients Who Are Not Critically Ill
Specific clinical recommendations for noncritically ill patients are as follows:
• For most noncritically ill patients receiving insulin therapy, the premeal blood glucose target should generally be less than 140 mg/dL (< 7.8 mmol/L), and random blood glucose levels should be less than 180 mg/dL (< 10.0 mmol/L), provided these targets can be safely achieved.
• In stable patients in whom tight glycemic control was previously achieved, more rigorous targets may be appropriate.
• In terminally ill patients or in those with severe comorbidities, less stringent targets may be appropriate.
• For achieving and maintaining glucose control, the preferred method is scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components.
• Prolonged treatment with sliding-scale insulin as the only therapeutic agent is discouraged.
• For most hospitalized patients who require treatment of hyperglycemia, noninsulin antihyperglycemic agents are not appropriate.
• Day-to-day decisions concerning treatment of hyperglycemia must be based on clinical judgment and ongoing evaluation of clinical status.
Safety Recommendations
Specific recommendations geared toward improving safety in management of inpatient hyperglycemia are as follows:
• Major safety issues include overtreatment and undertreatment of hyperglycemia.
• Hospital staff must be educated to engage the support of those involved in the care of inpatients with hyperglycemia.
• In patients with anemia, polycythemia, hypoperfusion, or use of some medications, caution is needed when interpreting results of point-of-care glucose meters.
• To promote a rational systems approach to inpatient glycemic management, buy-in and financial support from hospital administration are required.
The guidelines also propose a selected number of research questions and topics to guide the management of inpatient hyperglycemia in different hospital settings.
“Appropriate inpatient management of hyperglycemia is cost-effective,” the guidelines authors conclude. “Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management.”
Some of the guidelines authors have disclosed various financial relationships with sanofi-aventis U.S. LLC; Amylin Pharmaceuticals, Inc;Takeda Pharmaceuticals North America, Inc; AstraZeneca; GlaxoSmithKline; Johnson & Johnson Services, Inc; Eli Lilly & Co; Medtronic, Inc; Novo Nordisk A/S; Halozyme Therapeutics; MannKind Corporation; Abbott Laboratories; F. Hoffman La Roche Ltd. (Roche); and/or Merck & Co.
Endocr Pract. 2009;15:1-15.
Diabetes Care. Published online May 8, 2009.
Clinical Context
Hyperglycemia is common in the inpatient setting, and reducing high blood glucose levels is associated with better patient outcomes. However, a study by Finfer and colleagues, which was published in the March 26, 2009, issue of The New England Journal of Medicine, found that more intense glucose treatment could actually result in higher mortality rates in critically ill patients.
Compared with a cohort of patients randomly assigned to a target blood glucose level of 180 mg/dL or less, participants randomly selected to target glucose levels of 81 to 108 mg/dL experienced a 14% increase in the risk for death. Rates of hypoglycemia were much higher in the intensive vs standard-control group, and intensive therapy did not significantly alter the duration of hospital stay, the need for renal replacement therapy, or the number of days of mechanical ventilation.
The current review examines the sum of evidence for the management of hyperglycemia in inpatient settings and makes treatment recommendations.
Study Highlights
- Treatment of hyperglycemia is associated with reduced rates of wound infection after cardiothoracic surgery, lower rates of infection and lower poor neurologic outcomes in patients with traumatic brain injury, and reduced rates of congestive heart failure after acute myocardial infarction.
- The current recommendations state that hyperglycemia be treated at a threshold of 180 mg/dL in critically ill patients. The target glucose level should be between 140 and 180 mg/dL.
- Intravenous insulin infusion is the preferred means of treatment of hyperglycemia in critically ill patients.
- There is less clinical evidence regarding the treatment of hyperglycemia in hospitalized patients who are not critically ill, so the current recommendations regarding this subject are based on clinical experience and judgment. The authors suggest that premeal glucose targets should be less than 140 mg/dL, and random blood glucose values should be less than 180 mg/dL.
- Less stringent treatment criteria may be appropriate for terminally ill patients and those with severe comorbidities.
- To avoid hypoglycemia in patients without critical illness, clinicians should consider altering the insulin regimen if blood glucose levels decline below 100 mg/dL.
- The ideal treatment of hyperglycemia in noncritically ill hospitalized patients should involve basal, nutritional, and correction insulin delivered subcutaneously.
- Treatment with sliding-scale insulin therapy alone is discouraged, and noninsulin antihyperglycemic agents do not have a significant role among inpatients.
- Hyperglycemia develops in many patients receiving corticosteroids. These patients should receive at least 48 hours of blood glucose monitoring and treatment as appropriate.
- In patients receiving continuous enteral or parenteral nutrition, blood glucose monitoring should be performed every 4 to 6 hours. Glucose testing should be performed every 30 minutes to 2 hours in patients receiving intravenous insulin infusions.
- Appropriate inpatient management of hyperglycemia is cost-effective.
- Multidisciplinary teams can establish and enforce local hospital recommendations regarding inpatient treatment of hyperglycemia, and preprinted order sets and computerized ordering systems can improve guideline adherence.
Clinical Implications
- A recent study found a higher risk for death associated with more intensive treatment of hyperglycemia in critically ill patients.
- The current recommendations suggest that antihyperglycemic treatment should begin when the blood glucose level reaches 180 mg/dL among critically ill inpatients, and blood glucose levels should be maintained between 140 and 180 mg/dL in these patients. Blood glucose levels should be maintained below 140 mg/dL before meals and below 180 mg/dL at random times among other inpatients.
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Author(s)
Laurie Barclay, MD
Laurie Barclay, MD, is a freelance writer and reviewer for Medscape.
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
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Brande Nicole Martin is the News CME editor for Medscape Medical News.
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Accreditation Coordinator, Continuing Professional Education Department, MedscapeCME; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland
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CME Author(s)
Charles P. Vega, MD
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Charles P. Vega, MD, FAAFP, is an associate professor and residency director in the Department of Family Medicine at the University of California, Irvine.Disclosure: Charles Vega, MD, FAAFP, has disclosed no relevant financial relationships. |
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CME/CE Released: 05/11/2009; Valid for credit through 05/11/2010
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Advancing Insomnia Treatment to Enhance Quality of Sleep
Michael J. Thorpy, MB, ChB
CME Released: 04/30/2009; Valid for credit through 04/30/2010
Pre-Assessment: Measuring Educational Impact
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Introduction
Normal adults spend approximately one third of their life asleep, a physiologically active state necessary for emotional, mental, and physical health.[1] Many people are affected with difficulty sleeping, although estimates of prevalence of insomnia vary depending on how it is defined. Insomnia affects approximately 1% to 10% of the general adult population and up to 25% of the elderly.[2] The 1-year prevalence of insomnia ranges from 30% to 45% in adults.[2] Up to 21% of the population has serious symptoms and functional impairment as a result of insomnia.[3] Insomnia is more prevalent in women, with increasing age,[2] and in those with lower socioeconomic status.[1]
Insomnia is generally considered both a symptom and a disorder. According to the International Classification of Sleep Disorders (ICSD-2) by the American Academy of Sleep Medicine, insomnia is generally defined as a “a complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically unrestorative or poor in quality” (Table 1).[4] The ICSD-2 subsequently classifies insomnia into distinct etiologic categories. The fourth Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association, on the other hand, separates primary insomnia from insomnia secondary to other disorders (Table 1).[2]
Table 1. Diagnostic Criteria for Insomnia
| International Classification of Sleep Disorders-2 General Criteria for Insomnia[4] | A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early, or sleep that is chronically unrestorative or poor in quality. In children, the sleep difficulty is often reported by the caretaker and may consist of observed bedtime resistance or inability to sleep independently. |
| The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep. | |
| At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the patient: fatigue or malaise; attention, concentration, or memory impairment; social or vocational dysfunction or poor school performance; mood disturbance or irritability; daytime sleepiness; motivation, energy, or initiative reduction; proneness for errors or accidents at work or while driving; tension, headaches, or gastrointestinal symptoms in response to sleep loss; concerns or worries about sleep. | |
| Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision Criteria for Primary Insomnia[2] | The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month. |
| The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. | |
| The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia. | |
| The disturbance does not occur exclusively during the course of another mental disorder (eg, major depressive disorder, generalized anxiety disorder, delirium). | |
| The disturbance is not the direct physiologic effects of a substance (eg, a drug of abuse, a medication) or a general medical condition. |
The cause of primary insomnia is unknown but is thought to be related to a state of “hyperarousal” associated with higher levels of adrenocorticotropic hormone, cortisol, and increased beta activity and decreased theta and delta on electroencephalogram (EEG).[5] A positron emission tomography study in which 7 patients with insomnia were compared with 20 healthy controls demonstrated greater global cerebral glucose metabolism during sleep and wake states in the subjects with insomnia that was consistent with hyperarousal.[6] Subjects with insomnia also had a smaller decline in relative metabolism between wake and sleep states in wake-promoting regions and decreased relative metabolism in the prefrontal cortex while awake.[6] However, the underlying brain mechanisms of hyperarousal remain unknown.[6]
Secondary insomnia is more common than primary insomnia[5] and may be classified as adjustment insomnia (caused by psychosocial stressors), or as being the result of inadequate sleep hygiene (lifestyle), psychiatric disorders, medical conditions, or drugs or substances (Table 2). A less than optimal sleep environment, such as may occur in patients hospitalized for medical, surgical, or psychiatric illness, may result in secondary insomnia.[7] Insomnia may be characterized by problems falling asleep (prolonged sleep latency [SL]), problems staying asleep (sleep maintenance), insufficient sleep duration, or nonrestorative sleep (not rested) that results in daytime impairment despite adequate opportunity for sleep.[8] Sleep initiation problems are more common in young adults, whereas older individuals tend to have problems with sleep maintenance and early morning awakening.[2]
Table 2. Classification of Adult Insomnia
| Primary Insomnia | Idiopathic (begins in infancy with unremitting course) |
| Psychophysiologic (bed associated with increased arousal, not sleep) | |
| Paradoxic (polysomnographic findings inconsistent with sleep report) | |
| Secondary Insomnia | Adjustment insomnia associated with psychosocial stressors |
| Inadequate sleep hygiene (lifestyle habits that impair sleep) | |
| Psychiatric disorder (eg, anxiety, depression) | |
| Medical condition (eg, chronic pain, nocturnal cough, dyspnea, hot flashes, restless legs syndrome) | |
| Drug or substance (eg, medication, alcohol, caffeine, substance abuse) |
From Silber MH. Chronic insomnia. N Engl J Med. 2005;353:803-810.
Insomnia is commonly associated with psychiatric and medical disorders (comorbid insomnia).[3] In one study, 72% of people affected with anxiety disorder had insomnia; insomnia also appeared in more than 40% of people later diagnosed with a mood disorder.[3] Medical disorders commonly associated with insomnia include asthma, chronic obstructive pulmonary disease, congestive heart failure, chronic pain, end-stage renal disease, gastroesophageal reflux, hyperthyroidism, ischemic heart disease, neurodegenerative disease, and rheumatologic disorders.[3]
Insomnia may also be secondary to other sleep-related disorders. Restless legs syndrome, characterized by uncomfortable leg sensations that are relieved by walking, is a common sleep disorder associated with sleep-onset and sleep-maintenance insomnia and may result in severe insomnia.[3] Restless legs syndrome affects up to 10% of the general population and is more common in pregnancy.[3] Restless legs syndrome may be linked to periodic limb movements of sleep and obstructive sleep apnea.[3] Obstructive sleep apnea, circadian rhythm disorders, and periodic limb movement disorder may also result in insomnia. Rarely, parasomnias may result in insomnia and include disorders of arousal from nonrapid eye movement (NREM) sleep (sleepwalking and sleep terrors), abnormal behaviors associated with obstructive sleep apnea, REM sleep behavior disorder, and nocturnal sleep-related eating disorder.[3]
Duration of Insomnia
In both the ICSD-2 and DSM-IV criteria, a diagnosis of insomnia requires that the insomnia last at least 1 month and cause some form of impaired daytime function. “Transient” insomnia lasts less than 1 week, “short-term” insomnia lasts 1 to 4 weeks,[5] and “chronic” insomnia persists for more than 1 month[8] or 6 months.[3] Chronic insomnia affects 10% to 15% of the population and is more frequent in the elderly, in women, and in patients with medical and psychiatric illness.[5] A thorough evaluation for the cause of chronic insomnia may be time-consuming,[8] but the cause can usually be found.[5]
Chronic insomnia is associated with reduced quality of life, impaired daytime functioning, absence from work, and increased healthcare costs.[9] People with chronic insomnia are more likely to be depressed and to use hypnotic drugs chronically.[9] The diagnosis of insomnia is based on subjective complaints rather than on laboratory tests such as actigraphy or polysomnography.[9]
Whether primary or secondary to medical, psychiatric, substance abuse, or other causes, insomnia should be identified and addressed to prevent adverse consequences associated with sleep disruption.[9] Unfortunately, many people with insomnia fail to report it to their physicians.[10]
Slow-Wave Sleep
Normal sleep is composed of 2 distinct states: REM sleep and NREM sleep. REM sleep may be identified by low-amplitude, mixed-frequency EEG (see the section Sleep Architecture and Polysomnography), active extraocular movements, and muscle atonia, evidenced by absent chin electromyogram. NREM is divided into 4 stages characterized by increasing slow waves on the EEG. NREM stages 3 and 4 are termed slow-wave sleep (SWS).[11] These EEG parameters can be used to categorize the amount of sleep depth, with SWS corresponding to deep sleep.[12]
SWS decreases with age; significant reductions in the amount of SWS are already observed in middle-aged subjects (48 to 55 years old) in comparison with younger subjects (18 to 25 years old).[13] The amount of time spent in SWS, as evaluated by duration or percentage of SWS during a sleep session, correlates with preceding periods of wakefulness and sleep. Subjects with 4 hours of sleep deprivation during an 8-hour sleep period had a longer duration of SWS during a sleep recovery period the next night.[14] Other studies demonstrated that the time of the day when a subject takes a nap (eg, later in the day vs earlier in the day) also correlates with SWS, with the longest period of SWS occurring after a longer period of prolonged wakefulness or when naps are taken later in the day.[12] A study by Ferrara and colleagues[15] demonstrated that the amount of SWS from the proceeding night determines the amount of SWS during the subsequent night; healthy subjects were deprived of SWS for 2 consecutive nights while sparing other stages of sleep, and these subjects had a significant increase in the amount of stage 4 and SWS during the recovery night sleep vs baseline night sleep. Collectively, these data suggest that SWS plays a role in regulating sleep, and if deprived of SWS, rebound SWS occurs during the next sleep period. Thus, SWS is the first and most robust sleep stage to return when a person is deprived of sleep.
