Fatal Spontaneous Retroperitoneal Hematoma Secondary Enoxaparin

from Southern Medical Journal

Discussion

Fatal hemorrhage is an infrequent complication of enoxaparin use. This is only the second reported case of a patient with enoxaparin-induced fatal spontaneous retroperitoneal hematoma,[10] and the first when enoxaparin was used in the management of an acute coronary syndrome.

The ESSENCE study showed that enoxaparin was more effective than IV unfractionated heparin in reducing the incidence of death, myocardial infarction or recurrent angina in patients with unstable angina or NQWMI.[1] Benefit was maintained after one year of follow-up; only minor hemorrhage (injection-site ecchymosis) was more common with enoxaparin.[1-6] However, enoxaparin is not without risk. Among 1,578 patients receiving enoxaparin and aspirin for management of acute coronary syndromes, 17 (1%) cases of major bleeding episodes were reported (package insert; Aventis Pharmaceuticals, Inc., Bridgewater, NJ). These included intraocular, retroperitoneal, and IC hemorrhage, hemoglobin decrease by at least 3 g/dl or transfusion requirement of 2 U or more of blood products.

Physicians should be vigilant for symptoms and signs that suggest retroperitoneal hemorrhage (hypotension, decreasing hemoglobin, abdominal distention, peritoneal signs, flank and/or hip pain, increasing bruising), IC hemorrhage (neurologic deficits, nausea, vomiting, headache, mental status changes), or intraocular hemorrhage (visual changes, nausea, vomiting, photophobia, pain, headache). Enoxaparin should be used very cautiously in elderly patients and in patients with renal insufficiency (creatinine clearance <30 ml/min) because of the risk of delayed clearance. Other patients needing close monitoring include those with bleeding diatheses, uncontrolled hypertension, or recent gastrointestinal bleeding (Table 1).[6] In these high-risk patients, the activity of enoxaparin should be monitored by anti-factor Xa assay. Since enoxaparin is highly active against factor Xa, anti-factor Xa values that are within the determined therapeutic range are consistent with adequate drug efficacy and safety. Anti-factor Xa values that are elevated above the determined therapeutic range should alert clinicians to the potential for bleeding complications.

Supportive care for enoxaparin-induced hemorrhage is multifactorial and best provided in an intensive care setting.[6] First, enoxaparin must be discontinued. Second, protamine should be given to neutralize the anticoagulant effects of enoxaparin (Table 2). The protamine dose depends upon the time elapsed since the last enoxaparin dose. Third, fresh frozen plasma and packed red blood cells should be administered, and hemoglobin and coagulation studies monitored serially. Fourth, surgical intervention may be necessary if all other measures fail to stabilize the patient.

Conclusion

This case demonstrates that, despite its proven benefits in the management of patients with acute coronary syndromes, enoxaparin use is not without risk. A high index of suspicion is necessary if patients display any of the symptoms and signs that suggest substantial hemorrhage. In high-risk patient groups, enoxaparin activity should be monitored with the anti-Factor-Xa assay. Treatment of enoxaparin-induced hemorrhage is multi-factorial and best implemented in an intensive care setting.

CDC Adds Laboratory Criteria to Case Definition for SARS

NEW YORK (Reuters Health) May 01 - The Centers for Disease Control and Prevention has updated its interim U.S. surveillance case definition for severe acute respiratory syndrome (SARS) to include laboratory evidence of infection with SARS-associated coronavirus (SARS-CoV).

Under the new laboratory criteria, a SARS case is laboratory-confirmed if one of the following criteria is met:

Detection of antibody to SARS-CoV by indirect fluorescent antibody (IFA) or enzyme-linked immunosorbent assay (ELISA).

Isolation of SARS-CoV in tissue culture.

Detection of SARS-CoV RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), which must be confirmed by a second PCR test.

The CDC emphasizes that a negative PCR, viral culture, or antibody test for SARS-CoV obtained within 21 days of illness does not rule out coronavirus infection. "In these cases, an antibody test of a specimen obtained more than 21 days after illness begins is needed to determine infection," CDC officials note in a statement.

The CDC has also revised the clinical criteria for SARS "to reflect the possible spectrum of respiratory illness associated with SARS-CoV." These clinical criteria include:

Asymptomatic or mild respiratory illness.

Moderate respiratory illness: temp > 100.4 degrees Fahrenheit with one or more of the following: cough, shortness of breath, difficulty breathing or hypoxia.

