Medicolegal Issues

In the Literature


 

Literature at a Glance

A guide to this month’s studies.

CLINICAL SHORTS

Statins Reduce All-Cause Death and Nonhemorrhagic Stroke

A meta-analysis including 121,000 patients found decreased death and nonhemorrhagic stroke associated with statin use. For every unit increase in LDL, mortality risk increased by 0.3%.

Citation: O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. Am J Med. 2008 Jan;121(1):24-33.

VTE Prophylaxis is Underutilized

Cross-sectional chart review of 68,138 surgical (45%) and medical (55%) patients found that only 58.5% of surgical and 41.5% of medical patients received recommended VTE prophylaxis.

Citation: Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371:387-394.

Mechanical Ventilation Weaning Protocol Improved Outcomes

Random controlled trial in four tertiary care hospital ICUs found daily spontaneous waking paired with spontaneous breathing trials in mechanically ventilated patients compared with standard care decreased mechanical ventilation days, length of ICU stay, length of hospital stay, and one-year mortality.

Citation: Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial. Lancet. 2008; 371:126-134..

Idraparinux Increased Bleeding in Atrial Fibrillation Patients Requiring Anticoagulation

This random, non-inferiority trial observed that weekly subcutaneous injection of idraparinux was not worse than standard anticoagulation therapy with warfarin or acenocoumarol in preventing thromboembolism, but increased bleeding complications.

Citation: The Amadeus investigators et al. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomized, open-label, non-inferiority trial. Lancet. 2008;371:315-321.

Thrombocytopenia Associated With Death and MI in Patients on Prolonged Heparin Therapy

Prospective observational study showed increased death (OR 3.4) and myocardial infarction (OR 2.1) in hospitalized patients who develop thrombocytopenia after treatment with four or more days of heparin (unfractionated or low molecular weight).

Citation: Oliveira GBF, Crespo EM, Becker RC, et al. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med. 2008;168:94-102.

Medicare Part D Benefit Increased Drug Use, Decreased Out-of-pocket Costs For Older Adults

Using data from a national retail pharmacy chain, study shows Medicare Part D decreased out-of-pocket expenditures by approximately $9 a month and slightly increased drug use among older adults.

Citation: Yin W, Basu A, Zhang JX, Rabbani A, Meltzer DO, Alexander GC. The effect of the Medicare Part D prescription benefit on drug utilization and expenditures. Ann Intern Med. 2008;148:169-177.

Hospital Populations Report Benefits From Chaplain Visitations

A survey of 1,500 consecutive recently hospitalized patients at one of two Minnesota facilities indicated that select populations desire and value support offered by chaplain visits during the inpatient stay.

Citation: Piderman K, Marek D, Jenkins S, Johnson M, Buryska J, Mueller P. Patients’ expectations of hospital chaplains. Mayo Clin Proc. 2008;83:58-65.

Heterogeneous Labeling of Drug Doses May Contribute to Clinically Significant Dosing Errors

A small, randomly controlled trial of physicians in simulated scenarios demonstrated overdose errors were more likely to occur when using epinephrine labeled with ratio concentrations rather than mass concentrations.

Citation: Wheeler DW, Carter JJ, Murray LJ, et al. The effect of drug concentration expression on epinephrine dosing errors. Ann Intern Med. 2008;148:11-14.

Do Physiologic Doses of Hydrocortisone Benefit Patients With Septic Shock?

Background: Meta-analyses and guidelines advocate the use of physiologic dose steroids in patients exhibiting septic shock. However, recommendations are largely based on the results of a single trial where benefits were seen only in patients without a response to corticotropin.

Study design: Multicenter, randomized, double-blind, placebo-controlled study.

Setting: Fifty-two participating ICUs in nine countries.

Synopsis: A total of 499 patients with evidence of infection or a systemic inflammatory response characterized by refractory hypotension were randomly selected to receive either an 11-day tapering dose of hydrocortisone or a placebo. The primary outcome was death from any cause at 28 days. A corticotropin stimulation test was conducted on every patient to assess adrenal function. There were no differences in death rates or duration of hospitalization between study arms. Overall, there were 86 deaths in the hydrocortisone group and 78 deaths in the placebo group (p=0.51). Also, response to corticotropin appeared to have little bearing on outcomes.

The study was underpowered due to low enrollment and a lower-than-expected death rate. Nevertheless, this is the largest trial to date examining the role of steroids in the management of septic shock and calls into question the strength of prior data and published guidelines.

Bottom line: This study failed to demonstrate a clinically or statistically significant treatment effect from the administration of physiologic-dose steroids in patients with septic shock.

Citation: Sprung C, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124.