Further supporting the idea that SWS contributes to the regulation of sleep are studies of patients diagnosed with primary insomnia. Increased fast EEG activity during sleep onset and NREM sleep have been observed in patients with primary insomnia, and these particular EEG activities have been correlated with a perception of reduced quality of sleep.[16] In studies that compared “good sleepers” with those with primary insomnia, patients with insomnia had a deficiency of SWS, as assessed by duration and percentage of SWS.[16] In addition, patients with primary insomnia have been shown to increase their amount of SWS following successful treatment, suggesting that the SWS homeostasis is capable of functioning normally when initially impaired.[16]
Consequences of Insomnia
Daytime consequences of insomnia include decreased energy, difficulty concentrating, decreased memory, fatigue, low motivation, and productivity loss.[2,3] Sleep-related psychophysiologic problems may be increased, such as gastric distress, tension headache, and increased muscle tension.[2] In addition, decreased feelings of well-being,[2] including anxiety, depression, and increased worry may occur, as well as interpersonal difficulties.[3] Increased healthcare use is another consequence of insomnia.[2] Between 1999 and 2003, those with insomnia had estimated direct and indirect healthcare costs that were approximately $1253 greater in adults aged 18 to 64, and approximately $1143 greater in adults aged 65 and over compared with healthcare costs of age-matched adults who did not have insomnia.[17]
Normal sleep is an important regulator of many physiologic functions, including appetite, weight maintenance, and energy balance.[18] Disturbed sleep may result in altered mood, excessive daytime sleepiness, and neurocognitive changes with a resultant increased risk for work-related and automotive accidents.[19]
Nonrestorative sleep is a subjective classification indicating that sleep is restless or of poor quality, even though the actual sleep duration seems normal.[20] Nonrestorative sleep can be associated with decreased performance and excessive daytime sleepiness.[20] In a population study of 25,580 people in 7 European countries, the prevalence of nonrestorative sleep was 10.8% and was significantly more frequent in women (12.5%) than in men (9%). Nonrestorative sleep was also reported more frequently in subjects < 55 years old, separated/divorced individuals, night-shift workers, and those with 9 years or less of education.[20] Compared with subjects who have difficulty initiating or maintaining sleep, subjects with nonrestorative sleep were more likely to have symptoms of daytime impairment such as irritability and physical and mental fatigue, and were more likely to consult a physician about insomnia.[20]
Sleep and Physical Function
A century ago, a good night’s sleep was about 9 hours.[19] According to a recent poll, 33% of Americans sleep less than 6.5 hours a night.[19] Along with a decrease in sleep duration, the general population has experienced an increase in obesity.[19] A prospective study of 924 adults between 18 and 91 years old revealed a nearly linear relationship between sleep duration and weight, with less sleep correlating with overweight and obese status.[19] Sleep disorders were common in this population, with 32% of the subjects reporting insomnia, 8% reporting restless legs syndrome, 8% reporting periodic limb movements of sleep, 6% reporting obstructive sleep apnea syndrome, and 0.2% reporting narcolepsy.[19] Those with medical disorders such as arthritis, diabetes mellitus, gastroesophageal reflux, and hypertension had a significantly greater body mass index than other participants.[19] Being overweight is also associated with shorter sleep duration in children, regardless of gender, race, or maternal education level.[18] A study of Japanese junior high school students revealed a significant relationship between increased sleepiness and body mass index in both boys and girls.[21]
The effect of shortened sleep duration on obesity may be related to changes in circulating leptin, ghrelin, insulin, and glucose levels affecting appetite and carbohydrate metabolism.[18] Insufficient sleep may play a role in the development of metabolic and cardiovascular disorders known as the metabolic syndrome.[22] However, although insufficient sleep and weight gain are linked, a cause and effect relationship has not been firmly established.[19]
Insufficient sleep duration and poor sleep efficiency may lower resistance to infection.[23] For example, a controlled study of 153 volunteers exposed to a rhinovirus demonstrated that a cold was 3 times more likely to develop in those who had less than 7 hours of sleep than in those who had 8 hours or more of sleep. Further, a cold was 5.5 times more likely to develop in those with less than 92% sleep efficiency than in those with sleep efficiency of 98% or more.[23] In the laboratory, sleep deprivation decreases immune function, as evidenced by reduced natural killer cell activity, suppressed interleukin-2 production, and increased circulating proinflammatory cytokines, supporting the clinical observation of increased susceptibility to infection.[23] Sleep may play an important role in acute response to infection and host defense.[24]
Sleep and Mental Health
Insomnia is a risk factor for anxiety, mood, and substance use disorders and is an essential or associated feature of major depressive disorder, generalized anxiety disorder, and schizophrenia.[2] Insomnia is a risk factor for first onset and recurrent major depressive disorder[25] and may exacerbate the severity, duration, and relapse rates of depression.[25] Treatment of the insomnia should not be overlooked, as it may help improve and possibly prevent the depression.[25] In children and young adolescents, poor sleep quality and decreased sleep quantity are associated with increased aggression, conduct disorders, impaired memory, and decreased academic performance.[18]
Poor sleep efficiency has also been associated with increased anxiety.[26] In one study, 3040 women (mean age 83.6) had sleep actigraphy for at least 3 nights and completed the 9-item Goldberg Anxiety Scale and the 15-item Geriatric Depression Scale. Elevated scores on the Goldberg Anxiety Scale (≥ 6) in 280 women (9.2%) were associated with poor sleep efficiency and more time awake after sleep onset (sleep fragmentation), even after correcting for depressive symptoms, medical comorbidities, and use of antianxiety medications.[26]
Assessment and Diagnosis
Primary insomnia may begin suddenly, and may be associated with medical, psychological, or social stress, although a clear precipitant is not always apparent and symptom onset may be gradual.[2] However, a state of heightened arousal and negative conditioning may cause insomnia to persist.[2] The clinical course is variable,[2] but 50% to 75% of individuals with insomnia have chronic symptoms that last a year or more.[2] A prior episode of insomnia is the strongest risk factor for the development of later insomnia.[2] The role of genetic factors in primary insomnia is unclear.[2] Insomnia related to a mental disorder, such as major depression or schizophrenia; to physical disorders such as congestive heart disease or chronic obstructive pulmonary disease; or to substance abuse, such as excessive caffeine intake, is not considered primary insomnia.[2]
Insomnia may be precipitated by a life event, such as a death in the family, illness, medication, pain, stress, travel, or other precipitant, but it often continues long after the initial event has passed.[3] The patient’s bed may become associated with not sleeping, and the insomnia persists. This is known as “conditioned insomnia.”[3] One clue to the diagnosis of conditioned insomnia is that the person sleeps better outside his or her own bedroom.
Assessment for the presence of insomnia begins with a history from the patient and bed partner (if available) followed by a physical examination.[3] The typical physical examination for a patient with primary insomnia is unremarkable or consistent with fatigue. However, findings of a crowded oropharynx, hypertension, obesity, or peripheral edema raise suspicion for sleep apnea. The history should include possible precipitating factors such as exercise, illness, medication, stress, timing of meals, and use of caffeine, alcohol, and drugs.[3] For clinicians, 2 questions may be sufficient to detect the presence of an underlying sleep disturbance: (1) In general are you sleeping well? (2) Are you able to maintain alertness throughout the day? Negative responses to these questions dictate a more in-depth evaluation.
A sleep diary that includes naps and is kept for 2 weeks may help elicit the timing, amount, and continuity of a patient’s sleep.[3,27] A urine toxicology screen to exclude stimulant drugs such as amphetamines, ephedrine, and cocaine may be useful when indicated.[3] The bed partner can provide information regarding snoring and breathing patterns, which may point toward a diagnosis of sleep apnea,[3] or unusual physical activity, which suggests a movement disorder or parasomnia.
One useful assessment tool is the Epworth Sleepiness Scale, which can be administered in just a few minutes.[28] The scale contains 8 questions (Table 3). Responses are scored 0 (no chance of dozing) to 3 (high chance of dozing). A score of 10 or more is considered “sleepy,” and a score of 15 or more is considered “very sleepy.” Patients who score > 10 should be cautious about driving until their sleepiness improves.
Table 3. Epworth Sleepiness Scale
| Situation | Chance of Dozing* |
| Sitting and reading | |
| Watching television | |
| Sitting inactive in a public place (eg, a theater or a meeting) | |
| As a passenger in a car for an hour without a break | |
| Lying down to rest in the afternoon when circumstances permit | |
| Sitting and talking to someone | |
| Sitting quietly after a lunch without alcohol | |
| In a car, while stopped for a few minutes in traffic |
*Scoring: 0 = no chance of dozing; ≥ 10 = excessive sleepiness; 1 = slight chance of dozing; ≥ 15 = severe sleepiness; 2 = moderate chance of dozing; 3 = high chance of dozing
From Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540-545.
Another useful and easy-to-complete sleep questionnaire is the 5-item subjective Insomnia Severity Index (ISI) (Figure). A score of 8 to 14 indicates subthreshold insomnia, and a score of 15 or greater indicates clinical insomnia.[29]
Figure. Insomnia Severity Index. From Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297-307.
Both the Epworth Sleepiness Scale and the ISI are useful questionnaires to assist in patient evaluation, but their scores in and of themselves do not make the diagnosis of a sleep disorder. Scores on the Epworth Sleepiness Scale and ISI do not correlate well with polysomnographic findings and are not intended as screening measures for polysomnographic sleep abnormalities.[30]
To assess for anxiety and depression, the most common psychiatric conditions associated with insomnia, the Beck Depression and Beck Anxiety Inventories are simple, validated tools that may be used.[3] These tools should be administered when anxiety or depression is suspected, or when the history fails to reveal an underlying cause for the insomnia.[3] If a psychiatric disorder is present, concurrent management by a psychiatrist may benefit the insomnia.[3]
Sleep Architecture and Polysomnography
The average duration of sleep for most adults is 7 to 8 hours.[11] Characteristic changes in the EEG, electro-oculogram, and muscle activity measured by surface electromyogram correspond to distinct sleep stages that occur throughout the sleep period.[11] These parameters may be continuously monitored in the laboratory by polysomnography.
Polysomnography is the formal physiologic monitoring of sleep in an overnight laboratory with EEG, electrocardiogram, air flow, respiratory and muscle movement, and other monitoring. Increased SL, intermittent wakefulness, and decreased sleep efficiency are typical polysomnographic findings in subjects with insomnia.[2]
Changes in sleep architecture can provide sensitive markers in insomnia. Insomnia is usually characterized by an increased time to fall asleep (SL), an increased amount of wake time after sleep onset and decreased sleep efficiency. There are an increased number of arousals, awakenings, and lighter sleep stages. Time spent in stage 1 may be increased and time spent in deep sleep (stage 3 and 4) may be decreased.[2] Considerable variability in polysomnographic findings from night to night may be expected.[2] Subjective complaints of insomnia may correlate poorly with polysomnographic findings because subjects tend to underestimate the quantity of their sleep.[2]
Polysomnography has limited value in the routine evaluation of insomnia.[2] However, polysomnography may be useful in identifying specific sleep disorders that may contribute to insomnia, such as sleep apnea or periodic leg movements of sleep.[2] Indications for polysomnography include the diagnosis of sleep-related breathing disorders, continuous positive airway pressure titration, evaluation of potentially violent or dangerous parasomnias, evaluation of narcolepsy (with a Multiple Sleep Latency Test), or evaluation of insomnia that is refractory to treatment.[5,31]
Another objective test that can provide information on the sleep state is actigraphy, which uses a motion-sensitive wrist monitor to record movement.[3] Activity and rest can correlate well with awake and sleep states, respectively, and the procedure is simple.[3] However, actigraphy may be inaccurate because some people with insomnia lie awake for prolonged periods without much movement.[3] Although it is not necessary for the routine diagnosis of restless legs syndrome or periodic limb movement disorder, actigraphy may be useful in documenting response to treatment.[31] Actigraphy is particularly useful in the diagnosis of circadian rhythm disorders.[3,31]
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Insomnia Treatment
A logical approach to the treatment of insomnia will benefit from the classification of insomnia into 1 of 4 categories depending on the cause. These include: (1) stress, bad habits, or poorly timed activities (ie, late exercise); (2) primary sleep disorder (chronic insomnia, circadian rhythm disorder, obstructive sleep apnea, restless legs syndrome, periodic limb movements disorder); (3) insomnia secondary to a medical or neurologic disorder; and (4) insomnia secondary to a psychiatric disorder.
For the short-term management of transient insomnia, no treatment at all may be appropriate or a hypnotic medication may be required.[3] However, the management of chronic insomnia is more complex, often requiring behavioral modification as well as medication treatment.[3]
Interventions include nonpharmacologic behavioral techniques such as sleep hygiene training, relaxation training, stimulus-control therapy, and sleep-restriction therapy (Table 4).[3] Treatment often includes a combination of nonpharmacologic and pharmacologic methods. Pharmacologic management includes benzodiazepine agonists, benzodiazepine hypnotics and anxiolytics, sedating antidepressants, a melatonin agonist, and combined pharmacotherapies.[3] When chronic insomnia is related to a medical or psychiatric illness, treatment for these comorbidities should be optimized.[1]
Table 4. Cognitive-Behavioral Therapy
| Sleep hygiene education |
| Stimulus-control therapy |
| Sleep-restriction therapy |
| Relaxation therapy |
| Cognitive therapy |
From Schenck CH, Mahowald MW, Sack RL. Assessment and management of insomnia. JAMA. 2003;289:2475-2479 and Silber MH. Chronic insomnia. N Engl J Med. 2005;353:803-810.
Nonpharmacologic Therapy
Nonpharmacologic strategies include a group of techniques that can be very effective, enduring therapy for chronic insomnia and should not be overlooked as treatment options.[3,32] Overall, they are as effective as pharmacotherapy and can have longer-lasting effects.[33] These techniques include sleep hygiene education, stimulus-control therapy, sleep-restriction therapy, relaxation therapy, and cognitive-behavioral therapy.
Attention to sleep hygiene should not be neglected. Many people with insomnia are unaware of simple behavioral steps that may improve their insomnia. For example, long naps, naps late in the day, or excessive caffeine intake may interfere with nighttime sleep.[3] A comfortable sleep environment should be provided with respect to light, noise level, and temperature.[9] Exercise is generally recommended to facilitate sleep, but not late in the day, where it may result in unwanted arousal.[3] Other stressful activities should also be avoided late in the day.[3] Abstaining from illicit drugs and excessive alcohol are important features of good sleep hygiene.
Sleep restriction therapy reinforces the concept that the bed is a place for sleeping; when patients cannot sleep, they should not stay in bed. The time in bed is set to the time spent sleeping. This approach improves sleep efficiency and alters the perception of the bed from a place where one cannot sleep to a place where one can sleep. Sleep restriction is most likely to be effective in motivated patients.[3] Stimulus-control therapy involves having the patient go to bed when sleepy; if unable to sleep, the patient should get out of bed and do something quietly until he or she feels the need for sleep. Possibilities for relaxation training include biofeedback, guided imagery, hypnosis, meditation, progressive muscle relaxation, and yoga.[3] Cognitive therapy attempts to counter dysfunctional beliefs about sleep. Cognitive-behavioral therapy may require a specially trained clinician, usually a clinical psychologist.
The American Academy of Sleep Medicine Practice Parameters endorsed psychological and behavioral interventions as effective in the treatment of chronic primary and secondary insomnia.[9] Cognitive-behavior therapy, stimulus-control therapy, and relaxation training are individually effective for chronic insomnia with a high degree of certainty.[9] Biofeedback and paradoxic intention, multicomponent therapy (without cognitive therapy), and sleep-restriction therapy are effective for chronic insomnia with a moderate degree of clinical certainty.[9]
Cognitive-behavioral therapy is likely to result in meaningful clinical improvement in about 50% of patients with primary insomnia and may be equivalent or superior to medication therapy.[5] In one study of older adults with chronic primary insomnia, cognitive-behavior therapy was superior to medication treatment (zopiclone).[34] The combination of pharmacotherapy and cognitive-behavioral therapy does not appear to be more effective than either one alone,[5] although some studies have shown benefit using a combined approach.[35] If the clinician does not have the time to teach the patient, a sleep-trained nurse or psychologist may provide behavioral treatment in a general medical practice.[3] However, significant benefits can be achieved with even a few short sessions delivered by the primary care physician.[5]
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Pharmacotherapy
Multiple options exist for pharmacotherapy of insomnia and many have an effect on sleep architecture (Table 5). US Food and Drug Administration-approved treatments include 3 benzodiazepine drugs (estazolam, temazepam, and triazolam) and 3 benzodiazepine receptor agonists (eszopiclone, zaleplon, and zolpidem). Class effects of benzodiazepines include reduced REM and SWS.[36] Studies on benzodiazepine receptor agonists suggest that they promote NREM while sparing REM.[37] Some of the benzodiazepine receptor agonists, such as zaleplon, have been shown to promote SWS while reducing REM sleep.[38]
Table 5. US Food and Drug Administration-Approved Pharmaceutical Therapy
| Generic Name | Duration of Action | Half-Life (hr)* | Indications |
| Benzodiazepines | |||
| Temazepam | Intermediate | 8-15 | Mainly for sleep-maintenance insomnia† |
| Estazolam | Intermediate | 10-24 | Mainly for sleep-maintenance insomnia† |
| Triazolam | Short | 2-5 | Mainly for sleep-onset insomnia |
| Benzodiazepine receptor agonists | |||
| Zaleplon | Ultrashort | 1 | For sleep-onset or sleep-maintenance insomnia†‡ |
| Zolpidem | Short | 3 | For sleep-onset or sleep-maintenance insomnia§ |
| Eszopiclone | Intermediate | 5-7 | For sleep-onset or sleep-maintenance insomnia§ |
| Melatonin receptor agonist | |||
| Ramelteon | Short | 2-5 | Mainly for sleep-onset insomnia |
* Half-life of the drug and its active metabolites.
