Early Treatment of Ocular Hypertension May Reduce Risk for Glaucoma

March 16, 2010 — Early treatment of ocular hypertension appears to reduce the risk for the development of glaucoma, especially in individuals at the highest risk, according to the results of a randomized controlled trial reported in the March issue of Archives of Ophthalmology.

"Elevated intraocular pressure (IOP) (ocular hypertension [OHT]) is a leading risk factor for the development of primary open angle glaucoma (POAG) and the only modifiable risk factor at present," write Michael A. Kass, MD, from Washington University School of Medicine in St. Louis, Missouri, and colleagues for the Ocular Hypertension Treatment Study (OHTS) Group. "It is estimated that 4% to 7% of the US population older than 40 years has OHT. There is substantial controversy on how to manage this large group of individuals who are at higher risk of developing glaucoma than the general population."

The goal of the study was to compare the safety and efficacy of earlier vs later treatment in reducing the risk for POAG in 1636 individuals with ocular hypertension, with baseline IOP ranging from 24 to 32 mm Hg in 1 eye and 21 to 32 mm Hg in the other eye. Participants were randomly assigned to observation or to receive topical ocular hypotensive medication. In the medication group, median duration of treatment was 13.0 years, whereas the observation group had a median duration of 7.5 years without treatment and then received medication for a median of 5.5 years.

To evaluate whether delaying treatment was associated with any harms, the investigators compared the cumulative proportion of participants who went on to have POAG in the original observation group and in the original medication group at a median follow-up of 13 years.

Overall, this proportion was 0.22 in the original observation group (95% confidence interval [CI], 0.19 - 0.25) vs 0.16 (95% CI, 0.13 - 0.19) in the original medication group (P =. 009), or a 27% reduction in glaucoma risk associated with early treatment. For participants at the highest tertile of baseline risk for the development of POAG, based on age, corneal thickness, and baseline IOP, the cumulative proportion of participants who went on to have POAG was 0.40 (95% CI, 0.33 - 0.46) and 0.28 (95% CI, 0.22 - 0.34), respectively.

"There was little evidence of increased adverse events associated with medication," the study authors write. "Absolute reduction was greatest among participants at the highest baseline risk of developing POAG. Individuals at high risk of developing POAG may benefit from more frequent examinations and early preventive treatment."

Limitations of the OHTS study include choice of a target IOP reduction of 20% from baseline, design not that of an epidemiologic study, use of very high thresholds for diagnosing POAG, and use of a convenience sample vs a population-based sample.

"We believe individualized assessment of the risk of developing POAG will be useful to patients and clinicians for deciding on the frequency of examinations and tests as well as the possible administration of preventive treatment," the study authors write. "Clinicians need to consider the patient's age, health status, life expectancy, and personal preferences when making such decisions. Ultimately, the full extent of the penalty for delaying treatment will require longer follow-up to ascertain the incidence and degree of visual impairment by randomization group."

In an accompanying editorial, Alfred Sommer, MD, MHS, from Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland, notes that clinicians should consider whether treating patients with IOP might do more harm than good.

"In the end, the physician is stuck with the persistent problem of whom to treat and whom to watch," Dr. Sommer writes. "The fascinating article by Kass et al provides interesting insights as to many of the issues at stake, but offers little definitive information to guide us. It probably still makes sense that young patients with lots of high risk factors should receive prophylaxis, while elderly patients with few risk factors should not. The endless symposia and debates on how best to manage patients with ocular hypertension will probably continue unabated."

The National Eye Institute and the National Center on Minority Health and Health Disparities, National Institutes of Health; Merck Research Laboratories; Pfizer Inc; and Research to Prevent Blindness supported this study. The study authors and Dr. Sommer have disclosed no relevant financial relationships.

Arch Ophthalmol. 2010;128:276-287.

Clinical Context

Glaucoma is one of the most common causes of blindness in the United States worldwide and has a higher incidence among African Americans than other racial groups. Elevated IOP is a leading risk factor for POAG, with 4% to 7% of the US population older than 40 years having ocular hypertension. Early medical treatment with topical hypotensive treatment in those with ocular hypertension has been shown to delay or prevent the onset of POAG but it is uncertain if duration of treatment affects the protective effects.