Does Open or Endovascular Repair of Abdominal Aortic Aneurysm Benefit the Medicare Population?

Background: Randomized controlled trials (RCT) have shown a perioperative survival benefit of endovascular repair over open repair with fewer complications and shorter recovery. There is concern that late morbidity may be increased with endovascular repair. Patients enrolled in the trials were highly selected at specialty centers, so the results may not reflect actual practice.

Study design: Retrospective, propensity-matched, observational cohort study.

Synopsis: 22,830 patients were matched in each cohort. Patients were eligible if they had an abdominal aortic aneurysm repair without rupture and excluded if they were enrolled in health maintenance organizations.

Outcomes included death within 30 days and late survival, perioperative complications, aneurysm rupture, reintervention, and laparotomy-related complications. The average age was 76, and 20% were women. Perioperative mortality was lower after endovascular repair (1.2% vs. 4.8%, p<0.001), and older patients had a greater benefit. Late survival was similar. By four years, rupture was more likely in the endovascular group (1.8% vs. 0.5%, p<0.001), as was reintervention (9% vs. 1.7%, p<0.001).

In contrast, by four years, surgery for laparotomy-related complications was more likely in the open-repair group (9.7% v 4.1%, p<0.001), as was hospitalization for bowel obstruction or abdominal-wall hernia (14.2% v 8.1%, p<0.001). Limitations included the non-randomized design and use of administrative data for important categorical variables including medical co-morbidities.

Bottom line: As compared with open repair, endovascular repair of abdominal aortic aneurysm is associated with lower short-term death and complications and higher late reinterventions. This is balanced by an increase in laparotomy-related reinterventions after open repair.

Citation: Schermerhorn ML, O’Malley AJ, Jhaveri A, Cotterill P, Pomposelli F, Landon BE. Endovascular vs. open repair of abdominal aortic aneurysms in the Medicare population. N Engl J Med. 2008 Jan 31;358(5):464-474.

What Therapy Improves Outcomes in ICU Patients With Severe Sepsis or Septic Shock?

Background: Evidence suggests lower mortality with intensive insulin therapy in post-surgical cardiac patients. There is no proven benefit for non-surgical ICU patients. Despite lack of data, intensive insulin in severe sepsis has been widely advocated. Little is known to guide the use of colloid or crystalloid for fluid resuscitation in sepsis.

Study design: Multicenter, two-by-two factorial, open-label trial.

Setting: Multidisciplinary ICUs at 18 academic tertiary hospitals in Germany.

Synopsis: Data were analyzed for 537 patients with severe sepsis. They were randomly selected to receive intensive insulin therapy (n=247) or conventional insulin therapy (290), with either 10% hydroxyethyl starch (HES) (262) or modified Ringer’s lactate (LR) (275) for fluid resuscitation.

Co-primary endpoints were all-cause mortality at 28 days and morbidity as measured by the mean score on the Sequential Organ Failure Assessment (SOFA). The trial was stopped early for safety reasons. Intensive insulin therapy was terminated due to an increased number of hypoglycemic events in the intensive-therapy group compared with conventional therapy (12.1% vs. 2.1%, p<0.001), and there was no difference in mortality between groups at 28 and 90 days.

Interim analysis of 600 patients showed patients given HES had higher incidence of renal failure compared with LR (34.9% vs. 22.8%, p=0.002), required more days of renal replacement therapy, had lower median platelets and received more units of packed red cells. There was a trend toward higher rate of death at 90 days in those treated with HES (41% vs. 33.9%, p=0.09).

Bottom line: Intensive insulin therapy in ICU patients with severe sepsis and septic shock does not improve mortality and increases hypoglycemia and ICU length of stay. Use of colloid over crystalloid should be avoided, showing a trend toward increased death at 90 days, higher rates of acute renal failure, and need for renal replacement therapy..

Citation: Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139.

How Does Laparoscopic Adjustable Gastric Banding Affect Obese Adults With Type 2 Diabetes?

Background: Observational studies related surgical weight loss to improved glycemic control, but clinical trials did not test this relationship. The current trial examined this hypothesis.

Study design: Unmasked, randomized controlled trial.

Setting: University Obesity Research Center, Australia.

Synopsis: Sixty adults age 20-60 with body-mass index (BMI) of 30-40 and diagnosed with diabetes mellitus type 2 (DM2) within two years of recruitment were randomized into conventional therapy and surgical groups.

While both groups were treated similarly, only the surgical group received laparoscopic adjustable gastric banding. Primary outcome was remission of DM2 (a fasting glucose less than 126 mg/dl, HbA1C less than 6.2%, and off all hypoglycemic agents). At two years, 73% in the surgical group compared with 13% in the conventional group attained this outcome (relative risk [RR] 5.5, 95% confidence interval [CI] 2.2-14.0; p<0.001). Compared with the conventional group, the surgical group demonstrated statistically significant improvements in several secondary outcomes including mean body weight, waist circumference, insulin resistance, and lipids.