† FDA-approved for short-term management of insomnia (generally lasting 7-10 days)
‡ For sleep-maintenance insomnia, drug is administered on waking during the night.
§ Zee PC, Avidan AY. Sleep Disorders. In Biller J, ed. Practical Neurology. Third Edition. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2008:765-782.
Adapted from Silber MH. Chronic insomnia. N Engl J Med. 2005;353:803-810.
In addition to benzodiazepines and benzodiazepine receptor agonists, a single melatonin receptor agonist, ramelteon is indicated for sleep-onset insomnia.[5] Melatonin is commonly used but is of uncertain efficacy.[5]
Antidepressants such as amitriptyline, doxepin, imipramine, trimipramine, and trazodone are commonly used to treat insomnia, and may have a particular role when concomitant depression is present. However, antidepressants do not have a US Food and Drug Administration-approved indication for insomnia. Over-the-counter antihistamines such as diphenhydramine have not been proven effective for insomnia.[3] They may result in daytime drowsiness, hypotension, and anticholinergic effects; generally they should be avoided.
Short-acting agents are more effective for decreasing SL, and agents with longer half-lives tend to be more effective for improving total sleep time.[5] Physicians should closely monitor medication treatment of insomnia, with attention to potential adverse events such as morning sedation and memory dysfunction. Particularly for benzodiazepines, physicians should watch closely for morning sedation, memory dysfunction, dosage tolerance, or signs of misuse.[3] Rebound insomnia and clinically significant amnesia are more likely with triazolam, a shorter-acting drug.[5] Next-day hangover effects are more common with longer-acting compounds.[1] Side effects from benzodiazepines are more common in the elderly, who require decreased doses.[5] Benzodiazepine receptor agonists have a lower incidence of adverse events, including less daytime sleepiness, orthostatic hypotension, and respiratory depression than benzodiazepines.[1] Eszopiclone has a relatively long half-life (5 to 6 hours), which leads to recommendations for lower doses for sleep-onset insomnia and higher doses for sleep-maintenance insomnia.[1] Eszopiclone has been successfully used for 6 months without the development of tolerance.[5] Zolpidem can be effective for sleep-onset insomnia, and in the longer-acting zolpidem-MR form, can be useful for sleep-onset and sleep-maintenance insomnia. Ramelteon, a selective melatonin MT1 and MT2 receptor agonist, has little potential to become habit-forming and may be particularly appropriate in the elderly.[1] Long-term pharmacologic therapy may be appropriate for some patients with chronic insomnia, especially those who have unresolvable medical or psychiatric disorders.[5]
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Drugs in Development
A new class of drugs is under development for the treatment of insomnia, the selective antagonists/inverse agonists of the 5-HT2A serotonin receptor. These include APD125, AAVE8488, eplivanserin, HY-10275, pimavanserin, and pruvanserin.[1] Two other drugs, quetiapine, approved as an antipsychotic, and esmirtazapine, approved for depression (as mirtazapine, the racemic compound), also are relatively potent antagonists of 5-HT2A receptors and are in phase 3 trials for insomnia.[1] This new drug class has no addictive properties or withdrawal symptoms, which may permit long-term treatment.[1]
These drugs may be more effective in improving sleep maintenance than existing treatments because they affect the 5-HT2A receptor. Activation of 5-HT2 receptors directly increases the firing rate of the dorsal raphe nucleus,[39] part of the reticular activating system that modulates arousal.[1] In particular, the 5-HT2A receptors strongly modify NREM sleep. The 5-HT2 receptor antagonists have been shown to increase NREM sleep in humans.[40] More recently in mouse models, a 5-HT2A receptor antagonist induced an increase in NREM sleep in wild-type animals but not in animals with the 5-HT2A receptor knocked out; in fact, the 5-HT2A receptor knock-out mice had less spontaneous NREM sleep than their wild-type counterparts.[41] In another animal study, 5-HT2A receptor antagonists increased the amount of NREM sleep and delta power (SWS) during NREM sleep. Although the exact role of these receptors in causing a change in sleep-wake activity needs to be further elucidated, taken together, these studies suggest that 5-HT2A receptor antagonists can viably increase NREM and SWS,[42] potentially resulting in more restorative sleep.[1]
In addition to the new class of drugs that target 5-HT2A, there are drugs in development for insomnia that target other neurotransmitters and their receptors, such as melatonin (eg, tasimelteon, an MT1 and MT2 melatonin receptor agonist),[43] histamine (eg, doxepin, a histamine H1 antagonist),[44] GABA (eg, indiplon, an allosteric modulator of the GABAA receptor),[45] and orexin (eg, almorexant, an orexin receptor antagonist).[46] Many of the drugs that target other neurotransmitter receptors do not selectively increase the amount of time spent in SWS. For patients administered doxepin, the stages of sleep were generally maintained and there were no changes in the amount of time spent in SWS compared with patients administered placebo.[44] Doxepin modified parts of the sleep architecture — doxepin-treated patients had a significant increase in the percentage and amount of time in REM sleep and stage 1 and stage 2 of NREM sleep.[44] Indiplon had no effect on SWS (stages 3 and 4) vs placebo, but it did modify the sleep architecture, with an increase in stage 2 sleep and a decrease in REM sleep.[47] With the administration of almorexant, there was an increase in both REM and NREM sleep.[46]
Conclusions
Insomnia may be primary or secondary and is a common complaint that may result in decreased performance and quality of life. Proper classification of the type of insomnia and an environment conducive to sleep are the first steps toward treating insomnia. In those with primary insomnia, behavioral treatments aimed at reducing the negative conditioning associated with insomnia are the focus of treatment. In those with secondary insomnia, optimized treatment of the comorbid medical, psychiatric, or substance abuse is an essential part of the treatment for insomnia. Both nonpharmacologic and pharmacologic treatments are available for most patients with chronic insomnia.[5] Because SWS plays an important role in regulating sleep, and SWS abnormalities have been observed in patients with primary insomnia, drugs that increase the duration of SWS provide a rational approach to promoting improved quality of sleep.[12,14,16] Therefore drugs in development that modify sleep architecture and increase SWS via activity on the 5-HT2A receptor may offer additional potential advantages for patients.
Post-Assessment: Measuring Educational Impact
Thank you for participating in the CME activity. Please take a few moments to read the following cases and complete the questions that follow to help us assess the effectiveness of this medical education activity.
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References
- Teegarden BR, Al Shamma H, Xiong Y. 5-HT(2A) inverse-agonists for the treatment of insomnia. Curr Top Med Chem. 2008;8:969-976.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
- Schenck CH, Mahowald MW, Sack RL. Assessment and management of insomnia. JAMA. 2003;289:2475-2479.
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Diagnostic and Coding Manual. Westchester, Ill: American Academy of Sleep Medicine; 2006.
- Silber MH. Chronic insomnia. N Engl J Med. 2005;353:803-810.
- Nozfinger EA, Buysse DJ, Germain A, Price JC, Miewalk JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161:2126-2129.
- Young JS, Bourgeois JA, Hilty DM, Hardin KA. Sleep in hospitalized medical patients, Part 1: Factors affecting sleep. J Hosp Med. 2008;3:473-482.
- Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487-504.
- Morganthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine Report. Sleep. 2006;29:1415-1419.
- Hatoum HT, Kania CM, Kong SX, et al. Prevalence of insomnia: a survey of the enrollees at five managed care organizations. Am J Manag Care. 1998;4:79-86.
- Czeisler CA, Winkelman JW, Richardson GS. Sleep Disorders. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc.; 2008:171-179
- Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms. 1999;14:557-568.
- Backhaus J, Born J, Hoeckesfeld R, Fokuhl S, Hohagen F, Junghanns K. Midlife decline in declarative memory consolidation is correlated with a decline in slow wave sleep. Learn Mem. 2007;14:336-341.
- Gillberg M, Åkerstedt T. Sleep restriction and SWS-suppression: effects on daytime alertness and night-time recovery. J Sleep Res. 1994;3:144-151.
- Ferrara M, De Gennaro L, Bertini M. Selective slow-wave sleep (SWS) deprivation and SWS rebound: do we need a fixed SWS amount per night? Sleep Res Online. 1999;2:15-19.
- Pigeon WR, Perlis ML. Sleep homeostasis in primary insomnia. Sleep Med Rev. 2006;10:247-254.
- Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep. 2007;30:263-273.
- Lumeng JC, Somashekar D, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH. Shorter sleep duration is associated with increased risk for being overweight at ages 9 to 12 years. Pediatrics. 2007;120:1020-1029.
- Vorona RD, Winn MP, Babineau TW, Eng BP, Feldman HR, Ware CJ. Overweight and obese patients in a primary care population report less sleep than patients with a normal body mass index. Arch Intern Med. 2005;165:25-30.
- Ohayon MM. Prevalence and correlates of nonrestorative sleep complaints. Arch Intern Med. 2005;165:35-41.
- Gaina A, Sekine M, Hamanishi S, et al. Daytime sleepiness and associated factors in Japanese school children. J Pediatr. 2007;151:518-522.
- Bass J, Turek FW. Sleepless in America. A pathway to obesity and the metabolic syndrome? Arch Intern Med. 2005;165:15-16.
- Cohen S, Doyle WJ, Alper CM Janicki-Deverts D, Turner RB. Sleep habits and susceptibility to the common cold. Arch Intern Med. 2009;169:62-67.
- Opp MR. Sleeping to fuel the immune system: mammalian sleep and resistance to parasites. BMC Evol Biol. 2009;9:8.
- Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10:473-481.
- Spira AP, Stone K, Beaudreau, Ancoli-Israel S, Yaffe K. Anxiety symptoms and objectively measured sleep quality in older women. Am J Geriatr Psychiatry. 2009;17:136-143.
- American Academy of Sleep Medicine. Two week sleep diary. Available at http://www.sleepeducation.com/pdf/sleepdiary.pdf. Accessed April 7, 2009.
- Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540-545.
- Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297-307.
- Buysse DJ, Hall ML, Strollo PJ, et al. Relationships between the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and clinical/polysomnographic measures in a community sample. J Clin Sleep Med. 2008;4:563-571.
- Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep. 2005;28:499-521.
- Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. Cognitive behavioral therapy for treatment of chronic primary insomnia. A randomized controlled trial. JAMA. 2001;285:1856-1864.
- Goodie JL, Isler WC, Hunter C, Peterson AL. Using behavioral health consultants to treat insomnia in primary care: a clinical case series. J Clin Psychol. 2009;65:1-11.
- Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults. JAMA. 2006;295:2851-2858.
- Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281:991-999.
- Ebert B, Wafford KA, Deacon S. Treating insomnia: current and investigational pharmacological approaches. Pharmacol Ther. 2006;112:612-629.
- Faulhaber J, Steiger A, Lancel M. The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans. Psychopharmacology (Berl). 1997;130:285-291.
- Drake CL, Roehrs TA, Mangano RM, Roth T. Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia. Hum Psychopharmacol. 2000;15:595-604.
- Martín-Ruiz R, Puig MV, Celada P, et al. Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci. 2001;21:9856-9866.
- Idzikowski C, Mills FJ, James RJ. A dose-response study examining the effects of ritanserin on human slow wave sleep. Br J Clin Pharmacol.1991;31:193-196.
- Popa D, Léna C, Fabre V, et al. Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci. 2005;25:11231-11238.
- Morairty SR, Hedley L, Flores J, Martin R, Kilduff TS. Selective 5HT2A and 5HT6 receptor antagonists promote sleep in rats. Sleep. 2008;31:34-44.
- Rajaratnam SM, Polymeropoulos MH, Fisher DM, et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet. 2009;373:482-491.
- Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2008;69:1557-1564.
- Petroski RE, Pomeroy JE, Das R, et al. Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther. 2006;317:369-377.
- Brisbare-Roch C, Feletti L, Koberstein R, Nayler O, Jenck F. Transient orexin receptor blockade induces sleep without cataplexy in rats. Program and abstracts of the 5th World Congress of the World Federation of Sleep Research and Sleep Medicine Societies; September 2-6, 2007; Cairns, Australia; PO271.
- Rosenberg R, Roth T, Scharf MB, Lankford DA, Farber R. Efficacy and tolerability of indiplon in transient insomnia. J Clin Sleep Med. 2007;3:374-379.
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From Medscape Nurses > Nursing Perspectives
An Update on Preventing Ventilator-Associated Pneumonia in Adults
Laura A. Stokowski, RN, MS
Published: 04/28/2009
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Editor’s Note: This is Part 1 of a 2-part series on VAP. Part 1 describes prevention of VAP in critically ill adult patients. Part 2 will describe prevention of VAP in pediatric and neonatal patients.
Ventilator-Associated Pneumonia
Ventilator-associated pneumonia (VAP) is the onset of pneumonia at least 48 hours after a patient is intubated. It is the endotracheal tube, rather than the need for mechanical ventilation, that leads to VAP. VAP causes more death than any other healthcare-associated infection, exceeding the rate of death from central line infection, sepsis, and respiratory tract infection in nonintubated patients.[1] Mortality varies according to the type of organism causing VAP and is highest when pneumonia is caused by multidrug-resistant organisms.[2]
Between 10% and 20% of patients intubated for more than 48 hours will develop VAP.[3] VAP complicates recovery and extends the duration of mechanical ventilation. Length of hospital stay is significantly longer in VAP patients, who incur at least $10,000 and as much as $40,000 in additional hospital costs.[1,3] VAP is no longer considered an inevitable consequence of treatment; it is now considered a preventable healthcare error.[4]
Pathogenesis of VAP
Of all the plausible mechanisms through which bacteria can reach the lower respiratory tract, the most likely is micro- or bolus aspiration of oropharyngeal organisms.[1] Hospitalized patients have high rates of oropharyngeal or tracheobronchial colonization with Gram-negative bacilli.[1] Subglottic pooling of these secretions with leakage around the endotracheal tube cuff is the primary route of bacterial entry.[5] Bacteria from the dorsal tongue are also frequently found in the lungs of patients with VAP.[6] Gastric colonization with translocation into the respiratory tract, proposed as another route of pulmonary infection, is not believed to be as important as oropharyngeal colonization.[1,7]
There is no shortage of disease-causing bacteria in the typical patient care environment. The hands or clothing of caregivers, dust, air, and water can all convey microorganisms.[7] Bacteria can gain entry to the respiratory tract when bacteria-laden aerosols or ventilator circuit condensate are inhaled through the endotracheal tube.[1] Contaminated nebulizers used to provide airway humidification can transmit bacteria by the aerosol route. Endotracheal suctioning procedures can introduce bacteria from equipment or caregivers’ hands.[5]
Evidence-Based Prevention of VAP
In consideration of our current shortage of nurses and consequent heavy workloads, we cannot afford to adopt new practices unless they are evidence based. Intuitive or traditional interventions, however much sense they make or how long we have performed them, no longer have a place in patient care. Because VAP is such a serious problem, many studies have documented the effectiveness (or ineffectiveness) of various interventions designed to prevent VAP, supplying the evidence base that nurses require. However, in spite of an abundance of experimental data demonstrating that VAP can be prevented, the gap between knowledge and practice remains wide.