This is a randomized controlled trial conducted in adults with ocular hypertension to determine if medical vs delayed medical treatment in those with ocular hypertension is associated with reduced risk for POAG and if the effects differ in different risk groups.

Study Highlights

• Inclusion criteria were ages 40 to 80 years, qualifying IOP of 24 mm Hg or higher or 32 mm Hg or less in 1 eye and 21 mm Hg or higher or 32 mm Hg or less in the other eye, gonioscopically open angles, 2 normal and reliable visual fields per eye, and normal optic discs.
• Excluded were those with vision worse than 20/40 in either eye, with a history of ocular surgery, diabetic retinopathy, or optic disc degeneration.
• The study involved 2 phases.
• In phase 1, at baseline 817 participants were randomly assigned to topical ocular hypotensive agents and were observed for 13 years.
• 819 were randomly assigned to observation only at baseline with no ocular hypotensive agents.
• In phase 2, after 7.5 years, the observation group was given ocular hypotensive treatment for the next 5.5 years and thus received delayed treatment.
• Follow up visits occurred every 6 months and included a medical and ocular history, determination of refraction and visual acuity, Humphrey white-on-white 30-2 visual field test, slit-lamp examination, IOP measurement, and direct ophthalmoscopy.
• Participants also completed self-administered questionnaires consisting of the Glaucoma Symptom Checklist, the National Eye Institute Visual Function Questionnaire (every 24 months from 114 months), and the Medical Outcomes Study-Short Form with 36 questions.
• POAG was defined as the development of reproducible visual field abnormality or clinically significant optic disc deterioration in 1 or both eyes that was attributed to POAG.
• Optic disc degeneration was defined as generalized or localized disc thinning of the neuroretinal rim vs baseline stereoscopic disc photographs.
• Primary endpoint was proportion of participants in whom POAG developed.
• Mean age was 55 years, and median follow-up was 13 years.
• Those in the observation with delayed treatment group had no medication for 7.5 years and were treated for 5.5 years.
• The cumulative proportion of participants in whom POAG developed from baseline to 13 years was 0.19 overall, 0.22 for the observation with delayed treatment group, and 0.16 for the treatment group (P = .009), with a relative risk of 0.42 (P < .001) for the medication group.
• In phase 2, the cumulative proportion who had POAG to 13 years was similar in the 2 groups (hazard ratio, 1.06; P = .77).
• More participants in the observation vs the treatment group went on to have bilateral POAG at 13 years (6.2% vs 3.9%).
• Similarly, more participants in the observation group vs the treatment group experienced glaucomatous visual field loss (2.3% vs 1.2%).
• The cumulative proportion of African Americans in whom POAG developed was higher vs other races (0.28 vs 0.16).
• The protective effect of treatment was significant during phase 1 for African Americans (hazard ratio, 0.47), but the proportions were similar in phase 2 when both groups received treatment.
• African American status was a significant predictor of development of POAG (hazard ratio, 1.70).
• The number of Hispanic patients was too small (n = 59) to determine risk.
• When examined by baseline risk tertile, the cumulative proportion of participants who had POAG to 13 years were 6%, 6% to 13%, and more than 13% for the first, second, and third tertiles, respectively.
• The numbers needed to treat to prevent 1 case of POAG during 13 years of treatment were 98, 16, and 7 for the first, second, and third tertiles of risk, respectively.
• There were no significant differences in adverse effects or mortality rates in the observation and treatment groups.
• The authors concluded that hypotensive ocular treatment reduced the risk for POAG in those with increased IOP, and the protective effect was greatest in those at highest risk and in African Americans.

Clinical Implications

• Use of ocular hypotensive agents in those with IOP is associated with a reduced risk for POAG at 13 years.
• The protective effect of ocular hypotensive medications is greatest in those with the highest baseline risk for POAG.