The limitations of the study are that it examined a small number of patients with shorter duration of DM2 and a shorter follow-up. The lower surgical complication rates cannot be generalized to other centers.

Bottom line: This study is a step forward in examining the relationship of surgical weight loss and remission of DM2. However, large multicenter trials with longer periods of follow-up in diverse group of patients would result in a better understanding of this relationship.

Citation: Dixon JB, O’Brien PE, Playfair J, et. al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-323.

What is the Prevalence of Delayed Defibrillation and its Association With Survival to Discharge?

Background: Despite advances in resuscitation, survival rates following cardiac arrest remain low. Previous studies observed the effect of the timing of defibrillation on survival. This study examined the magnitude of delayed defibrillation and its association with survival in adults who sustained cardiac arrest specifically from ventricular fibrillation and pulseless ventricular tachycardia.

Study design: National Registry of Cardiopulmonary Resuscitation (NRCPR), a multicenter prospective cohort.

Setting: 369 U.S. hospitals providing acute care.

Synopsis: Data from NRCPR relating to 6,789 cardiac arrests secondary to ventricular fibrillation or pulseless ventricular tachycardia, at 369 hospitals in hospitalized adults were analyzed. Delayed defibrillation was defined as occurring more than two minutes from the identification of ventricular fibrillation or pulseless ventricular tachycardia to the administration of the first shock to the patient.

Delayed defibrillation occurred in 2,045 (30.1%) subjects. A lower proportion of subjects who received delayed defibrillation (22.2%) compared with those who received defibrillation in two minutes or less (39.3%) survived to hospital discharge. This was statistically significant (adjusted odds ratio [OR] 0.48, 95% CI 0.42 to 0.54; p<0.01).

Bottom line: This study not only reported that delayed defibrillation was prevalent in adult hospitalized patients, but also reinforced the importance of defibrillation within two minutes of identification of cardiac arrest secondary to ventricular fibrillation and pulseless ventricular tachycardia for better survival outcomes.

Citation: Chan PS, Krumholz HM, Nichol G, Nallamothu BK. Delayed time to defibrillation after in-hospital cardiac arrest. N Engl J Med. 2008;358(1):9-17.

Does Right-Ventricle Enlargement in Acute PE Increase In-hospital Death From PE or All-cause Mortality?

Background: Previous studies have shown conflicting results regarding the risk of death with right-ventricular enlargement in acute pulmonary embolism (PE). The role of thrombolysis in hemodynamically stable patients with acute PE and right-ventricular enlargement remains controversial.

Study design: Retrospective analysis of prospective cohort study.

Setting: Academic centers housing inpatients and outpatients in the United States and Canada.

Synopsis: Patients enrolled in PIOPED II who were diagnosed with acute PE and had multidetector computed tomographic (CT) angiography were retrospectively reviewed for the presence of right-ventricular enlargement. Study determined that 181 patients had PE and a CT, and 157 were adequate for measurement of right-ventricular size. PE treatment was anticoagulation in 138, anticoagulation and inferior vena cava filter in 15, inferior vena cava filter alone in two, and thrombolysis in two.

Right-ventricular enlargement was found in 78 (50%) patients; 76 were treated with anticoagulation alone or in combination with inferior vena cava filter. For patients with and without right-ventricular enlargement, there was no difference in in-hospital death from PE (0% vs. 1.3%) or all-cause mortality (2.6% vs. 2.5%). The results were unchanged when examined for septal motion abnormality and previous cardiopulmonary disease.

Bottom line: In hemodynamically stable patients with acute pulmonary embolism, right ventricular enlargement does not increase mortality. Further, thrombolytic therapy is unlikely to improve outcomes.

Citation: Stein PD, Beemath A, Matti F, et al. Enlarged right ventricle without shock in acute pulmonary embolus: prognosis. Am J Med. 2008;121:34-42.

What Are Short-term Thromboembolism, Hemorrhage Risks When Interrupting Warfarin Therapy for Procedures?

Background: The risks of thromboembolism and hemorrhage during the periprocedural interruption of warfarin therapy are not known. The risks and benefits of heparin bridging therapy are not well described.

Study design: Multicenter, prospective, observational cohort study.

Setting: Community-based physician practices.