Evidence-based guidelines can serve as a catalyst for knowledge translation to the clinical arena.[8] In addition to reducing the overall length of time that patients are intubated, strategies to prevent VAP arise directly from the 3 mechanisms believed to cause VAP: microaspiration of colonized secretions, colonization of the digestive tract, and exposure to contaminated hands or equipment.[9]
Reduce the Duration of Ventilation
The risk of VAP increases with each day the patient is intubated.[10] The best and most obvious way to prevent pneumonia in critically ill patients is to avoid intubation altogether and implement noninvasive ventilation whenever possible.[7,9] When an endotracheal tube is necessary, unplanned extubation and reintubation must be avoided, because reintubation increases the risk for VAP.[11]
Daily assessment and documentation of patient readiness to wean from mechanical ventilation and daily interruption of sedative infusions (sedation vacations) have resulted in shorter duration of mechanical ventilation and length of stay.[12,13] These 2 distinct interventions are often combined, as they are interdependent in practice.[13] Effective ventilator weaning requires the cooperation of the patient; therefore, in adults, sedation must be lightened before weaning is attempted.[14]
A sedation vacation with spontaneous breathing trial typically involves lightening sedative infusions long enough to achieve alertness (responsive to commands) in the patient, but before anxiety and restlessness set in. The patient is tested for spontaneous breathing capacity and assessed for readiness to wean from mechanical ventilation, and results are documented. The risks of interrupting sedative infusions include spontaneous extubation, pain, anxiety, dyssynchrony with mechanical ventilation that results in arterial desaturation, and unknown effects of arousing patients and then putting them back to sleep.[15] Patients must be closely observed throughout these procedures, and steps must be taken to prevent self-extubation.[14]
If sedation is to be continued following the weaning attempt, the dose is generally reduced, often to half of the original infusion rate. Many facilities use sedation scales, such as the Riker, to avoid oversedation.[12,16]
Prevent Microaspiration of Secretions
The normal human mouth contains hundreds of bacteria species, but these are continually flushed from the oral cavity by saliva production and swallowing. An estimated 100-150 mL of oral secretions can accumulate in the adult mouth in a 24-hour period.[17] The intubated patient who receives nothing by mouth produces very little saliva. The mouths of critically ill patients can become colonized as quickly as 24 hours following admission. Virulent bacteria can proliferate and, if unchecked, will build up in the form of dental plaque, a reservoir of bacteria. Secretions that pool in the aerodigestive tract above the endotracheal tube cuff can be aspirated into the lungs, causing pneumonia. This mechanism is supported by findings that, in the majority of intubated patients, the bacteria colonizing the mouth and the lungs are the same.[1] Although all intubated patients are at risk of developing pneumonia by this route, patients with neurologic disease are even less able to protect their own airways, making them highly prone to aspiration of oral secretions.[18]
Both intermittent and continuous suction of subglottic secretions have been shown to decrease VAP rates by preemptively removing the source of infection.[19] Intermittent suctioning of the oral cavity before a position change can significantly reduce the incidence of VAP, number of days on mechanical ventilation, and length of intensive care unit (ICU) stay.[20,21] Continuous aspiration of subglottic secretions, although more expensive, achieves greater protection against VAP.[22] Subglottic secretion drainage is an evidence-based preventive measure, yet it is not widely practiced. In a survey of 719 US hospitals, only 21% reported using subglottic secretion drainage.[23]
Oral Hygiene
Oral care has traditionally been a low priority in the care of critically ill, ventilated patients. Nurses may view oral care primarily as a comfort measure or lack conviction that oral care makes a difference in VAP.
Frequent, thorough oral hygiene can reduce colonization of the teeth, tongue, and gums. Significant reductions in VAP have occurred when oral care is performed consistently and meticulously. In one study that compared tooth brushing every 8 hours with routine oral care for intubated patients, an immediate, dramatic drop in VAP rate to 0 occurred in the intervention group.[18]
The American Association of Critical Care Nurses has developed a guideline for oral hygiene in the critically ill patient. The basic elements of this protocol include oral assessment; brushing teeth, tongue, and gums with a soft toothbrush (at least twice daily); application of moisturizing agents to the oral mucosa and lips; and an antiseptic rinse in selected patients.[24] Simple foam-tipped dental swabs do not remove plaque as efficiently as toothbrushes or specially designed oral care systems.[25] Some facilities use a suction toothbrush, a Yankauer suction device with a toothbrush end, to clean and suction the oral cavity at the same time. Wearing gloves during suctioning minimizes the introduction of bacteria from the caregiver’s hands.
Oral decontamination with chlorhexidine reduces oropharyngeal colonization and has been successfully used to prevent VAP, particularly in cardiac surgery patients.[26] The extra costs for oral care supplies such as oral care kits or suction toothbrushes are easily offset if a single case of VAP is prevented.
Endotracheal Tube Care
Formation of an endotracheal tube biofilm, permitting bacteria to accumulate and persist, may play a contributory role in the development of VAP, especially in late-onset infection. Silver- and antiseptic-impregnated endotracheal tubes show promise in reducing this colonization.[7] Most experts recommend using orotracheal tubes, rather than nasotracheal tubes, because the latter can increase the risk of sinusitis, a likely precursor to VAP.[19] Attention to proper endotracheal tube cuff pressure in adults (at least 20 cm H2O but no greater than 30 cm H2O) is also important to prevent oral secretions from migrating into the lungs.[19]
The endotracheal tube should have an evacuation lumen proximal to the cuff for intermittent or continuous subglottic suctioning.[9] Neither research nor guidelines have, to date, determined conclusively that closed suction systems are preferred over open systems for suctioning endotracheal tubes.[27]
Other Evidence-Based Approaches to VAP Prevention
Maintain a Semirecumbent Position
Head-of-bed elevation reduces the risk for aspiration of oro- and nasopharyngeal secretions, thereby reducing the risk for VAP.[1] A randomized controlled trial comparing semirecumbent and supine position in mechanically ventilated patients was halted early when data analysis revealed that the semirecumbent position was superior in preventing VAP.[28] The advantage was greatest for patients receiving enteral nutrition. This study and others have led to the recommendation to elevate the bed of mechanically ventilated patients, if not contraindicated by patient condition, to a 30° to 45° angle. In spite of some evidence that this degree of elevation does not prevent tracheal colonization,[29] it remains a common VAP prevention recommendation. Additional potential benefits of bed elevation are reducing the risk of aspirating gastrointestinal contents and improving spontaneous ventilation.[14]
Keeping patients in the desired upright position can be difficult to achieve in practice. In one multicenter study, the target backrest elevation of 45° was achieved only 85% of the time, and the maximum achieved elevation of 28° failed to prevent VAP.[30] In another study, beds intended to be elevated to 30° were actually at 19°, on average, and many patients were found in the supine position.[31] Angle indicators on hospital beds are often small, poorly located, and difficult to read.[32]
Williams and colleagues[32] introduced a simple, easy-to-view, and easy-to-interpret angle indicator that displayed, from as far away as the doorway of the patient’s room, whether the head of the bed was adequately elevated.[32] During a control period prior to introducing the new angle indicator, head-of-bed elevation averaged 21.9° ± 9.1°. Using the new angle indicator, bed angles averaged 30.9° ± 7.5° (P < .005). Compliance with proper head-of-bed elevation improved from 23% without to 72% with the angle indicator device.
Increase Patient Mobility
Immobility contributes to the development of VAP. In the immobile patient, secretions and mucus tend to pool, secretions are harder to expel, and overall pulmonary functioning declines. Increasing the mobility of a ventilated patient, however, is not a simple task. Linda Greene, RN, MPS, CIC, emphasizes the benefits that can be attained by increasing patients’ mobility, even marginally. Greene is lead author of a new guide for preventing VAP that is currently being developed by the Association for Professionals in Infection Control and Epidemiology (APIC). As one component of an overarching initiative known as Targeting Zero, the VAP elimination guide (available in summer 2009) will assist hospitals in their efforts to prevent VAP by outlining a comprehensive, evidence-based prevention program.
“Mobility promotes weaning and, therefore, may shorten length of ICU stay,” advises Greene. In Targeting Zero, mobility interventions are suggested for each stage of a patient’s disease course. A mobility protocol is essentially an algorithm for advancing patients’ degree of mobility, from repositioning, to sitting up, to standing at the side of the bed. “Nurses aren’t always comfortable with mobility protocols for these critically ill patients,” acknowledges Greene. “But just because the patient has a tube doesn’t mean the patient can’t sit up on the side of the bed or even ambulate.”
Even basic interventions such as repositioning, although challenging, are extremely important in the prevention of VAP. Some hospitals have purchased kinetic beds, which continually rotate the patient’s body, reducing the effect of stagnating secretions. Evidence to date indicates that kinetic beds may reduce VAP, but the cost and other complications associated with these beds may be significant barriers to their widespread use.[19,33]
Control Gastric Secretions
Clinically important aspiration of gastric contents usually occurs in patients who have one or more of the following conditions, common in mechanically ventilated patients: a depressed level of consciousness, dysphagia due to neurologic or esophageal disorders, an endotracheal tube, tracheostomy, indwelling enteral tube, or ongoing enteral feeding.[1] An indwelling enteral tube may increase nasopharyngeal colonization, cause reflux of gastric contents, or allow bacterial migration via the tube from the stomach to the upper airway. Contamination of the enteral solution during its preparation may also lead to gastric colonization.
The semiupright position used to prevent aspiration of oral secretions also serves to prevent gastric reflux leading to aspiration. Gastric overdistention must also be avoided.[9] Whether routine digestive tract decontamination and avoidance of H2 agonists and protein pump inhibitors should be included in VAP prevention protocols remain unresolved issues.[9]
Prevent Contamination of Equipment
Any reusable respiratory device can become contaminated and introduce pathogens to the respiratory tract.[19] The Healthcare Infection Control Practices Advisory Committee offers a set of detailed instructions for cleaning and maintaining medical equipment, including respiratory care equipment. Reusable respiratory equipment must be disinfected, sterilized (as appropriate), and stored properly.[9] Sterile water should be used to rinse reusable equipment.[9] The frequency of ventilator circuit changes has no effect on VAP rates, so changing ventilator circuits routinely only adds to the cost of care. Instead, ventilator circuits should be changed when they are visibly soiled. Condensate should be drained regularly from ventilator tubing (without opening the circuit) and prevented from flowing into the patient’s endotracheal tube.[9]
Evidence suggests that the use of heat and moisture exchangers (except where contraindicated), rather than heated humidifiers, can reduce the incidence of VAP because they generate less condensate.[19] If used, these devices should be changed weekly.[8]
Ventilator Bundles
A care “bundle” is a set of evidence-based clinical practices that individually improve care and, when combined, magnify improvement.[14] The scientific evidence for each element of a bundle is sufficient for that element to represent a standard of care.[14] The Institute for Healthcare Improvement’s (IHI) ventilator bundle combines 4 components of care: elevating the head of the bed, daily sedative interruption and assessment of readiness to extubate, peptic ulcer disease prophylaxis, and deep vein thrombosis prophylaxis.[14] The ventilator bundle was initially designed as an overall strategy to improve care of ventilated patients, not necessarily to prevent VAP. However, many hospitals documented a reduction in VAP rates (by an average of 45%) following implementation of the bundle. When teams in some facilities unfailingly apply every bundle element on every patient every time, they have experienced months without a single case of VAP.[14]
The IHI ventilator bundle is not intended to be a comprehensive plan of care to prevent VAP. The IHI recognizes that oral care, subglottic suctioning, gut decontamination, and continuous lateral rotation are also important preventive strategies.[14] Many hospitals have added one or more of these strategies to their VAP prevention protocols. Care should be taken to avoid overly extensive care bundles, because care bundles are most effective when the number of elements is small.[14] The IHI emphasizes that implementing the ventilator bundle requires planning and takes time; it will not be achieved overnight.[14] Recommendations for how to implement and evaluate the ventilator bundle, including useful documentation forms, are available online from the IHI.
Other VAP prevention bundles have been published as well. A bundle of interventions collectively known as FASTHUG (daily evaluation of feeding, analgesia, sedation, thromboembolic prophylaxis, elevation of the head of the bed, ulcer prophylaxis, and glucose control), consistently applied for 2 years, led to a significant drop in VAP (from 19.3 to 7.3 per 1000 ventilator days) among surgical intensive care patients.[34]
Some experts recommend going “beyond the bundle,” and employing other evidence-based processes that may lead to a zero VAP rate. Linda Greene emphasizes that hospitals should first “hardwire the basics,” such as compliance with handwashing, and then gradually incorporate evidence-based practices into the routine standard of care. “Measure your basic processes, such as head-of-bed elevation, hand hygiene, and oral care, first,” suggests Greene. “If you’re not doing well there, introducing advanced, extensive protocols will not be successful.”
Teamwork, Collaboration, and Feedback
It may not be just the individual interventions, or even a combination of interventions, that achieves the reduction in VAP. When evidence-based interventions or bundles are implemented through teamwork and collaboration, it could be this new emphasis on working together toward common goals that actually drives the improvements.[14]
Respiratory therapists are important members of the team in the prevention of VAP, as they work side by side with nurses in patient care and are largely responsible for the maintenance and handling of respiratory equipment. The respiratory therapist also strives, along with the nurse, to maintain patients in semirecumbency, to conduct daily assessments of readiness to wean, and to maintain airway humidity. To address antibiotic stewardship, an initiative that reduces VAP by preventing the emergence of multidrug-resistant organisms, collaboration with physicians, pharmacy, and infection control professionals is also required.[35]
“It’s not enough to have a policy about preventing VAP,” cautions Greene. “It needs to be consistently implemented and measured, with feedback given to caregivers to improve processes.” Greene describes 2 types of professionals in the ICU setting, the “early innovators” and the “laggards,” both individuals who can influence success or failure. “You need to identify your early innovators, the ones who move ahead quickly and achieve success, and then spread their successes by engaging the others.” Dissemination of results must occur on a regular basis. “Nurses want to know how well they are doing,” explains Greene.
Deterrents to VAP Prevention
It is well known that staffing shortages and heavy workloads impede the nurse’s ability to comply with basic hygiene and infection control measures. Low nurse staffing and low nurse-to-patient ratios have been shown to increase the risk for late-onset VAP.[36] Fear of change, communication failures, poor teamwork, and partial buy-in on the part of nurses, physicians, and respiratory therapists are other possible impediments to successfully implementing a VAP prevention protocol. A lack of understanding of the principles underlying recommended practices can also contribute to failure of protocols to produce results.
Studies of intensive care nurses’ knowledge and implementation of evidence-based guidelines for preventing VAP are not universally encouraging.[37,38] Many nurses and respiratory therapists do not know the rate of ventilator-associated pneumonia in their units.[17,39] Although both nurses and respiratory therapists self-report high rates of utilization for some evidence-based VAP practices, other practices, such as subglottic suctioning and routine drainage of ventilator condensate, may be less often performed.[39] In survey research by Ricart and colleagues,[40] reported nonadherence to evidence-based guidelines for preventing VAP on the part of physicians and nurses was surprisingly high. Cason and colleagues[17] found inadequate rates of handwashing, glove wearing, subglottic suctioning, oral hygiene, and head-of-bed elevation among intensive care nurses.
Furthermore, both nurses and respiratory therapists report fairly high rates of adherence to ineffective interventions, such as such as routine circuit changes, in-line suction catheter changes, or chest physiotherapy. Time spent on ineffective interventions is time taken from proven interventions.
Therefore, in addition to a supportive culture, adequate staffing, and ample resources, education for all team members and the development of specific protocols and order sets for the prevention of VAP are critical. Ideally, the individuals who will be implementing these protocols and order sets should be involved in their creation.[40] Healthcare professionals who understand the reasons behind the protocols are much more likely to be dedicated to following them.[41] An evidence-based education program regarding oral care, for example, improved oral care compliance and reduced one unit’s VAP rate by 50%.[42] Education sessions as short as 30 minutes can improve infection control compliance.[43]
The Bottom Line
VAP is a patient safety concern that can be prevented with evidence-based interventions. Lessening VAP rates will shorten hospitalization and reduce morbidity, saving lives as well as money. Innumerable resources exist to aid individuals and units to improve their understanding of VAP and to apply preventive strategies in critical care.