Unintentional Therapeutic Errors Involving Insulin in the Ambulatory Setting Reported to Poison Centers

Background: Adverse drug events in the ambulatory care setting are not uncommon and can cause significant morbidity. Little research has been published on the management of adverse drug events involving insulin in the outpatient setting.
Objective: To analyze data on patients with unintentional therapeutic errors involving insulin managed by 9 regional poison control centers.
Methods: A retrospective search was performed for all records involving insulin at 9 poison centers, covering the population of 4 states for the years 2000–2009. A subgroup of the study population was selected with a reason for exposure of "unintentional—therapeutic error."
Results: There were 3819 insulin exposures reported, with an increase in the annual incidence of insulin exposures of 279% (from 170 to 645 patients/year) and a mean annual increase of 18%. Of the insulin exposures, 2584 were unintentional therapeutic errors (68%). The percentage of all insulin exposures that were unintentional therapeutic errors increased progressively, from 41% to 78%. There was a 495% increase in annual incidence of unintentional therapeutic errors involving insulin, with a mean annual increase of 28%. Unintentional therapeutic errors involving insulin occurred primarily in adults >40 years (73%), with 63% occurring in women. There was a pronounced increase in unintentional therapeutic errors involving insulin in the later evening hours, with 71% occurring between 1800 and 2400 and reaching a peak at 2200. The majority (n = 1803; 70%) of patients were managed in a non–health-care facility location, primarily their own residence.
Conclusions: This is the first report of an increasing trend of insulin-related unintentional therapeutic errors in the ambulatory setting. Our study highlights a number of striking features, including: (1) a consistent and dramatic increase of unintentional therapeutic errors involving insulin over the 10-year period, (2) a high incidence of unintentional therapeutic errors involving insulin in the late evening hours, and (3) a high incidence of unintentional therapeutic errors involving insulin involving adults >40 years and females. With their 24/7 availability, poison centers appear to be an increasingly important resource for patients experiencing unintentional therapeutic errors involving insulin.

Introduction

Adverse drug events in the ambulatory care setting are not uncommon and can cause significant morbidity.^[1–4]Insulin is one of the leading medications involved in adverse drug events leading to an emergency department visit, especially in older adults.^[2] However, the published data on insulin adverse drug events have focused primarily on the hospital setting.^[1–4] There is a lack of information on the epidemiology of insulin-associated adverse drug events in the ambulatory care or non–hospital-based setting. One study of a poisons unit in Germany found that 5% of insulin overdoses were accidental, and 90% of the cases were intentional suicidal insulin overdose, with all inquiries coming from the physician caring for the patient, suggesting these cases were not being managed in the ambulatory setting.^[5]

In the US, poison control centers are able to manage the majority of their patients in the ambulatory care setting, often reducing the need for an unnecessary emergency department visit. Poison control centers manage more than 200,000 adverse drug events annually, with 88% of these patients managed outside of the hospital setting.^[3,7] The real-time database of these centers would be a rich source of information on insulin adverse drug events in the ambulatory care setting. To date, no information has been published evaluating insulin adverse drug events in this setting. The objective of this study was to delineate characteristics and outcomes of unintentional therapeutic errors involving insulin, with a focus on cases in the ambulatory care setting.

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Gone for few years. I am back to continue blogging :D

Foreign Body Removal, Rectum

Anorectal foreign bodies are usually inserted transanally for sexual or medicinal purposes. Rectal foreign bodies may also be observed with body packing or stuffing or after prior oral ingestion of the object. Anorectal foreign bodies are more common in men than in women.

Rectal foreign bodies may include such objects as bottles, vibrators, fruit, vegetables, and balls. Cylindrical objects are common. In addition, thermometers may accidentally break while a rectal temperature is being obtained.

Be aware that patients have usually made multiple attempts to remove the object prior to presentation in the emergency department. Patients may create unusual stories to explain how the object became lodged in the rectum.

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Astrocytoma

Background

Astrocytomas are CNS neoplasms in which the predominant cell type is derived from an immortalized astrocyte. Two classes of astrocytic tumors are recognized—those with narrow zones of infiltration (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Members of the latter group share various features, including the ability to arise at any site in the CNS, with a preference for the cerebral hemispheres; clinical presentation usually in adults; heterogeneous histopathological properties and biological behavior; diffuse infiltration of contiguous and distant CNS structures, regardless of histological stage; and an intrinsic tendency to progress to more advanced grades.

