SciQuest.org

Christine Aguilera is a talented, beautiful young woman who is all over the magazines and internet with her beautiful new baby. It is a lovely sight to see and I am sure she influences young women around the world on the wonders of new motherhood. But my eyes and ears perked up when I read that she had a planned, elective (read “Doctor, I want that!”) C-section at 37 weeks because “I’d heard horror stories about tearing. I really wanted a calm and peaceful environment. I didn’t want any surprises.”

Now I don’t blame a 27 year old narcissistic diva for how she feels. I also understand the fears new prospective mothers have about their changing bodies, new responsibilities and major life changes a child brings. But where are the doctors in all of this? Is this the new trend? C-Sections, rather than nature’s natural childbirth for anyone who asks?

Cesarean Section childbirth is major surgery. The abdominal wall and muscles are cut as well as the uterus.

There is a higher risk of blot clots following a C-section than a vaginal birth. Hysterectomy is more common after cesarean. The risk of maternal death is higher.

The risk of uterine infection is much higher after a C-section than it is after a vaginal birth. There is usually a longer hospital stay for the mother, and she is at a higher risk of being re-admitted to the hospital later for complications.

The severity and length of pain after a Cesarean is much greater than after a vaginal birth. You may feel more pain during a vaginal birth than you would during a Cesarean. But shortly after birth most of that pain will be gone (unless you receive intervention such as episiotomy). Pain from Cesarean surgery continues on into the early weeks and for some women, months.

C-Sections that are done in life threatening situations are necessary and preferable to any risk to the mother or baby. Elective, planned C-Sections because the mom is “afraid” or “vain” or just misinformed is really an indictment of the medical community.

I suspect we will have many young women wanting to follow in Mama Aguilera’s footsteps. It will be interesting to follow the C-Section rates over the next few years.

FDA needs an expanded budget of about $375 million in fiscal year 2009 to reverse longtime funding shortfalls, the agency’s Science Board subcommittee said on Tuesday, CongressDaily reports. The subcommittee estimated that FDA needs an additional $2.2 billion over five years to bring the agency’s funding level to $3.7 billion by FY 2013. In addition, the subcommittee recommended that FDA receive an additional $128 million in food safety funding in FY 2009 and $750 million over five years. President Bush in his proposed budget requested $51 million in additional agency funding, which would bringing total funding to $1.7 billion, with $42 million dedicated to food safety.

House Energy and Commerce Committee Chair John Dingell (D-Mich.) said, “These estimates show that the president’s budget has completely missed the mark in terms of what is truly needed to protect Americans,” noting that the science board recommendations are seven times Bush’s proposed levels (Edney, CongressDaily, 2/27).

In related news, FDA Commissioner Andrew von Eschenbach — “in an unusual public departure from Bush administration policy” — said in an interview that he had requested a greater funding increase for the agency than was present in Bush’s budget plan. Von Eschenbach also said that the agency needs better organization to oversee drug safety and other issues more effectively. He said, “I think to do what we need to do requires substantially more dollars than what has been invested in the FDA thus far,” adding that “there are issues that this agency needs to have addressed and that it’s going to have to be transformed” (Wilde Mathews, Wall Street Journal, 2/27).

Postmarket Oversight
Meanwhile, FDA on Tuesday announced a proposal that aims to improve postmarket oversight of prescription drugs, the Wall Street Journal reports. Announced in an e-mail to employees, the “Safety First” plan will create a new database to list the potential side effects of prescription drugs and provide a schedule for following up on questions. The agency also will revise its procedure for making certain regulatory decisions, “particularly those based on emerging safety worries, though the new moves don’t go as far as some critics have advocated,” according to the Journal. The plan gives new authority to the Office of Surveillance and Epidemiology, stopping “short of divorcing the two functions” of the office, which is to approve drugs and monitor for safety issues after approval, the Journal reports.

Under the plan, the office will:

* Implement multidisciplinary groups, including the premarket approval group and the safety office, to work together to make decisions and allow the groups to make appeals to higher-level officials in instances of disagreement;

* Appoint new, dedicated officials who will be responsible for focusing on safety in each of the divisions;

* Have primary authority to approve drug brand names and labeling; and

* Have the authority to commission certain kinds of research, including requiring drug makers to conduct studies.

The office will not have the authority to approve label changes and to remove a prescription drug from the market. Von Eschenbach said, “What we’re doing is to create an integrated approach … that isn’t going to perpetuate problems of the past but really try to embrace what have to be solutions of the future.”

In the future, FDA will implement a second phase of the plan, called Safe Use, which will focus on the safety of prescription drugs in real-world settings. However, there are few details available on that plan as of yet, according to an agency official (Wilde Mathews, Wall Street Journal, 2/26).

Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.

Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 µg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 µg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.