This article is part of a CE certified activity. The complete activity is available at:
http://cme.medscape.com/viewprogram/19320
Related Resources
- American Association of Critical Care Nurses. Practice Alerts: Ventilator-Associated Pneumonia. Includes VAP prevention tool, educational program, and audit tools for HOB monitoring:
http://www.aacn.org/WD/Practice/Content/practicealerts.pcms?menu=Practice - Institute for Healthcare Improvement:
http://www.ihi.org - Infectious Disease Society of America:
http://www.idsociety.org - Society for Healthcare Epidemiology of America:
http://www.shea-online.org - Association for Professionals in Infection Control:
http://www.apic.org
Suggested Reading
- Schorr AF. The NASCENT randomized trial: ventilator-associated pneumonia (VAP). Medscape Pulmonary Medicine, 2008. Available at: http://www.medscape.com/viewarticle/580045. Accessed April 1, 2009.
- Siempos II, Vardakas KZ, Falagas ME. Closed tracheal suction systems for prevention of ventilator-associated pneumonia. Br J Anaesth. 2008;100:299-306. Available at: http://www.medscape.com/viewarticle/574223. Accessed April 1, 2009.
References
- Tablan OC, Anderson LJ, Besser R, et al. CDC Healthcare Infection Control Practices Advisory Committee. Guidelines for preventing healthcare-associated pneumonia, 2003: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep. 2004;53(RR-3):1-36. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5303a1.htm. Accessed April 1, 2009.
- Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Bruisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient: the Canadian Clinical Trials Group. Am J Respir Care. 1999;159:1249-1256.
- Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of ventilator-associated pneumonia; a systematic review. Crit Care Med. 2005;33:2184-2193.
- Stockwell JA. Nosocomial infections in the pediatric intensive care unit: affecting the impact on safety and outcome. Pediatr Crit Care Med. 2007;8(2 suppl):S21-37.
- Leong JR, Huang DT. Ventilator-associated pneumonia. Surg Clin North Am. 2006;86:1409-1429.
- Bahrani-Mougeot FK, Paster BJ, Coleman S. Molecular analysis of oral and respiratory bacterial species associated with ventilator-associated pneumonia. J Clin Microbiol. 2007;45:1588-1593.
- Safdar N, Crnich CJ, Maki DG. The pathogenesis of ventilator-associated pneumonia: its relevance to developing effective strategies for prevention. Respir Care. 2005;50:725-739.
- Dodek P, Keenan S, Cook D, et al. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med. 2004;141:305-313.
- Coffin SE, Klompas M, Classen D, et al. Strategies to prevent ventilator-associated pneumonia. Infect Control Hosp Epidemiol. 2008;29:S31-S40. Available at: http://www.journals.uchicago.edu/doi/full/10.1086/591062. Accessed January 3, 2009.
- Koenig SM, Truwit JD. Ventilator-associated pneumonia: diagnosis, treatment, and prevention. Clin Microbiol Rev. 2006;19:637-657.
- Torres A, Gatell JM, Aznar E, et al. Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care Med. 1995; 152:137-141.
- Schweickert WD, Gehlbach BK, Pohlman AS, Hall JB, Kress JP. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32:1272-1276.
- Ely EW. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med. 1996;335:1864-1869.
- Institute for Healthcare Improvement. Getting started kit: prevent ventilator-associated pneumonia. How-to guide. 2008. Available at: http://www.premierinc.com/safety/topics/bundling/downloads/03-vap-how-to-guide.pdf. Accessed January 3, 2009.
- Egerod I. Is taking a sedation vacation all it’s cracked up to be? Crit Care Med. 2008;36:2205-2206.
- Riker RR, Picard GT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27:1325-1329.
- Cason CL, Tyner T, Saunders S, Broome L. Nurses’ implementation of guidelines for ventilator-associated pneumonia from the Centers for Disease Control and Prevention. Am J Crit Care. 2007;16:28-38.
- Fields LB. Oral care intervention to reduce incidence of ventilator-associated pneumonia in the neurologic intensive care unit. J Neurosci Nurs. 2008;40:291-298.
- Lorente L, Blot S, Rello J. Evidence on the measures for preventing ventilator-associated pneumonia. Eur Respir J. 2007;30:1193-1207.
- Chao YF, Chen YY, Wang KW, Lee RP, Tsai H. Removal of oral secretion prior to position change can reduce the incidence of ventilator-associated pneumonia for adult ICU patients: a clinical controlled trial study. J Clin Nurs. 2009;18:22-28.
- Tsai HH, Lin FC, Chang SC. Intermittent suction of oral secretions before each positional change may reduce ventilator-associated pneumonia: a pilot study. Am J Med Sci. 2008;336:397-401.
- Bouza E, Pérez MJ, Muñoz P, Rincón C, Barrio JM, Hortal J. Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery. Chest. 2008;134:938-946.
- Krein SL, Kowalski CP, Damschroeder L, Forman J, Kaufman SR, Saint S. Preventing ventilator-associated pneumonia in the United States: a mixed methods study. Infect Control Hosp Epidemiol. 2008;29:933-940.
- American Association of Critical Care Nurses. Practice alert: Oral care in the critically ill. 2006. Available at: http://classic.aacn.org/AACN/practiceAlert.nsf/Files/ORAL%20CARE/$file/Oral%20Care%20in%20the%20Critically%20Ill%208-2006.pdf. Accessed January 12, 2009.
- Pearson L, Hutton J. A controlled trial to compare the ability of foam swabs and toothbrushes to remove dental plaque. J Adv Nurs. 2002;30:480-489.
- Chlebicki MP, Safdar N. Topical chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. Crit Care Med. 2007;35:595-602.
- Niele-Weise BS, Snoeren RL, van den Broek PJ. Policies for endotracheal suctioning of patients receiving mechanical ventilation: a systematic review of randomized controlled trials. Infect Control Hosp Epidemiol. 2007;28:531-536.
- Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogue S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354:1851-1858.
- Girou E, Buu-Hoi A, Stephan F, et al. Airway colonisation in long-term mechanically ventilated patients: effect of semi-recumbent position and continuous subglottic suctioning. Intensive Care Med. 2004;30:225-233.
- van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34:396-402.
- Grap MJ, Munro CL, Bryant S, et al. Predictors of backrest elevation in critical care. Intensive Crit Care Nurs. 2003;19:68-74.
- Williams Z, Chan R, Kelly E. A simple device to increase rates of compliance in maintaining 30-degree head-of-bed elevation in ventilated patients. Crit Care Med. 2008;36:1155-1157.
- Delaney A, Gray H, Laupland KB, Zuege DJ. Kinetic bed therapy to prevent nosocomial pneumonia: a systematic review and meta-analysis. Crit Care. 2006;10:R70.
- Papadimos TJ, Hensley SJ, Duggan JM, et al. Implementation of the “FASTHUG” concept decreases the incidence of ventilator-associated pneumonia in a surgical intensive care unit. Patient Saf Surg. 2008;2:3. Available at: http://www.pssjournal.com/content/2/1/3. Accessed April 1, 2009.
- Dellit TH, Owens RC, McGowan JE, et al. Infectious Disease Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177.
- Hugennot S, Uckay I, Pittet D. Staffing level: a determinant of late-onset ventilator-associated pneumonia. Crit Care. 2007;11:R80. Available at: http://www.medscape.com/viewarticle/564384. Accessed April 1, 2009.
- Biancofiore G, Barsotti E, Catalani V. Nurses’ knowledge and application of evidence-based guidelines for preventing ventilator-associated pneumonia. Minerva Anestesiol. 2007;73:129-134.
- Labeau S, Vandijck DM, Claes B. Critical care nurses’ knowledge of evidence-based guidelines for preventing ventilator-associated pneumonia: an evaluation questionnaire. Am J Crit Care. 2007;16:371-377.
- Kaynar AM, Mathew JJ, Hudlin MM, et al. Attitudes of respiratory therapists and nurses about measures to prevent ventilator-associated pneumonia: a multicenter, cross-sectional survey study. Respir Care. 2007;52:1687-1694.
- Ricart M, Lorente C, Diaz E, Kollef MH, Rello J. Nursing adherence with evidence-based guidelines for preventing ventilator-associated pneumonia. Crit Care Med. 2003;31:2693-2696.
- Vandijck DM, Labeau SO, Blot SI. Facilitating clinician adherence to guidelines in the intensive care unit. Crit Care Med. 2008;36:655.
- Ross A, Crumpler J. The impact of an evidence-based practice education program on the role of oral care in the prevention of ventilator-associated pneumonia. Intensive Crit Care Nurs. 2007;23:132-136.
- Tolentino-DelosReyes AF, Ruppert SD, S-YPK Shiao. Evidence-based practice: use of the ventilator bundle to prevent ventilator-associated pneumonia. Am J Crit Care 2007;16:20-27. Available at: http://www.medscape.com/viewarticle/550502. Accessed April 1, 2009.
Medscape Nurses © 2009 MedscapeCME.
Contents of An Update on Preventing Ventilator-Associated Pneumonia
[http://cme.medscape.com/viewprogram/19320]
- An Update on Preventing Ventilator-Associated Pneumonia in Adults
[http://cme.medscape.com/viewarticle/591015]
This article is part of a CE certified activity. The complete activity is available at:
http://cme.medscape.com/viewprogram/19320
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CE Released: 04/28/2009; Valid for credit through 04/28/2010
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From British Journal of Cardiology
10 Steps Before You Refer: Heart Failure
Ann Marie Johnson; Paul Brooksby
Published: 05/08/2009
Introduction
Congestive heart failure (CHF) is an increasingly widespread condition, the prognosis for moderate and severe heart failure is almost identical to colorectal cancer[1] and worse than breast[2] or prostate cancer.[3]
CHF has an overall population prevalence of approximately 1–3% rising to approximately 10% in the very elderly CHF accounts for about 5% of all medical admissions and approximately 2% of total healthcare expenditure.[4] Nearly one million new cases are diagnosed annually worldwide, making it the most rapidly growing cardiovascular disorder.
The consequences of heart failure for primary care are profound. CHF has been reported to be second only to hypertension as a cardiovascular reason for a surgery appointment.[5] Despite improvements in medical management, undertreatment is common, many patients with CHF still do not receive treatment optimised according to current guidelines.[4,6]
The introduction of the 2009/10 heart failure Quality Outcomes Framework (QOF) additions will bring financial incentives for the prescribing of beta blockers for patients with a diagnosis of heart failure. This will apply to all diagnosed heart failure patients. There are, however, no additional QOF points for optimising medication or maximum tolerated levels, therefore, patient care will rely on good practice and receiving treatment according to current guidelines.
The prevalence of heart failure nationally in QOF is just over 1%. Because of the increase in survival after acute myocardial infarction and ageing of the population, the number of patients with heart failure will increase rapidly in most industrialised countries. Heart failure will continue to be a challenge to healthcare.
The profile of heart failure management has been raised with the publication of the Coronary Heart Disease (CHD) National Service Framework (NSF) Chapter 6 in 2000[7] and the National Institute for Health and Clinical Excellence (NICE) Heart Failure Clinical Guideline 2003.[8] The heart failure publications have supported the development of community heart failure services, and heart failure specialist nurse roles.
The development of the General Practitioner with Special Interest (GPSI) in cardiology qualification and the accreditation in community echocardiography in 2004 has enabled the development of community heart failure services. The training and development of the workforce in primary care has led to improvements in the treatment and management of heart failure patients. A referral to a community specialist heart failure service or secondary care will still be relevant in certain instances, however, the 10 steps will assist in the decision to continue the management in primary care or refer for expert advice and a future management plan.
1. Make the Diagnosis
Take a history to assist in determining the diagnosis of heart failure – a history of CHD (previous myocardial infarction), murmur, valve replacement, rheumatic fever, thyroid disease, atrial fibrillation and hypertension are conditions that would predispose a heart failure diagnosis. Establish the number of units of alcohol per week (consider alcoholic cardiomyopathy). The patient’s smoking history should be noted as this may suggest chronic obstructive pulmonary disease (COPD) as an alternative diagnosis and spirometry should be undertaken to rule out COPD and asthma as a cause for breathlessness.
Weigh and measure the patient, observe for possible cachexia hidden by the oedema. Enquire about shortness of breath, on exertion, at rest or at night.
The New York Heart Association (NYHA) classification scale (Table 1) can be used to classify symptom severity. Examine for any ankle, leg or abdominal oedema. Consider an alternative cause (low protein diet, renal disease, venous stasis). Examine the patient for a raised jugular venous pressure (JVP) and listen to the heart for added heart sounds or murmur. Measure the blood pressure, which may be normal or low, and take the pulse to assess whether it is irregular or fast. Could the patient be in fast atrial fibrillation which has precipitated heart failure?
Table 1. The New York Heart Association (NYHA) Classification of Heart Failure Symptoms
| Class I | No limitations. Ordinary physical activity does not cause undue fatigue, dyspnoea or palpitation (asymptomatic left ventricular dysfunction) |
| Class II | Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or angina pectoris (symptomatically ‘mild’ heart failure) |
| Class III | Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity will lead to symptoms (symptomatically ‘moderate’ heart failure) |
| Class IV | Inability to carry out any physical activity without discomfort. Symptoms of congestive cardiac failure are present even at rest. With any physical activity increased discomfort is experienced (symptomatically ‘severe’ heart failure) |
Clinical assessment alone is unreliable since the symptoms and signs of heart failure may be insensitive and non-specific, however, when used in a systematic manner it can be effective in determining a diagnosis of heart failure and potentially reduce the effect on the echocardiogram service by excluding patients who are not likely to have heart failure (Figure 1).[9]
Figure 1. Echocardiogram in a patient with chronic atrial fibrillation, where the left atrium is significantly enlarged.
LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle
2. Carry Out the Initial Investigations
Take routine bloods: full blood count, urea and electrolytes (U&E), liver function tests, thyroid function and blood glucose. If brain natriuretic peptide (BNP) is available, then this will aid diagnosis (normal ranges for BNP vary with age and gender and by laboratory). The specificity of the chosen cut-off point will vary between 30% and 50%. Therefore, BNP alone is not conclusive, though it is a reliable ‘rule-out’ test. If there is a history of breathlessness (with or without oedema) indicating a heart failure diagnosis, and in addition the electrocardiogram (ECG) is abnormal, consider a trial of furosemide 40 mg daily and review in two to three days.
The patient should be reviewed with the results of the blood tests. Ensure BNP investigation is undertaken prior to commencing on furosemide, as the BNP result will be lower following diuretics. However, if the condition of the patient is unstable, then consider admission.
An ECG should be performed in every patient with suspected heart failure. Electrographic changes are common in patients suspected of having heart failure. An abnormal ECG has little predictive value for the presence of heart failure, however, if the ECG is completely normal, heart failure, especially with systolic dysfunction, is unlikely (<10%). ECG is a valuable diagnostic tool as it provides evidence of myocardial infarction or left ventricular hypertrophy (LVH).
Chest X-ray is an essential diagnostic component, indicated to exclude other causes of breathlessness. The chest X-ray is useful to detect cardiomegaly, pulmonary congestion and pleural fluid accumulation and can demonstrate the presence of pulmonary disease or infection contributing to dyspnoea. However, apart from congestion, findings are predictive only in the context of typical signs and symptoms. Cardiomegaly can be absent not only in acute but also in chronic heart failure. If ECG, chest X-ray and BNP are normal, heart failure is very unlikely. Consider other causes of breathlessness, such as overweight, unfit, smoker, anxiety, or hyperventilation.
Spirometry should be performed if there is a smoking history (smoker or passive smoker) or relevant occupational history with symptoms suggestive of COPD or asthma. If spirometry is positive, manage as per NICE COPD 2004 guidelines.[10] If a diagnosis of asthma is confirmed then manage the patient according to the British Guideline on the Management of Asthma, British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) guidelines.[11] COPD is a frequent co-morbidity in heart failure and the prevalence ranges between 20–30%. Evaluation of natriuretic peptide levels may be helpful in this population and the negative predictive value may be most useful.