Severe respiratory illness: Same as above, plus radiographic evidence of pneumonia, or respiratory distress syndrome, or autopsy findings consistent with pneumonia or respiratory distress syndrome without an identifiable cause.

As of April 30th, 289 SARS cases have been reported in the U.S. from 38 states. Of these, 233 (81%) were classified as suspected cases and 56 (19%) were classified as probable SARS cases (more severe illness with pneumonia or acute respiratory distress syndrome).

Of the 60 cases in which laboratory testing is complete, 6 have laboratory-confirmed SARS-CoV and 54 are negative for SARS-CoV infection.

The vast majority of U.S. cases of SARS have been linked to international travel to affected areas. There have been only two instances of secondary transmission to household contacts or healthcare workers.

More information about SARS case definition, travel advisories, and numbers of cases worldwide can be found at the CDC Web site at http://www.cdc.gov.

MMWR 2003;52:388-393.

SARS Virus Found in Recovered Patients

HONG KONG (Reuters) May 01 - Hong Kong physicians have discovered for the first time traces of the SARS virus in the stool and urine of patients thought to be free of the virus and discharged from the hospital, officials said on Thursday.

The news came after physicians in Hong Kong found evidence of permanent lung scarring and possible cases of relapses in patients with severe acute respiratory syndrome (SARS).

"Recovered patients have the virus in their stools and urine," David Hui, a doctor treating SARS patients, told Reuters.

Hong Kong's Director of Health told a news conference experts here were now trying to ascertain how long recovered patients in the territory may be passing the virus in their stool and urine. "Most patients spend at least 3 weeks in hospital, they must be clear of any symptoms for 5 days before they can be released," said Margaret Chan, adding that those discharged must remain at home for another 14 days.

Tests were being done to see if recovered patients with the traces of the virus were still infectious.

Authorities said the disease killed another 5 people in the city and infected 11 others on Thursday, bringing the death toll to 162 and cumulative cases to 1600.

Drug Companies Collaborating to Develop SARS Vaccine

LONDON (Reuters Health) Apr 30 - GlaxoSmithKline said on Wednesday it is collaborating with other companies and France's Institut Pasteur to accelerate development of a possible vaccine against SARS.

"We had a high level meeting with the US government that asked the main vaccine companies to come to the table and give their plans for how to deal with this issue," Chief Executive Jean-Pierre Garnier told reporters. "We committed to accelerate our development of a possible vaccine for SARS."

But Garnier warned this would take time. "This is not a matter of weeks or months, it is matter of years," he said. "It is better to start now because this infection might come back even if it gets contained in the short term. We need to be ready for the next wave, which could be more serious."

He said GSK normally competes against other companies but this time is collaborating to tackle the SARS threat. "We have at least exchange of some of the science. The Institut Pasteur is at the core of this."

Top scientists from the US Centers for Disease Control and the National Institutes of Health called companies to the meeting earlier this month.

The other companies included Merck, Wyeth, Chiron, Baxter, Johnson & Johnson, Aventis, Vical, Avant, PowderJect and Berna Biotech.
Of these, 43 patients were discharged from hospital on Thursday, bringing the total number of discharged patients to 834. The government also said 102 recovering patients were in convalescence and were about to be discharged.

The disease has spread to more than 25 countries in the last 2 months, infected more than 6000 people and killed nearly 400 of them since first emerging in southern China in November.

While daily numbers of new infections have fallen over the past week in Hong Kong, news on Wednesday that 12 people had to be readmitted to hospital brought fresh concerns. Six remain in hospital.

It was not clear if the 12 had experienced relapses.

Some physicians told Reuters these patients may not have fully recovered when they were first discharged, or that that their weakened immune systems may have left them vulnerable to secondary infections.

Chan said experts were still trying to pinpoint the cause of the relapses but she stressed that hospitals in Hong Kong were extremely cautious when handling SARS patients.

Combination Regimen Highly Effective in Lowering LDL Cholesterol Levels

By Will Boggs, MD

NEW YORK (Reuters Health) Apr 28 - The combination of ezetimibe and atorvastatin is well tolerated and highly effective in patients with hypercholesterolemia, according to a report in the April 29th rapid access issue of Circulation.

"It's great to have a new option for treating patients with high cholesterol as we get to the more aggressive targets suggested by recent guidelines," Dr. Christie M. Ballantyne from Baylor College of Medicine in Houston, Texas told Reuters Health.

