Primecuts – This Week In The Journals

August 8, 2011

By Bora Toklu, MD

Faculty Peer Review

My friend was sobbing when she called me on the weekend of July 4th. She had become upset when told by a physician that a possible cause of her chronic cough might be lung cancer. Given that my friend is a 30 year-old non-smoker with no family history of cancer, her actual risk of lung cancer is very small. In order to calm her down I found myself explaining the “July effect”. July 1st signals the beginning of a new academic year, when yesterday’s medical students begin their first days as actual doctors on the hospital floors. At the same time, the most experienced medical residents graduate and leave for greener pastures. For this reason, it is believed that July tends to be the month with highest rates of medical errors and that with the greatest degree of inefficiency. Is this just another medical legend or is it a truly evidence-based phenomenon?

This week the Annals of Internal Medicine published a review article assessing the “July effect” on patient outcomes at teaching hospitals during academic changeover [1]. The authors searched PubMed, EMBASE, Education Resource Information Center (ERIC), and the Cochrane Library between January 1989 and July 2010 and included 39 studies in their review. The authors included studies that examined emergency departments, hospital wards, operating rooms and intensive care units but did not include ambulatory care settings. They also studied a variety of medical specialties and included adult and pediatric patients. Of the 39 studies that were analyzed, 69% reported mortality, 49% reported efficiency (length of stay, duration of procedure, hospital charges), 59% reported morbidity, and 15% reported medical error outcomes. In their analysis, the authors found that studies with larger sample size and of higher-quality more often showed increased mortality and decreased efficiency at time of academic changeover. Studies examining morbidity and medical error outcomes were typically of lower quality and produced inconsistent results. Although this systematic review of literature on ‘July effect” suffers several limitations, mostly related to heterogeneity of the included studies, it clearly provides new evidence suggesting that the “July effect” exists.

As was covered in a previous Primecuts section, the final report of the National Lung Screening Trial (NLST) was recently published in the New England Journal of Medicine [2]. This study was the largest trial of its kind, including more than 50,000 heavy smokers and revealed a 20% relative mortality risk reduction from lung cancer in patients assigned to screening with low-dose computed tomography (CT) compared to those assigned to screening with chest radiography, with a survival benefit attributed to detection of cancers at an earlier stage. These findings, while marking a new era in lung cancer screening, instigated several discussions including some on the cost-effectiveness of such an expensive screening approach. Screening by CT scanning may over-diagnose small and slowly growing tumors that may actually be clinically irrelevant, as well as expose patients to adverse events associated with invasive diagnostic studies necessary to biopsy true-positive and false-positive lung lesions found by CT scanning. A related study published this week in the Annals of Internal Medicine complements the findings of the landmark NLST trial. The authors in this study looked at the discharge records of over 15,000 patients who received transthoracic needle biopsy to sample pulmonary nodules in order to estimate the risk of complications associated with this procedure [3]. The data source for this study was discharge records from the 2006 State Ambulatory Surgery Databases and State Inpatient Databases from California, Florida, Michigan, and New York, as well as from the Healthcare Cost and Utilization Project. The authors found that hemorrhage is a rare complication of transthoracic biopsies (1%) but that a substantial number (17.8%) of patients with hemorrhage required a blood transfusion. In contrast, the risk for pneumothorax was 15.0% and 6.6% of all biopsies resulted in pneumothorax requiring a chest tube. Compared to patients without complications, those who experienced hemorrhage or pneumothorax requiring a chest tube had longer lengths of hospital stay (P < 0.001) and were more likely to develop respiratory failure requiring mechanical ventilation (P = 0.020). Patients of older age, smokers, and those with chronic obstructive pulmonary disease (COPD) had a higher risk of complications. These findings will help us better inform our patients about the risks and benefits of transthoracic needle biopsy in a post-NLST era where we may be seeing more patients presenting with incidental pulmonary nodules found on CT scans performed for lung cancer screening.

A study published in the New England Journal of Medicine provides hope for patients awaiting a HLA-compatible kidney transplant [4]. Use of a protocol including plasmapheresis and administration of low-dose intravenous immune globulin (IVIG), Montgomery et al. desensitized 211 donor-specific HLA-sensitized patients who subsequently underwent renal transplantation. For desensitization, patients were treated with a mean of 4±4 plasmapheresis sessions before transplantation and 5±4 sessions after transplantation. After each plasmapheresis session, patients received IVIG. Most adverse events associated with plasmapheresis were minor although major events including anaphylaxis occurred in three patients (1.4%). For each patient in the group that underwent desensitization and transplantation (treatment group), authors identified five patients from the transplant waiting list who were most closely matched for the percentage of panel-reactive antibodies to the treatment patient. The groups were also matched in the following order of priority: age, blood type, number of previous transplantations, proportion of years of renal-replacement therapy with a functioning allograft, total number of years of renal replacement, race, sex, and the presence or absence of diabetes. They then compared the rates of death between the treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). In the treatment group, Kaplan–Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). The significant and substantial survival benefit by 8 years provides strong evidence for use of desensitization to overcome HLA-incompatibility issues in patients awaiting a HLA-compatible kidney transplant.

The final article that we will analyze praises the role of carvedilol in heart failure. Carvedilol has been shown to be one of the most effective beta blockers for heart failure, providing a significant survival benefit; carvedilol is therefore the beta blocker of choice in heart failure. The mechanism underlying its antiarrhythmic properties in heart failure remained unclear. In a study published in Nature Medicine [5], Zhou et al showed that carvedilol is the only beta blocker that effectively suppresses spontaneous calcium waves in the cardiac myocytes of mice, a pathway that leads to ventricular tachyarrhythmias in heart failure. This suppression by carvedilol is achieved by directly reducing the open duration of the cardiac ryanodine receptor (RyR) that functions as a gateway to the intracellular calcium stores. The authors then developed a minimally beta-blocking carvedilol analog, named VK-II-86, and showed that this newly manufactured analog is equally effective in suppressing calcium waves and arrhythmia in mice. These findings support RyR channel inhibition as a major mechanism for the antiarrhythmic property of carvedilol and may result in the development of a new class of antiarrhythmic medications: selective RyR channel inhibitors.

Dr. Bora Toklu, is a 3rd year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Michael Poles, MD, section editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Young JQ, Ranji SR, Wachter RM, Lee CM, Niehaus B, Auerbach AD. “July Effect”: Impact of the Academic Year-End Changeover on Patient Outcomes. A Systematic Review. Annals of Internal Medicine. 2011 July 11. Published online.

2. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011 August 4;365:395-409.

3. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Annals of Internal Medicine. 2011 August 2;155(3):137-44.

4. Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, Warren DS, Simpkins CE, Dagher NN, Singer AL, Zachary AA, Segev DL. Desensitization in HLA-incompatible kidney recipients and survival. New England Journal of Medicine. 2011 July 28;365(4):318-26.

5. Zhou Q, Xiao J, Jiang D, Wang R, Vembaiyan K, Wang A, Smith CD, Xie C, Chen W, Zhang J, Tian X, Jones PP, Zhong X, Guo A, Chen H, Zhang L, Zhu W, Yang D, Li X, Chen J, Gillis AM, Duff HJ, Cheng H, Feldman AM, Song LS, Fill M, Back TG, Chen SR. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca(2+) release. Nature Medicine. 2011 July 10;17(8):1003-1009.

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