3. Arrange an Echocardiogram
An echocardiogram is a vital diagnostic tool to support the initial suspicion of a heart failure diagnosis. Open access echocardiogram services may be available. The echocardiogram should be arranged to understand the underlying cause of the heart failure and rule out structural heart abnormalities. Only if the echocardiogram result is equivocal, the diagnosis is in doubt, the patient has a murmur and requires tertiary intervention, or the echocardiogram identifies advanced disease, possibly requiring device therapy, should the patient be referred for specialist care. If the clinician is confident to diagnose heart failure and no onward referral is required at the present time, then together with the patient and carer, a management plan will be agreed and, with the patient’s consent, medical therapy commenced – steps 4–8.
If a heart failure specialist nurse is available then consider referral to the service for a programme of patient education, self-management and support.
4. Angiotensin-converting Enzyme Inhibitors (ACEI)
Once a diagnosis of heart failure has been confirmed ACEI should be commenced, starting at the lowest dose once per day. The dose should be doubled at a minimum of two-week intervals to a target of the maximum tolerated dose available. The blood pressure and blood taken for U&E will be checked at seven to 14 days, prior to initiation, and following each dose increase. If the patient’s renal function is compromised, then consider stopping nephrotoxic drugs, such as non-steroidal anti-inflammatories, or if there is no congestion, reduce the loop diuretics. The patient should be monitored closely and U&E checked within one week. If the results are within acceptable limits, then continue the up-titration. However, if the renal function continues to deteriorate, then reduce the ACEI dose by half, monitor closely, checking the U&E within one week. If there is still no improvement following reduction in ACEI, stopping diuretics and nephrotoxic drugs, then consider referral to a specialist community heart failure service, or secondary care provider.
The ACEI should be stopped and a referral to a specialist service should be considered if: the potassium level is above 6.0 mmol/L or creatinine more than 350 µmol/L, or more than double the baseline reading.
5. Angiotensin II Receptor Antagonists (ARBs)
If the patient is intolerant of ACEI, then commence on ARBs. The evidence for ARBs is based on the Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARM),[12] Valsartan Heart Failure Trial (VAL-Heft),[13] and Valsartan in Acute Myocardial Infarction (VALIANT)[14] studies. The initial dose of ARB should be the lowest available and the dose should be doubled at each step (minimum of two-weekly intervals). The dose should be halved if the patient is over 75 years or has liver impairment.
Prior to initiation and up-titration, the blood pressure and U&E should be monitored and limits applied as per ACEI instructions in step 4. The cautions apply for ACEI and ARBs, and the drugs should not be used if the patient has diagnosed renal artery stenosis, aortic/mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
6. Initiate a Beta Blocker
Following successful initiation and up-titration to maximum dose of ACEI or ARB, then the next stage is to commence beta blockers. This should be on the condition that the patient is stable (defined by no admissions to hospital in the last month and no alteration of drug therapy in the previous two weeks). Patients who do not meet these criteria but would benefit from therapy should be referred to a specialist heart failure clinic (community clinic or secondary care). The choices of beta blocker with evidence of value in heart failure management are: bisoprolol, carvedilol, metoprolol and nebivolol. The lowest available dose should be initiated and titrated up over a period of 12 weeks.
Prior to initiation of beta blocker and four days following any dose increase, the following should be observed:
- the patient’s heart rate should not be lower than 50 beats per minute
- the patient should not be lightheaded or dizzy
- the patient’s systolic blood pressure should be more than 90 mmHg.
If any of the above applies, seek specialist advice, if not, continue to up-titrate. If the patient has a respiratory wheeze, but no weight gain, then specialist advice should be sought, or the patient referred to a community specialist clinic or secondary care heart failure service.
7. Titrating the Loop Diuretic Dose
Increasing, and decreasing, the patient’s loop diuretic dose is key to the management of the patient’s fluid overload. The patient’s dry weight should be documented. The dry weight is defined as the patient’s stable weight with no signs of fluid overload. The patient should be weighed in similar weight clothes and at a similar time on each occasion. The loop diuretic should be up-titrated if the patient has a sudden increase in dry weight of over 1 kg which has been sustained over the previous two days, or the patient has increasing oedema and breathlessness. Furosemide should be up-titrated every three days by 40 mg at each titration. If the dry weight is still not achieved following two incremental changes, or breathlessness and oedema have not subsided, then specialist advice or referral to secondary care is required.
If the patient is prescribed bumetanide, then titrate as above, remembering that 1 mg of bumetanide is the equivalent of 40 mg furosemide. The increased dose should be maintained for three days. If the patient’s dry weight is achieved, return to the original dose. However, if there are more than two episodes of fluid overload in a two to three week period, then consider a permanent increase in diuretic dose.
The loop diuretic dose of furosemide should be decreased in 40 mg steps if the patient’s dry weight is decreased by 1 kg, sustained over two days, or urea is increased by more than 5 mmol/L, or more than 25% from baseline. The patient may complain of dizziness and thirst if dehydrated significantly. The patient’s fluid status should be assessed within 48 hours of each step change and if the patient is back to dry weight, reassess in a further 48 hours. If the patient has remained at dry weight, consider a permanent decrease in diuretic. However, if the patient is still below dry weight, then seek, specialist advice.
Specialist advice should be sought if the patient is on a regular dose of more than 160 mg furosemide.
8. Consider Aldosterone Antagonists
An aldosterone antagonist can be considered if the patient remains symptomatic – the patient describes symptoms that classify as NYHA II–IV, despite treatment with an ACEI, a diuretic and, where indicated, a beta blocker (based on randomized aldosterone evaluation study [RALES] trial).[15]
U&E should be checked prior to initiation, and also one week after initial dose. Before commencing on spironolactone 25 mg once per day, potassium supplements and potassium-sparing diuretics should be discontinued.
However, if creatinine is more than 200 µmol/L, or urea is more than 11–12 mmol/L and/or potassium is more than 5.5 mmol/L, then seek specialist advice/refer.
One week after initiation, if the creatinine is less than 200 µmol/L, urea less than 18 mmol/L and potassium less than 5.5 mmol/L, in addition the patient has no diarrhoea or vomiting, then continue 25 mg spironolactone and monitor U&E every four weeks for three months, then every three months for six months and every six months thereafter. The target dose of spironolactone is 25–50 mg once daily. If the patient experiences significant gynaecomastia, then eplerenone at the same dose can be used as a replacement, clinical monitoring and treatment regimen remains the same.
If the creatinine level is more than 200 µmol/L, urea more than 18 mmol/L and potassium is more than 5.9 mmol/L, then consider reducing to 12.5 mg daily, re-check U&E in two weeks, however, if concerned regarding the result, then seek advice/refer.
9. Palliative Care
The prognosis of patients with advanced heart failure is often very difficult to determine, as there is no simple method for measuring organ function accurately in clinical practice. There are many factors causing exacerbation of heart failure, however, these can be improved if the correct therapies are instituted in time. In addition, a proportion of heart failure patients will die suddenly (sudden cardiac death [SCD]). This is generally unpredictable, although the majority of heart failure patients will die from progressive cardiac pump dysfunction. These uncertainties about prognosis need to be explained and discussed openly with the patient, their families and carers, as even those confidently identified as ‘end-stage’ may include some who recover and improve and others who die prematurely through SCD. Thus, true ‘end-stage’ is reached when: the patient is chronically and severely symptomatic (NHYA III or IV), and no further conventional therapy is available that will provide any realistic prospect of improvement without incurring undue risks to the patient.[16]
Therefore, what needs to be considered is whether such therapies will enhance the quality of life of an individual patient. If this is in doubt, such cases should be referred to a specialist service for further investigation and clarification.
10. Heart Failure Nurse Role
The previous nine steps outline the diagnosis and management of heart failure, and when to seek specialist advice or refer patients for specialist management. As outlined, careful monitoring is vital and intensive. This role is ideally undertaken jointly with GPs and specialist heart failure nurses in the community where this role is available. The heart failure nurse can offer the patient and carers ongoing support, education and self-management, e.g. daily weight measurement, and reduced salt and fluid intake. The heart failure nurse specialist will discuss advice on lifestyle, smoking cessation, alcohol consumption, diet and physical activity, including sexual activity and the sexual positions less likely to strain a patient with a heart failure diagnosis.
The heart failure nurse can discuss the diagnosis and prognosis, palliative and end-of-life care, following discussion with the GP, patient, carer and family.
In areas where heart failure rehabilitation is available, the heart failure nurse can assess the patient’s condition and together with the patient and rehabilitation/physiotherapist, devise a heart failure rehabilitation programme to improve the patient’s functional capacity. The implantation of a cardiac resynchronisation device or an implantable defibrillator (Figure 2) can be life-saving and improve the quality of the patient’s life. The heart failure nurse specialist can assess against NICE criteria for device therapy[17,18] and discuss referral to a specialist cardiologist with the GP, patient and carer. The patient can be assessed for surgical options, e.g. revascularisation and/or heart transplantation. This assessment will be undertaken by a specialist cardiologist.
Figure 2. Selected patients at high risk of sudden cardiac death may be suitable to have an implantable cardioverter defibrillator (ICD)
Courtesy of Dr B. Chandrasekaran and Dr R. Sharma
Sidebar: Causes of Heart Failure
- Ischaemic heart disease
- Hypertension
- Alcohol
- Valvular disease
- Viral myocarditis
- Thyroid disease
- Cytotoxic drugs
- Familial congenital heart disease
- Amyloidosis
- Sarcoidosis
- Haemachromatosis
References
- Joint Report of the West Midlands, Director of Public Health and the West Midlands Regional Cancer Registry. Cancer and health. Birmingham: WMRHA, 1995:210.
- Joint Report of the West Midlands, Director of Public Health and the West Midlands Regional Cancer Registry. Cancer and health. Birmingham: WMRHA, 1995:71.
- Joint Report of the West Midlands Director of Public Health and the West Midlands Regional Cancer Registry. Cancer and health. Birmingham: WMRHA, 1995:82.
- McMurray JJW, Stewart S. The burden of heart failure. Eur Heart J 2002;4(Suppl D):D50–D58.
- O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107–S112.
- McMurray JJ. Failure to practice evidence-based medicine: why do physicians not treat patients with heart failure with angiotensin-converting enzyme inhibitors? Eur Heart J 1998;19(Suppl L):15–21.
- Department of Health. Coronary heart disease national service framework. London: DoH, 2000.
- National Institute of Health and Clinical Excellence. Clinical Guideline 5. Management of chronic heart failure in adults in primary and secondary care. London: NICE, July 2003.
- Chambers J, Fuat A, Liddiard S et al. Community echocardiography for heart failure. Br J Cardiol 2004;11:399–402.
- National Institute of Health and Clinical Excellence. Clinical Guideline 12. Management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: NICE, 2004.
- British Thoracic Society (BTS), Scottish Intercollegiate Guideline Network (SIGN). British guideline on the management of asthma: a national clinical guideline. Thorax 2008;63(Suppl IV):Iv1–Iv121.
- Pfeffer MA, Swedberg K, Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759–66.
- Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75.
- Pfeffer MA, McMurray JJV, Velazquez EJ et al.; for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–906.
- Pitt B, Zannad F, Remme WJ et al.The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17.
- West Yorkshire Cardiac Network 2008. Symptom management guidelines for patients in the later stages of heart failure and criteria for referral to specialist palliative care. Available from: http://www.yorksandhumberhearts.nhs.uk/upload/WYCN/Guidelines/Symptom%20Management%20Guidelines%20%20HF%20Jul%2008%20Version%202.pdf
- National Institute of Health and Clinical Excellence. Technology appraisal 120 guidance. Heart failure cardiac resynchronisation. London: NICE, 2007.
- National Institute of Health and Clinical Excellence. Technology appraisal 95 guidance. Arrhythmia: implantable cardioverter defibrillators (review of TA11 guidance). London: NICE, 2008.
Br J Cardiol. 2009;16(1):30-35. © 2009
From Medscape General Surgery > Viewpoints
A “Cool” Way to Reduce Pain During Intravenous Cannulation
Albert B. Lowenfels, MD
Published: 05/08/2009
Effect of Topical Alkane Vapocoolant Spray on Pain With Intravenous Cannulation in Patients in Emergency Departments: Randomised Double Blind Placebo Controlled Trial
Hijazi R, Taylor D, Richardson J
BMJ. 2009;338:b215
Summary
In this report, the authors evaluated the utility of a topical cooling spray as a way to reduce pain during intravenous cannulation in an emergency department setting. The study group compared 103 patients whose cannulation sites were spray-cooled with 98 control patients who were cannulated after exposure to a water spray. Pain scores were significantly reduced with use of a coolant spray (P = .001), and there were no unexpected events following its use.
Viewpoint
Starting an intravenous drip can be a painful experience, but using an intradermal analgesic would require another needle injection. In this study, a topical coolant spray significantly reduced the patients’ perception of pain. The accuracy of blinding must be questioned because the coolant spray must have imparted a different sensation to the skin than a similar jet of water. The results of this study differ from those of other smaller, unblinded studies. In addition, the 20-gauge needle used throughout the study, if skillfully inserted, should have caused only minimal pain.
Medscape General Surgery © 2009 Medscape, LLC
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From Medscape General Surgery > Viewpoints
Do Anticoagulants Reduce the Risk for Thromboembolism in Cancer Patients With Central Venous Catheters?
Albert B. Lowenfels, MD
Published: 05/05/2009
Warfarin Thromboprophylaxis in Cancer Patients With Central Venous Catheters (WARP): An Open-Label Randomised Trial
Young AM, Billingham LJ, Begum G, et al
Lancet. 2009;373:567-574
Summary
The aim of this study was to determine whether anticoagulants reduced the risk for venous thromboembolism in cancer patients receiving chemotherapy. The authors compared the risk for catheter-related thrombosis in 404 control patients with 408 patients treated with warfarin. The number of catheter-related thrombotic events was identical in the 2 groups (24), and there was no difference in the overall frequency of any type of thromboembolic event (odds ratio, 0.78; 95% confidence interval, 0.5-1.24)
Viewpoint
At the onset of this large multicenter trial, clinicians were certain that anticoagulants would prove beneficial. This belief proved to be wrong. Rather than being beneficial, use of anticoagulants increased the likelihood of bleeding complications. The overall rate of catheter-related thrombotic events was low (6%), and the authors concluded that there is no longer a need for warfarin in the management of central venous catheters inserted in cancer patients.
Medscape General Surgery © 2009 Medscape, LLC
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From Medscape Medical News
Multidisciplinary Information Technology Program May Help Improve Blood Pressure
Laurie Barclay, MD
May 12, 2009 —- A multidisciplinary information technology–supported program that provides feedback to patients and healthcare providers may significantly improve blood pressure levels in primary care, according to the results of a randomized controlled trial reported in the May 5 Online First issue of Circulation: Cardiovascular Quality and Outcomes.
“Hypertension is a leading mortality risk factor yet inadequately controlled in most affected subjects,” write Stéphane Rinfret, MD, MSc, from the University of Montreal in Montreal, Quebec, Canada, and colleagues from the LOYAL (Lowering blood pressure by improving cOmpliance with hYpertension therapy through the Assistance of technoLogy) study investigators. “Effective programs to address this problem are lacking. We hypothesized that an information technology-supported management program could help improve blood pressure (BP) control.”
The study sample consisted of 223 subjects with hypertension who were observed in primary care. At baseline, mean 24-hour blood pressure level measured with ambulatory monitoring was greater than 130/80 mm Hg, and daytime blood pressure level was greater than 135/85 mm Hg. Participants randomly assigned to the intervention were given a blood pressure monitor and access to an information technology–supported adherence and blood pressure monitoring system providing monthly reports to nurses, pharmacists, and physicians, whereas control subjects received usual care. Mean duration of follow-up was 348 ± 78 days in the intervention group and 349 ± 84 days in the control group.