Synopsis: Patients were eligible if they were on long-term warfarin and underwent outpatient procedures requiring interruption of therapy. The primary outcomes were thromboembolism or hemorrhage within 30 days of therapy interruption. In all, 1,024 eligible patients (7.1% considered high risk) had 1,293 interruptions of warfarin therapy. The most common procedures were colonoscopy (25.1%), oral or dental surgery (24.9%), and ophthalmologic surgery (8.9%). Warfarin interruption was five or fewer days in 83.8% of episodes.

Thromboembolism occurred in seven (0.7%) patients, and major or clinically significant bleeding occurred in 23 (0.6%, and 1.7%, respectively) patients. Periprocedural bridging with heparin was used in 88 (8.6%) patients. Of the patients who received periprocedural heparin therapy, none had thromboembolism, and 14 (13%) had bleeding episodes.

Bottom line: In patients whose warfarin therapy is interrupted to undergo outpatient procedures, the risk of thromboembolism is low and the hemorrhagic risk of heparin bridging therapy is significant.

Citation: Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168(1):63-69.

Are Minor Injuries an Independent Risk Factor For Development of DVT?

Background: Prior studies focus on major injuries as a risk factor for deep-vein thrombosis (DVT) and PE. However, major injury is often associated with other risks for venous thrombosis, such as surgery, plaster casting, hospitalization, and extended bed rest. Risk of DVT with minor injuries that don’t lead to these factors is unknown.

Study design: Large population-based case-control study.

Setting: Six anticoagulation clinics in the Netherlands.

Synopsis: 2,471 consecutive cases (patients with first episode of DVT or PE) and 3,534 controls (partners of cases or random digit dialing contacts) were enrolled. Participants were mailed a questionnaire, including a list of eight common injuries.

Participants with history of cast, surgery, recent hospitalization, extended bed rest, or prior history of cancer were excluded. A subset of patients and controls underwent DNA and blood collection to evaluate for presence of a hypercoagulable state. Of the cases, 289 (11.7%) had a minor injury within three months of the index date, compared with 154 (4.4%) of controls, representing a threefold increased risk of DVT/PE with minor injury (OR 3.1). Partial ruptures of muscles or ligaments in the leg (OR 10.9), multiple simultaneous injuries (OR 9.9), and injury within four weeks of presentation (OR 4.0), were associated with increased risk of DVT/PE.

Patients found to be Factor V Leiden carriers with injury had an almost 50-fold increased risk of venous thromboembolism (VTE) compared with non-carriers without injury (OR 49.7). Authors appropriately address possible limitations, including recall and referral bias.

Bottom line: Minor leg injury is associated with threefold risk of DVT/PE, especially in the four weeks following injury. Providers should consider short-term prophylactic treatment in patients with Factor V Leiden or high-risk injuries.

Citation: Van Stralen KJ, Rosendaal FR, Doggen CJ. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med. 2008;168(1):21-26.

Is Oral Amox-Clav Non-inferior to IV Antibiotics in Pediatric Pyelonephritis?

Background: Present guidelines recommend initial treatment for pediatric pyelonephritis to be a parenteral third-generation cephalosporin followed by oral antibiotics. One prior randomly selected controlled trial compared oral antibiotics only with antibiotics started parenterally, but there was a higher-than-usual incidence of vesicoureteral reflux and female gender in the study.

Study design: Non-inferiority, multicenter, random, open label, controlled trial.

Setting: Twenty-eight pediatric units in northeast Italy from 2000-2005

Synopsis: 502 children age 1 month to less than 7 years with a clinical diagnosis of first occurrence of acute pyelonephritis according to urinalysis and urine culture (requiring two concordant consecutive tests) with at least two of the following conditions: fever of 38 degrees C or more or elevated erythrocyte sedimentation rate (ESR) or c-reactive protein (CRP), and elevated neutrophil count were randomized to receive oral amoxicillin-clavulanate (AC) or parenteral ceftriaxone followed by oral AC. Exclusion criteria were sepsis, dehydration, vomiting, and creatinine clearance of 70 ml/min or less.

Also, 400 children had dimercaptosuccinic acid (DMSA) scintigraphy within 10 days of study entry. Meantime, 223 had repeat DMSA at one year, and 177 had normal scans at study entry so were not repeated. At one year, 20% of patients were lost to follow-up. The primary outcome was renal scarring at one year. Secondary outcomes included time to fever defervescence, reduction in inflammatory indices, and percentage with sterile urine after 72 hours. Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome 13.7% vs. 17.7% (95% CI, -11.1% to 3.1%), and secondary outcomes.

Bottom line: Treatment with oral antibiotics is as effective as parenteral then oral treatment for first episode of acute pediatric pyelonephritis.

Citation: Montini G, Toffolo A, Zucchetta P, et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ. 2007 Aug 25;335(7616):386.

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