Dr. Ballantyne and associates examined the safety and effectiveness of various combinations of ezetimibe, a novel cholesterol absorption inhibitor, and atorvastatin, one of several HMG-CoA reductase inhibitors or statins, in treating 628 patients with primary hypercholesterolemia.

Mean reductions of direct LDL-cholesterol from baseline to final assessment were significantly greater with combination treatment (54.5% reduction) than with either atorvastatin alone (42.4%) or ezetimibe alone (18.4%), the authors report.

Coadministration of ezetimibe significantly reduced LDL-cholesterol across all atorvastatin doses, the report indicates, and the combination of ezetimibe with the lowest dose of atorvastatin provided cholesterol lowering equivalent to that achieved with the highest dose of atorvastatin alone.

Combination therapy resulted in achievement of Adult Treatment Panel III LDL-cholesterol targets in 85% of patients, compared with only 73% of patients receiving atorvastatin monotherapy, the researchers note.

Moreover, the investigators report, HDL-cholesterol levels increased significantly more in patients receiving the combination (9%) than in those receiving the maximal dose of atorvastatin alone (3%).

"Interestingly and somewhat unexpectedly," Dr. Ballantyne said, "the addition of ezetimibe resulted in a significant reduction in C-reactive protein levels--by about 62%, suggesting that the combination might have some anti-inflammatory effects, too."

Safety measures, including treatment-related adverse events and elevations in liver enzymes, did not differ significantly between combination therapy and monotherapy, the results indicate.

"This is the first new class of drugs to treat hypercholesterolemia in 15 years," Dr. Ballantyne said. "It's a nice example of where science finds an easy way of treating a common medical problem."

"One pill once a day, and the monitoring is no different from current therapy."

"This should help us to achieve the targets in a greater number of patients, " he concluded.

Circulation 2003;107:000-000.

Antibiotic Resistance Now Deemed a "Public Health Crisis"

By Marilynn Larkin

NEW YORK (Reuters Health) Apr 30 - The medical community is losing the fight against antibiotic-resistant "superbugs" and few new drugs are in development to counter this growing threat, infectious diseases experts warned today at a briefing here.

Panelists from the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America, and the Society of Infectious Diseases Pharmacists called for "immediate national action" to limit the threat through judicious use of antibiotics and better infection-control practices.

"Every time you prescribe an antibiotic, you are affecting not just that patient, but all living and all future living organisms," Dr. Martin Blaser, chairman of the department of medicine at New York University School of Medicine and a representative of IDSA, told Reuters Health. "Antibiotic resistance is a function of antibiotic use, and we're currently using tons of antibiotics. And since there are relatively few antibiotics in the pipeline, when we reach a certain level of resistance, we'll have no reinforcements."

In 2002, the Food and Drug Administration approved 89 drugs, but no antibacterial agents, Dr. Blaser said in his presentation. Among the more than 400 drugs currently in development, "only five are antibacterials."

"Dr. Blaser woke you up. It's my job to scare you," Dr. Neil Fishman, director of the department of healthcare epidemiology and infection control and director of the antimicrobial management program at the University of Pennsylvania in Philadelphia, told attendees at the symposium.

"We used to think of resistance as predominantly a problem in hospitals. But it has become more and more common in the community. We also thought the organisms involved were different, but now, all the divisions are blurring." Dr. Fishman cited recent outbreaks of methicillin-resistant Staphylococcus aureus in a prison and on a high school wrestling team as examples of resistant strains normally seen mainly in hospitals making their way into the community.

"Resistance started the moment the first antibiotics were introduced in the 1940s," Dr. Fishman said. "It's been a 60-year plague and we haven't been able to control it yet."

Dr. Robert Weinstein, chairman of infectious diseases at Cook County Hospital in Chicago and chairman of the U.S. Healthcare Infection Control Practices Advisory Committee, stressed key strategies for clinicians to prevent the growth of resistant organisms: prevent infection, thereby reducing the need for antimicrobial exposure; optimize antimicrobial use by avoiding broad-spectrum drugs and antibiotic overuse; and prevent transmission of resistant organisms to other patients.

Insulin Resistance, Not Hyperglycemia, Predicts CAD in Type 1 Diabetes

NEW YORK (Reuters Health) Apr 25 - Traditional risk factors appear to be more important than glycemic control in predicting coronary artery disease (CAD) among patients with type 1 diabetes, according to results of the prospective Pittsburgh Epidemiology of Diabetes Complications (PEDC) Study.