Compared with the control group, the intervention group had a consistently greater primary endpoint of the change in the mean 24-hour ambulatory blood pressure both for systolic (–11.9 vs –7.1 mm Hg; P < .001) and diastolic blood pressure (–6.6 vs –4.5 mm Hg; P = .007). The intervention group also had a greater proportion of participants that achieved Canadian Guideline target blood pressure (46.0% vs 28.6%; P = .006).
Reductions in blood pressure values were similar for ambulatory monitoring and self-recorded home blood pressure, suggesting that the self-recorded home blood pressure could help confirm blood pressure control. Compared with the control group, the intervention group had more physician-driven antihypertensive dose adjustments and/or changes in agents (P = .03), more antihypertensive classes at study end (P = .007), and a nonsignificant trend towards improved adherence measured by prescription refills (P = .07).
Limitations of this study include lower sample size than planned, insufficient power to show any significant impact of the program on drug adherence, inability to determine the extent to which blood pressure improvements could be sustained beyond the duration of the study, and inability to exclude the possibility that some significant effects of the intervention on secondary endpoints occurred by chance.
“This multidisciplinary information technology supported program that provided feedback to patients and healthcare providers significantly improved blood pressure levels in a primary care setting,” the study authors write. “These results were achieved through regular automated patient contact, nursing support as needed and monthly feedback to physicians and pharmacists, which led to more medication dosage adjustments, changes or additions, a larger number of antihypertensive classes at study end and a trend towards improved adherence. Our results clearly support the need for further investigation on innovative approaches that can improve the management of hypertension and other chronic diseases.”
Pfizer Canada Inc, the Canadian Institutes for Health Research (CIHR/Rx&D program), and the Fonds de recherche en santé du Québec supported this study. Pfizer Canada Inc provided honoraria to 4 of the study authors. Two of the other authors were study employees paid by the study grants.
Circ Cardiovasc Qual Outcomes. Published online May 5, 2009.
Medscape Medical News © 2009 Medscape, LLC
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From Medscape Medical News > Alerts, Approvals and Safety Changes > Medscape Alerts
Tarceva Gets Safety Warnings for Potentially Fatal GI Perforation, Other Disorders
Emma Hitt, PhD
Published: 05/09/2009
May 9, 2009 — New safety information has been added to the Warnings and Precautions safety labeling for erlotinib (Tarceva, Genentech, Inc, OSI Pharmaceuticals, Inc), the US Food and Drug Administration (FDA) announced yesterday.
Information about 3 disorders has been added: gastrointestinal perforation; bullous, blistering, and exfoliative skin conditions; and ocular disorders. According to an alert sent from MedWatch, the FDA’s safety information and adverse event reporting program, the new safety information comes from routine pharmacovigilance activities of clinical study and postmarketing reports.
Gastrointestinal perforations, including some fatal cases, have been reported in patients receiving erlotinib. Those at increased risk include those taking concomitant anti-angiogenic agents, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease. The FDA advises that erlotinib should be permanently discontinued in patients who develop gastrointestinal perforation.
Another warning has been issued regarding bullous, blistering, and exfoliative skin conditions. Some cases are suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, and fatalities have been reported. A letter from the drug’s manufacturer recommends that healthcare professionals interrupt or discontinue erlotinib treatment if the patient develops severe bullous, blistering, or exfoliating conditions.
Ocular disorders include corneal perforation or ulceration and abnormal eyelash growth. Keratoconjunctivitis sicca or keratitis, which are both known risk factors for corneal ulceration/perforation, have also been described in patients receiving erlotinib. Clinicians are advised to interrupt or discontinue erlotinib therapy if patients present with acute/worsening ocular disorders such as eye pain.
Along with the Warnings and Precautions section, the Dosage and Administration section of the labeling has also been updated to reflect the new dose interruption and/or discontinuation instructions.
Erlotinib monotherapy is indicated for the treatment of patients with locally advanced or metastatic non–small cell lung cancer after failure of at least 1 prior chemotherapy regimen. In combination with gemcitabine, erlotinib is also indicated for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.
Any adverse events associated with use of erlotinib should be communicated to the FDA’s MedWatch program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.
Medscape Medical News © 2009 Medscape, LLC
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From American Journal of Clinical Dermatology
Tumor Immunotherapy in Melanoma – Strategies for Overcoming Mechanisms of Resistance and Escape
Maya Zigler; Gabriel J. Villares; Dina C. Lev; Vladislava O. Melnikova; Menashe Bar-Eli
Published: 05/06/2009
Abstract and Introduction
Abstract
The incidence of melanoma has been steadily increasing over the last 3 decades. Currently, there are several approved treatments for metastatic melanoma, including chemotherapy and biologic therapy as both single treatments and in combination, but none is associated with a significant increase in survival. The chemotherapeutic agent dacarbazine is the standard treatment for metastatic melanoma, with a response rate of 15–20%, although most responses are not sustained. One of the main problems with melanoma treatment is chemotherapeutic resistance. The mechanisms of resistance of melanoma cells to chemotherapy have yet to be elucidated. Following treatment with dacarbazine, melanoma cells activate the extracellular signal-regulated kinase pathway, which results in over-expression and secretion of interleukin (IL)-8 and vascular endothelial growth factor. Melanoma cells utilize this mechanism to escape from the cytotoxic effect of the drug. We have previously reported on the development of fully human neutralizing antibodies against IL-8 (anti-IL-8-monoclonal-antibody [ABX-IL8]). In preclinical studies, ABX-IL8 inhibited tumor growth, angiogenesis, and metastasis of human melanoma in vivo. We propose that combination treatment with dacarbazine and IL-8 will potentiate the cytotoxic effect of the drug. Furthermore, formation of metastasis is a multistep process that includes melanoma cell adhesion to endothelial cells. Melanoma cell adhesion molecule (MUC18) mediates these processes in melanoma and is therefore a good target for eliminating metastasis. We have developed a fully human antibody against MUC18 that has shown promising results in preclinical studies. Since resistance is one of the major obstacles in the treatment of melanoma, we propose that utilization of antibodies against IL-8 or MUC18 alone, or as part of a ‘cocktail’ in combination with dacarbazine, may be a new treatment modality for metastatic melanoma that overcomes resistance of the disease to chemotherapy and significantly improves survival of patients.
Introduction
The incidence and mortality rate of cutaneous melanoma have been increasing more rapidly than any other cancer over the last 3 decades.[1,2] Melanoma accounts for 1–3% of all malignant tumors, and its incidence is increasing by 6–7% each year. Melanoma that is detected early can be surgically resected, resulting in a 5-year patient survival rate of more than 80%. However, once melanoma has metastasized, it is almost always fatal; the 5-year patient survival rate is less than 5% and patients die within 6–9 months.[3-5] Different therapeutic approaches have been evaluated for the treatment of melanoma, including chemotherapy and biologic therapy, either alone or in combination.[5-8] Chemotherapy is the standard treatment for advanced (stage IV) melanoma. Various chemotherapeutic agents such as dacarbazine, platinum compounds (cisplatin, carboplatin), and taxanes (paclitaxel, docetaxel) have been used but have had limited effects in the treatment of malignant melanoma.[9] Dacarbazine, a non-classical alkylating agent, is the most widely used chemotherapeutic agent and has been approved by the US FDA for the treatment of melanoma.[8,10] The anti-tumor activities of dacarbazine result in growth arrest and cell death through nucleic acid methylation or direct DNA damage. However, use of dacarbazine as a single agent has yielded disappointing response rates ranging from 10% to 25%, with the duration of response often being as brief as 5–6 months and less than 5% of patients showing a complete response.[11,12]
Since notorious resistance to chemotherapy is exhibited in the treatment of metastatic melanoma, other approaches have been tested. Several cytokine immunotherapeutic agents have been studied as treatment for patients with advanced-stage melanoma. These include interferon-α and interferon-γ, granulocyte macrophage colony-stimulating factor, and interleukin (IL)-2, IL-4, IL-6, IL-12, and IL-18. However, only IL-2 and interferon-α have been associated with a limited response rate of 10–15% and have been approved by the FDA for adjuvant therapy in patients with stage IV and stage II/III disease, respectively. The mechanism of action of IL-2 involves activation and expansion of specific T cells, while interferon-α is immuno-augmentative, having anti-proliferative as well as anti-angiogenic effects.[13] Although several trials have shown that combining IL-2 with interferon-α and chemotherapy can produce an increase in response rates of 10–15%, this combination also results in moderate-to-severe toxicity.[14,15] Similarly, introduction of vaccines against melanoma has also failed to induce an immune response but has resulted in considerable cytotoxicity.[14,15]
Molecular Changes in Melanoma Progression
The transition of melanoma from radial growth phase to vertical growth phase is accompanied by several molecular changes leading to uncontrolled growth, apoptosis resistance, neo-angiogenesis, and an increase in invasive potential.[16] Changes in genetic and epigenetic events cause deregulation of expression of transcription factors (activator protein [AP]-2), angiogenic factors (IL-8, vascular endothelial growth factor [VEGF]), cellular adhesion molecules (MUC18), matrix degrading enzymes (matrix metalloproteinases [MMPs]), and other factors that interact with the tumor microenvironment. IL-8 is a chemotactic cytokine and acts as an angiogenic factor and, thus, contributes to the progression of melanoma. IL-8 and VEGF may act as autocrine and paracrine factors on tumor and endothelial cells, promoting growth and metastasis of melanoma.[17] The adhesion molecule MUC18 is upregulated in metastatic melanoma and its expression correlates with increased tumor thickness and metastatic potential.[18]
Mechanisms of Resistance and Escape
Melanoma is known for its prominent resistance to chemotherapeutic agents,[19] which causes difficulty in achieving successful treatment. The mechanism of drug resistance varies with different drugs. Chemotherapy resistance can be intrinsic or acquired and is referred to as multidrug resistance.[20]
The mechanisms of drug resistance and escape are being investigated, and several explanations have been suggested, including deregulation of tumor apoptotic pathways, impaired cell cycle checkpoints, and enhanced DNA repair.[20] It has been reported that resistance to these drugs by melanoma cells is achieved through dysregulation of apoptotic pathways by upregulation of survivin, B-cell leukemia/lymphoma (BCL)-2 and BCL-X/L or downregulation of both messenger RNA (mRNA) levels and protein levels of apoptotic protease activating factor-1 (pro-apoptotic) as well as partial silencing of tumor necrosis factor-related apoptosis-inducing ligands.[9] Some of these changes might occur as a result of activation of the PI3K and Ras/Raf pathways, which are known to be activated in melanoma.[21,22]
Alkylating agents form DNA cross-links that are cytotoxic. It has been shown that resistant melanoma cell lines have increased activity of a DNA repair enzyme, O6-alkylguanine DNA alkyltransferase, which reduces the cytotoxic activity of alkylating agents.[9] Other mechanisms such as impaired drug transport and detoxification also contribute to resistance. Impaired drug transport is mediated by multidrug resistance-related proteins and energy-dependent efflux pumps such as P-glycoprotein, which cause a decrease in drug accumulation.[23] Drug detoxification occurs mainly in response to alkylating agents and is mediated via increase of the glutathione S-transferase activity that causes inactivation of dacarbazine.[19] Studies targeting these factors have not shown significant results.
Furthermore, treatment of melanoma patients with dacarbazine and other chemotherapeutic agents such as paclitaxel might cause selection of cells that are more aggressive, thereby leading to resistance. Significantly higher amounts of angiogenic factors are secreted by dacarbazine-resistant cells. We have shown that a single exposure of melanoma cells to dacarbazine causes upregulation of mRNA and protein levels of IL-8 and VEGF.[24] Lev et al.[25] showed that generation of dacarbazine-resistant melanoma cell lines resulted in higher levels of IL-8 and VEGF secretion and thereby enabled these cell lines to be more tolerant to subsequent dacarbazine treatment than non-treated early primary melanomas. Generation of dacarbazine-resistant primary cutaneous melanoma cell lines caused an increase in metastasis and tumor growth in nude mice.[25] Moreover, these tumor cells exhibited increases in MMP-2 and CD31, higher proliferation rate, and upregulation of IL-8 and VEGF. These cells also showed increased phosphorylation of the protein kinases extracellular signal-regulated kinase (ERK), Raf, and mitogen-activated protein (MAP)/ERK kinase (MEK). Inhibition of phosphorylated MEK in dacarbazine-resistant cells caused an increase in their sensitivity to dacarbazine treatment. MAP kinase activity has been shown to stimulate the activity of AP-1 and nuclear factor (NF)-κB, which regulate the promoter activity of IL-8. We have shown by EMSA (electrophoretic mobility shift assay) gel analyses that dacarbazine treatment causes an increase in both the transcription levels of AP-1 and NF-κB and their DNA binding capability.[24] This is mediated through ERK1/2 phosphorylation and leads to upregulation in the transcription levels of IL-8. Moreover, treatment of melanoma cells with a specific MEK inhibitor (UO126) resulted in a significant reduction in luciferase activities driven by the IL-8 promoter. As has recently been recognized, one of the suggested mechanisms for the increased phosphorylation of ERK in melanoma is activating mutations in B-Raf or Ras oncogenes.[26-29] We showed that exposure of melanoma cells to dacarbazine did not lead to the acquisition of B-Raf or N-Ras mutations.[25] However, the melanoma cells studied had an activating mutation in both alleles of N-Ras at codon 61. Our data demonstrate that exposure of these cells to dacarbazine augmented Raf, MEK, and ERK phosphorylation.[25] Therefore, we propose that exposure of melanoma cells to dacarbazine causes upregulation in ERK activity beyond the existing levels imposed by activating B-Raf or N-Ras mutations. Other chemotherapeutic agents that are sometimes used for melanoma treatment, such as paclitaxel, also increase phosphorylated ERK activity.[30] In fact, it is possible that all therapeutic agents that cause the cells to enter into ‘crisis mode’ will cause ERK activation and over-expression of VEGF and IL-8. This evidence has encouraged us to believe that targeting IL-8 is important to overcome melanoma cell resistance to dacarbazine[25] and possibly other chemotherapeutic agents.
New Treatment Strategies
Several studies have utilized different targeted therapies in combination with chemotherapy in order to overcome chemoresistance.[31] These include anti-cytotoxic T-lymphocyte antigen 4 antibodies, protein kinase inhibitors (such as sofafenib), humanized monoclonal antibodies against αVß3 integrin (MEDI-522), and anti-BCL-2 antisense oligonucleotides. Clinical trials utilizing these drugs have shown modest but not significant results.[31]
Fully Human Anti-interleukin-8 Antibodies as a Modality for Bioimmunotherapy
As described in section 2, studies by Lev et al.[24,25] have shown that dacarbazine treatment causes an increase in IL-8 protein expression, which may explain escape and resistance of melanoma cells to chemotherapy. IL-8 plays an important role in the progression of human melanoma[32-36] as it is one of the most potent angiogenic factors produced by melanoma cells. It has been shown that IL-8 is constitutively secreted by metastatic melanoma cells as compared with non-metastatic cells and induces neovascularization in vivo. Expression of IL-8 in melanoma has been shown to positively correlate with disease progression. Moreover, patients with malignant melanoma have an increase in serum IL-8 levels.[37,38]
Luca et al.[39] have shown that primary cutaneous melanoma cells (IL-8 negative) that have been transfected with the IL-8 gene not only produce higher levels of MMP-2 and display higher invasiveness through Matrigel™ in vitro but also have increased tumorigenicity and metastatic potential in vivo. In these cells, IL-8 expression caused upregulation of MMP-2 and an increase in invasion through Matrigel™-coated filters, thereby enhancing invasion of host stroma cells. IL-8 can serve as a survival factor or as an angiogenic factor acting on endothelial cells.[40] Since dacarbazine treatment causes upregulation of IL-8, which is an important mediator of melanoma tumor growth, angiogenesis, and metastasis, it is considered as a potential target for immunotherapies against human melanoma.