Numerous grading schemes based on histopathologic characteristics have been devised, including the Bailey and Cushing grading system, Kernohan grades I-IV, World Health Organization (WHO) grades I-IV, and St. Anne/Mayo grades 1-4. Regions of a tumor demonstrating the greatest degree of anaplasia are used to determine the histologic grade of the tumor. This practice is based on the assumption that the areas of greatest anaplasia determine disease progression.

This chapter focuses on the widely accepted WHO grading scheme that relies on assessments of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and necrosis. WHO grade I corresponds to pilocytic astrocytoma, WHO grade II corresponds to low-grade (diffuse) astrocytoma, WHO grade III corresponds to anaplastic astrocytoma, and WHO grade IV corresponds to glioblastoma multiforme (GBM). This article is confined to low-grade and anaplastic astrocytomas. GBM and pilocytic astrocytoma are not discussed in this chapter (for more information, see Glioblastoma Multiforme).
Pathophysiology

Regional effects of astrocytomas include compression, invasion, and destruction of brain parenchyma. Arterial and venous hypoxia, competition for nutrients, release of metabolic end products (eg, free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators (eg, cytokines) disrupt normal parenchymal function. Elevated intracranial pressure (ICP) attributable to direct mass effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume may mediate secondary clinical sequelae. Neurological signs and symptoms attributable to astrocytomas result from perturbation of CNS function. Focal neurological deficits (eg, weakness, paralysis, sensory deficits, cranial nerve palsies) and seizures of various characteristics may permit localization of lesions.

Infiltrating low-grade astrocytomas grow slowly compared to their malignant counterparts. Doubling time for low-grade astrocytomas is estimated at 4 times that of anaplastic astrocytomas. Several years often intervene between the initial symptoms and the establishment of a diagnosis of low-grade astrocytoma. One recent series estimated the interval to be approximately 3.5 years. The clinical course is marked by a gradual deterioration in one half of cases, a stepwise decline in one third of cases, and a sudden deterioration in 15% of cases. Seizures, often generalized, are the initial presenting symptom in about one half of patients with low-grade astrocytoma.

For patients with anaplastic astrocytomas, the growth rate and interval between onset of symptoms and diagnosis is intermediate between low-grade astrocytomas and glioblastomas. Although highly variable, a mean interval of approximately 1.5-2 years between onset of symptoms and diagnosis frequently is reported. Compared to low-grade lesions, seizures are less common among patients with anaplastic astrocytomas. Initial presenting symptoms most commonly are headache, depressed mental status, and focal neurological deficits.
Mortality/Morbidity

Morbidity and mortality, as defined by the length of a patient's history and the odds of recurrence-free survival, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II), 2-5 years for those with anaplastic astrocytomas (WHO grade III), and less than 1 year for patients with glioblastoma (WHO grade IV).
Race

Although genetic determinants are recognized in astrocytoma development and progression, astrocytomas do not differ intrinsically in incidence or behavior among racial groups. Demographic and sociological factors, such as population, age, ethnic attitude toward disease, and access to care, have been reported to influence measured distributions.
Sex

No clear sex predominance has been identified in the development of pilocytic astrocytomas. A slight male predominance, with a male-to-female ratio of 1.18:1 for development of low-grade astrocytomas, has been reported. A more significant male predominance, with a male-to-female ratio of 1.87:1 for the development of anaplastic astrocytomas, has been identified.
Age

Most cases of pilocytic astrocytoma present in the first 2 decades of life. In contrast, the peak incidence of low-grade astrocytomas, representing 25% of all cases in adults, occurs in people aged 30-40 years. Ten percent of low-grade astrocytomas occur in people younger than 20 years; 60% of low-grade astrocytomas occur in people aged 20-45 years; and 30% of low-grade astrocytomas occur in people older than 45 years. The mean age of patients undergoing a biopsy of anaplastic astrocytoma is 41 years.

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