"The good news is that not all people with type 1 diabetes are insulin resistant, and for them the risk of heart disease may not be as high," lead author Dr. Trevor J. Orchard commented in a University of Pittsburgh Medical Center press release. However, "reducing or preventing insulin resistance through exercise, weight loss and possibly medication may help people with type 1 diabetes avoid heart disease," he adds.

Between 1986 and 1988, Dr. Orchard's group examined 603 subjects with type 1 diabetes, mean age 28 years, who were free of prevalent CAD. They discuss their findings in the May issue of Diabetes Care.

During 10 years of follow-up, incident CAD events occurred in 108 subjects. These included 5 CAD deaths, 25 nonfatal MIs, 12 cases of coronary stenosis of 50% or greater, 49 cases of angina and 17 of ischemic ECG changes.

Diabetes duration, hypertension, WBC, HDL-cholesterol, non-HDL cholesterol and smoking history independently predicted CAD. The average estimated glucose disposal rate, which is based on HbA1, waist/hip ratio and hypertension, was lower in patients with incident CAD and was an independent predictor of CAD, MI, and coronary stenosis.

There was no positive association between hemoglobin A1 (HbA1) and CAD, a finding that the authors call "concerning and intriguing." They point out that earlier research has indicated a relationship between HbA1 and lower extremity arterial disease (LEAD).

Therefore, they theorize that "though hyperglycemia leads to more extensive atherosclerosis, the plaques so formed are more stable and thus less likely to rupture and case acute coronary events."

HbA1 and Beck Depression Inventory scores were independent predictors of angina, the report indicates.

"The prediction of angina by greater smoking and depressive symptoms (and possibly lower HbA1) raises the possibility that a certain subset may have a susceptible... underlying psychological state that might exacerbate any tendencies to coronary artery spasm and is associated with smoking and possibly increased concern about blood sugar control," the EDC investigators add.

Most Cases of Cervical Dysplasia Do Not Progress to Cancer

By Stephen Pincock

LONDON (Reuters Health) Apr 25 - At least 80% of women with evidence of cell abnormalities on a Pap smear will not go on to develop cervical cancer, a new analysis by British researchers suggests.

"You can't escape the fact that to be effective in cancer screening you almost have to over-treat because the cell changes and tissue changes are so common," said lead investigator Dr. Angela Raffle, from Avon Health Authority in Bristol.

Her group's findings, based on screening records from 348,419 women in Bristol, appear in the April 26th issue of the British Medical Journal.

For every 10,000 women screened between 1976 and 1996, 1564 had abnormal cervical cytology detected in the Pap smear. Of those, 818 had further investigations, of whom 543 had evidence of abnormal cervical histology. Within this group, 176 had abnormalities that persisted for 2 or more years.

Without screening, the researchers estimate that 80 of these women would be expected to develop cancer by 2011, of whom 25 would die. Screening would avoid 10 of these deaths.

"In the NHS cervical screening programme, around 1000 women need to be screened for 35 years to prevent one death," they write.

An important implication of their results is the need to help women understand what an abnormal Pap smear really means, the researchers note. While it is important that women with abnormal cytology not ignore the test results, trauma caused by thinking it is something akin to a death sentence is not necessary.

"We really need to change people's perception of what's meant by an abnormal smear, because people think it's a [definitive] cancer test," Dr. Raffle said.

"Most of these abnormalities are no problem at all, but the treatment's simple...We really think that everyone with a high-grade abnormality needs treatment because we know that for 1 in 80 it will make that big life-saving difference."

Cervical cancer is ideal for screening, because doctors can access the cervix without surgery, and abnormalities can be treated locally, Dr. Raffle said. But the same cannot be said of all other cancers.

"I think the real implications for our findings are for prostate cancer, bowel cancer, ovarian cancer--all these others that people say we must start screening for," the Bristol researcher said.

It is possible that a large proportion of abnormalities detected in those organs will never develop into cancer, but the treatment can be much more damaging than that for cervical cancer--involving major surgery or radiation treatment.

"Our study points to the potential for harm. It's only minimal harm with the cervix because you're talking about worrying people, but if you're talking about an operation that could leave you dead, or impotent or incontinent, then it's a different equation really," Dr. Raffle said.