In collaboration with Abgenix (Formont, CA, USA), our laboratory has investigated the use of fully human antibodies against IL-8 (anti-IL-8 monoclonal antibody [ABX-IL8]). ABX-IL8 is a neutralizing antibody that binds IL-8 and blocks its ability to bind to its receptor. ABX-IL8 also inhibits migration, degradation, and activation of neutrophils.[41] We have shown that administration of ABX-IL8 suppresses the tumorigenic and metastatic potential of two highly metastatic melanoma cell lines (A375SM and TXM-13).[41] In addition, in vitro, these fully human anti-IL-8 antibodies decreased MMP-2 expression and its collagenase activity as well as reduced the invasion of metastatic melanoma cells through Matrigel™. In human umbilical vein endothelial cells (HUVEC), ABX-IL8 directly inhibits de novo formation of capillary-like structures but not pre-existing vascular networks. Furthermore, in vivo, ABX-IL8-induced inhibition of tumor growth and metastasis is associated with a decrease in neovascularization and an increase in tumor cell apoptosis.[41] Addition of ABX-IL8 to primary melanoma cell lines also sensitizes these cell lines to dacarbazine treatment. In vitro, a combination of dacarbazine and anti-IL-8 antibodies caused a decrease in cell viability in metastatic melanoma cell lines.[24]
Since the standard treatment of metastatic melanoma, dacarbazine, causes upregulation of the pro-angiogenic cytokines IL-8 and VEGF, combining conventional dacarbazine chemotherapy with anti-IL-8 antibodies might be beneficial in the treatment of metastatic melanoma and thereby reduce chemoresistance. Treatment with ABX-IL8 could potentiate the cytotoxic effect of dacarbazine.
Fully Human Anti-MUC18 Antibodies as a Modality for Bioimmunotherapy
MUC18 is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily and functions as a calcium-independent adhesion molecule that interacts with an unknown heterophilic ligand. Expression of MUC18 in human melanoma cell lines directly correlates with the ability of the cells to metastasize in vivo.[42]
MUC18 is strongly expressed on metastatic melanoma cells and less frequently expressed on nevus cells.[42] MUC18 is also expressed on endothelial cells, enabling heterotypic adhesion between melanoma cells and endothelial cells, which could indicate that MUC18 is involved in promoting intravasation and extravasation.[42,43] MUC18 is a mediator of several intracellular signaling mechanisms and causes upregulation of MMP-2, thus promoting dissociation and invasion. Previous studies have also shown that activation of MUC18 can influence cell migration through cytoskeleton reorganization by association with the cytoplasmic domain of tyrosine kinase p59fyn, resulting in phosphorylation of focal adhesion kinase p125.[44]
Enforced expression of MUC18 in the low metastatic melanoma cell line SB-2 caused an increase in tumorigenicity and metastatic potential in nude mice.[42] In vitro, these cells showed an increase in MMP-2 levels and in invasion through Matrigel™-coated filters; attachment of the cells to endothelial cells was also increased.[42] Satyamoorthy et al.[45] demonstrated that in vitro downregulation of MUC18 in highly metastatic melanoma cell lines negatively affected cell aggregation as well as their ability to grow in soft agar and in immunodeficient animals.
Complete inhibition of one of the steps in the metastatic cascade of human melanoma is crucial for preventing metastasis. The potential of tumor cells to form metastases relies not only on their ability to induce angiogenesis but also to extravasate. Thus, MUC18 serves as a potential immunotherapeutic target in the treatment of malignant melanoma and might help eliminate dacarbazine-resistant cells. As with IL-8, in concert with Abgenix we have developed fully humanized antibodies directed against MUC18 (anti-MUC18 monoclonal antibody [ABX-MA1]). We have shown that administration of ABX-MA1 results in a decrease in tumor growth and metastasis after injection of highly metastatic melanoma cell lines.[46] ABX-MA1-treated tumors also exhibited a decrease in angiogenesis. In vitro, ABX-MA1 caused disruption of spheroid formation, a decrease in transcription and activity of MMP-2, and a decrease in invasion through Matrigel™-coated filters. Moreover, MUC18 antibodies have also been shown to inhibit the attachment of melanoma cells to HUVEC and the tube-like formation of HUVEC[46] cells, suggesting that this approach may target not only the tumor but also the tumor microenvironment. Therefore, anti-MUC18 antibodies may be administered alone or in combination with chemotherapy to improve treatment of metastatic melanoma. Since ABX-MA1 acts at a different phase of the metastatic cascade than ABX-IL8, combination therapy using both antibodies given as a ‘cocktail’ should also be considered.
Conclusion
The mortality rate of patients with metastatic melanoma continues to rise, while the therapeutic agents currently in use show discouraging results. Melanoma cell resistance and escape is one of the major problems with current treatment modalities. We have demonstrated that in vitro treatment of melanoma cells with dacarbazine leads to an increase in the angiogenic factors IL-8 and VEGF, and further results in selection of resistant cells. Therefore, herein, we propose combining chemotherapy treatment with ABX-IL8 to potentiate the cytotoxic effect of dacarbazine. In addition, the melanoma adhesion molecule, MUC18, is strongly implicated in the progression of human melanoma and in the interaction of tumor cells with the microenvironment. Use of both ABX-IL8 and ABX-MA1 in orthotopic models demonstrated a decrease in tumor growth and metastasis. Therefore, by targeting multiple pathways and utilizing these antibodies in combination with the standard chemotherapeutic agent dacarbazine, we may be able to improve survival for patients with metastatic melanoma.
References
- Bevona C, Sober AJ. Melanoma incidence trends. Dermatol Clin 2002; 20 (4): 589-95, vii
- Howe HL, Wingo PA, Thun MJ, et al. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 2001; 93 (11): 824-42
- Johnson TM, Yahanda AM, Chang AE, et al. Advances in melanoma therapy. J Am Acad Dermatol 1998; 38 (5 Pt 1): 731-41
- Koh HK. Cutaneous melanoma. N Engl J Med 1991; 325 (3): 171-82
- Sun W, Schuchter LM. Metastatic melanoma. Curr Treat Options Oncol 2001; 2 (3): 193-202
- Becker JC, Kampgen E, Brocker E. Classical chemotherapy for metastatic melanoma. Clin Exp Dermatol 2000; 25 (6): 503-8
- Cassel WA, Olkowski ZL, Murray DR. Immunotherapy in malignant melanoma [letter]. J Clin Oncol 1999; 17 (6): 1963
- Crosby T, Fish R, Coles B, et al. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; (2): CD001215
- Grossman D, Altieri DC. Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev 2001; 20 (1-2): 3-11
- Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17 (9): 2745-51
- Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18 (1): 158-66
- Middleton MR, Lorigan P, Owen J, et al. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000; 82 (6): 1158-62
- Atkins MB. Cytokine-based therapy and biochemotherapy for advanced melanoma. Clin Cancer Res 2006; 12 (7 Pt 2): 2353s-8s
- Kirkwood JM, Moschos S, Wang W. Strategies for the development of more effective adjuvant therapy of melanoma: current and future explorations of antibodies, cytokines, vaccines, and combinations. Clin Cancer Res 2006; 12 (7 Pt 2): 2331s-6s
- Sondak VK, Sabel MS, Mule JJ. Allogeneic and autologous melanoma vaccines: where have we been and where are we going? Clin Cancer Res 2006; 12 (7 Pt 2): 2337s-41s
- Leslie MC, Bar-Eli M. Regulation of gene expression in melanoma: new approaches for treatment. J Cell Biochem 2005; 94 (1): 25-38
- Schadendorf D, Moller A, Algermissen B, et al. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 1993; 151 (5): 2667-75
- Lehmann JM, Riethmuller G, Johnson JP. MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci U S A 1989; 86 (24): 9891-5
- Koon HB, Atkins MB. Update on therapy for melanoma: opportunities for patient selection and overcoming tumor resistance. Expert Rev Anticancer Ther 2007; 7 (1): 79-88
- La Porta CA. Drug resistance in melanoma: new perspectives. Curr Med Chem 2007; 14 (4): 387-91
- Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353 (20): 2135-47
- von Gise A, Lorenz P, Wellbrock C, et al. Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 2001; 21 (7): 2324-36
- Röckmann H, Schadendorf D. Drug resistance in human melanoma: mechanisms and therapeutic opportunities. Onkologie 2003; 26 (6): 581-7
- Lev DC, Ruiz M, Mills L, et al. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2003; 2 (8): 753-63
- Lev DC, Onn A, Melinkova VO, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 2004; 22 (11): 2092-100
- Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 1994; 102 (3): 285-90
- Hazan RB, Kang L, Roe S, et al. Vinculin is associated with the E-cadherin adhesion complex. J Biol Chem 1997; 272 (51): 32448-53
- Jafari M, Papp T, Kirchner S, et al. Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol 1995; 121 (1): 23-30
- Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003; 63 (4): 756-9
- Okano J, Rustgi AK. Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently of activating the programmed cell death machinery. J Biol Chem 2001; 276 (22): 19555-64
- Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer 2007; 109 (3): 455-64
- Kunz M, Goebeler M, Brocker EB, et al. IL-8 mRNA expression in primary malignant melanoma mRNA in situ hybridization: sensitivity, specificity, and evaluation of data. J Pathol 2000; 192 (3): 413-5
- Nurnberg W, Tobias D, Otto F, et al. Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma. J Pathol 1999; 189 (4): 546-51
- Singh RK, Gutman M, Radinsky R, et al. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 1994; 54 (12): 3242-7
- Singh RK, Gutman M, Reich R, et al. Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. Cancer Res 1995; 55 (16): 3669-74
- Singh RK, Varney ML, Bucana CD, et al. Expression of interleukin-8 in primary and metastatic malignant melanoma of the skin. Melanoma Res 1999; 9 (4): 383-7
- Scheibenbogen C, Mohler T, Haefele J, et al. Serum interleukin-8 (IL-8) is elevated in patients with metastatic melanoma and correlates with tumour load. Melanoma Res 1995; 5 (3): 179-81
- Ugurel S, Rappl G, Tilgen W, et al. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 2001; 19 (2): 577-83
- Luca M, Huang S, Gershenwald JE, et al. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol 1997; 151 (4): 1105-13
- Yoshida S, Ono M, Shono T, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 1997; 17 (7): 4015-23
- Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 2002; 161 (1): 125-34
- Xie S, Luca M, Huang S, et al. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res 1997; 57 (11): 2295-303
- Shih IM, Speicher D, Hsu MY, et al. Melanoma cell-cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion. Cancer Res 1997; 57 (17): 3835-40
- Anfosso F, Bardin N, Frances V, et al. Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). J Biol Chem 1998; 273 (41): 26852-6
- Satyamoorthy K, Muyrers J, Meier F, et al. Mel-CAM-specific genetic suppressor elements inhibit melanoma growth and invasion through loss of gap junctional communication. Oncogene 2001; 20 (34): 4676-84
- Mills L, Tellez C, Huang S, et al. Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. Cancer Res 2002; 62 (17): 5106-14
Reprint AddressDr Menashe Bar-Eli, Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: mbareli@mdanderson.org
Am J Clin Dermatol. 2008;9(5):307-311. © 2008 Adis Data Information BV
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From Medscape Medical News
New Guidelines Address Treatment of Hospitalized Patients With High Blood Glucose Levels
Laurie Barclay, MD
May 8, 2009 — A consensus statement of the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) issues clinical recommendations on the proper treatment of hospitalized patients with high blood glucose levels.
The new guidelines, which target healthcare professionals, supporting staff, hospital administrators, and others involved in improved management of hyperglycemia in inpatient settings, are published in the May/June issue of Endocrine Practice and in the May issue of Diabetes Care.
“Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients,” write Etie S. Moghissi, MD, FACP, FACE, from the University of California in Los Angeles, and colleagues. “There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) suggested that intensive treatment of hyperglycemia improved hospital outcomes.”
In 2004, the American College of Endocrinology (ACE) and the AACE, in collaboration with the ADA and other medical organizations, developed recommendations for treatment of inpatient hyperglycemia. These guidelines generally endorsed tight glycemic control in critical care units. In 2005, the ADA annual Standards of Medical Care included recommendations for treatment of inpatient hyperglycemia. In 2006, the ACE and ADA collaborated on a joint “Call to Action” for inpatient glycemic control, highlighting several barriers to systematic implementation in hospitals.
Questions to Be Considered
The main objectives of the AACE and ADA in preparing this updated consensus statement were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. After extensive review of the most current literature, members of the consensus panel considered the following questions:
1. Does improving glycemic control for inpatients with hyperglycemia improve clinical outcomes?
2. What glycemic targets should be recommended for different patient populations?
3. In specific clinical situations, which available treatment options can safely and effectively achieve optimal glycemic targets?
4. What safety issues are associated with inpatient management of hyperglycemia?
5. What systems need to be in place to implement these recommendations?
6. Is it cost-effective to treat hyperglycemia in hospitalized patients?
7. What are the best strategies to shift management of hyperglycemia to outpatient care?
8. What additional research is needed?
Recommendations for Critically Ill Patients
Specific clinical recommendations for critically ill patients are as follows:
• For treatment of persistent hyperglycemia, beginning at a threshold of no greater than 180 mg/dL (10.0 mmol/L), insulin therapy should be started.
• For most critically ill patients, a glucose range of 140 to 180 mg/dL (7.8 – 10.0 mmol/L) is recommended once insulin therapy has been started.
• To achieve and maintain glycemic control in critically ill patients, the preferred method is intravenous insulin infusions.
• Validated insulin infusion protocols that are shown to be safe and effective and to have low rates of hypoglycemia are recommended.
• To reduce hypoglycemia and to achieve optimal glucose control, frequent glucose monitoring is essential in patients receiving intravenous insulin.
Recommendations for Patients Who Are Not Critically Ill
Specific clinical recommendations for noncritically ill patients are as follows:
• For most noncritically ill patients receiving insulin therapy, the premeal blood glucose target should generally be less than 140 mg/dL (< 7.8 mmol/L), and random blood glucose levels should be less than 180 mg/dL (< 10.0 mmol/L), provided these targets can be safely achieved.
• In stable patients in whom tight glycemic control was previously achieved, more rigorous targets may be appropriate.
• In terminally ill patients or in those with severe comorbidities, less stringent targets may be appropriate.
• For achieving and maintaining glucose control, the preferred method is scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components.
• Prolonged treatment with sliding-scale insulin as the only therapeutic agent is discouraged.
• For most hospitalized patients who require treatment for hyperglycemia, noninsulin antihyperglycemic agents are not appropriate.
• Day-to-day decisions concerning treatment of hyperglycemia must be based on clinical judgment and ongoing evaluation of clinical status.
Safety Recommendations
Specific recommendations geared toward improving safety in management of inpatient hyperglycemia are as follows:
• Major safety issues include overtreatment and undertreatment of hyperglycemia.
• Hospital staff must be educated to engage the support of those involved in the care of inpatients with hyperglycemia.
• In patients with anemia, polycythemia, hypoperfusion, or use of some medications, caution is needed when interpreting results of point-of-care glucose meters.
• To promote a rational systems approach to inpatient glycemic management, buy-in and financial support from hospital administration are required.
The guidelines also propose a selected number of research questions and topics to guide the management of inpatient hyperglycemia in different hospital settings.
“Appropriate inpatient management of hyperglycemia is cost-effective,” the guidelines authors conclude. “Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management.”
Some of the guidelines authors have disclosed various financial relationships with sanofi-aventis U.S. LLC; Amylin Pharmaceuticals, Inc;Takeda Pharmaceuticals North America, Inc; AstraZeneca; GlaxoSmithKline; Johnson & Johnson Services, Inc; Eli Lilly & Co; Medtronic, Inc; Novo Nordisk A/S; Halozyme Therapeutics; MannKind Corporation; Abbott Laboratories; F. Hoffman La Roche Ltd. (Roche); and/or Merck & Co.
Endocr Pract. 2009;15:1-15.
Diabetes Care. Published online May 8, 2009.
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