Results A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).

Conclusions Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.

Discussion

In this multicenter, randomized, double-blind trial of low-dose vasopressin as compared with norepinephrine in patients with septic shock, we were not able to demonstrate any significant difference in the 28-day mortality rate (35.4% in the vasopressin group vs. 39.3% in the norepinephrine group, P=0.26). We were also unable to demonstrate any significant difference between the two study groups in 90-day mortality or the rate of organ dysfunction. There was no difference in the rates of serious adverse events between the vasopressin and norepinephrine groups. Infusions of low-dose vasopressin (0.03 U per minute) increased plasma vasopressin levels to approximately 70 to 100 pmol per liter from extremely low baseline vasopressin levels (median, 3.2 pmol per liter). Consistent with at least 14 previous trials in humans10,11,12,13,14,20,21,22,23,24,25,26,27,28 of low-dose vasopressin (≤0.1 U per minute), vasopressin infusion allowed a rapid decrease in the total norepinephrine dose while maintaining mean arterial pressure.10,11,12,29

Our study was prospectively powered to detect an absolute difference in mortality of 10% from an expected 60%. However, the observed mortality rates in both the vasopressin and norepinephrine groups were considerably lower than those in previous studies, perhaps because of overall improvements in the care of patients who have septic shock. Nonetheless, our data exclude with 95% confidence a harm associated with the use of vasopressin that was greater than 2.9% or a benefit that was greater than 10.7%.

The overall rates of serious adverse events were approximately 10% each in the vasopressin and norepinephrine groups. Previous studies raised the possibility that vasopressin infusion may increase the incidence of cardiac arrest.29 In contrast, we found that of 11 cardiac arrests reported in this study, 8 occurred in the norepinephrine group and 3 occurred in the vasopressin group. Our selection of a low dose of vasopressin (0.03 U per minute) and careful exclusion of patients who had acute coronary syndromes or severe heart failure could account for the lack of adverse cardiovascular effects of vasopressin infusion. If vasopressin becomes routine therapy and is given at higher doses or to patients with septic shock who have coexisting heart disease, the adverse reactions to vasopressin could be increased. Other reported adverse effects of vasopressin and norepinephrine include decreased cardiac output,11,14,29 mesenteric ischemia,21,30 hyponatremia (with vasopressin only), skin necrosis,31 and digital ischemia.32 More patients in the vasopressin group than in the norepinephrine group had digital ischemia; one patient in the vasopressin group required surgical intervention.

Our secondary hypothesis was that the beneficial effects of vasopressin as compared with norepinephrine would be more pronounced in the subgroup of patients with more severe septic shock. No significant interaction between treatment group and shock-severity subgroup (as defined a priori) was shown. Some of the analyses we performed suggested that vasopressin may be more beneficial in patients with less severe septic shock. However, the statistical significance of these observations is uncertain, especially because of the many statistical tests performed, and this finding should be considered only as a hypothesis-generating concept to be tested in future trials.33

Several limitations of our trial should be mentioned. The vasopressin was infused over a set range of doses, and we did not measure vasopressin levels as a guide to the dose or the duration of infusion. In addition, in this trial the mean arterial pressure at baseline was 72 to 73 mm Hg, essentially making this a study of the effects of low-dose vasopressin as a “catecholamine-sparing drug,” not an evaluation of vasopressin in patients with catecholamine-unresponsive refractory shock. The mean time from meeting the criteria for study entry to infusion of the study drug (12 hours) was greater than the period that Rivers and colleagues4 identified as being important in early goal-directed therapy (6 hours), which may be one reason that we did not find a benefit of vasopressin as compared with norepinephrine.

In summary, we evaluated the effect of low-dose vasopressin (0.03 U per minute) when used in conjunction with catecholamine vasopressors in patients with septic shock. We did not find a significant reduction in mortality rates with vasopressin.

Supported by a grant (MCT 44152) from the Canadian Institutes of Health Research.

Drs. Russell, Walley, and Gordon report serving as officers and holding stock in Sirius Genomics, which has submitted a patent, owned by the University of British Columbia and licensed to Sirius Genomics, that is related to the genetics of vasopressin. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock. Drs. Russell, Walley, and Gordon report being inventors on this patent. Drs. Russell and Walley report receiving consulting fees from Ferring, which manufactures vasopressin. Dr. Russell reports receiving grant support from Sirius Genomics, Novartis, and Eli Lilly; and Dr. Wally, from Sirius Genomics. No other potential conflict of interest relevant to this article was reported.

* Investigators who participated in the Vasopressin and Septic Shock Trial (VASST) are listed in the Appendix.

Source Information

From the iCAPTURE Centre, Vancouver, BC (J.A.R., K.R.W., A.C.G., M.M.S.); St. Paul’s Hospital, Vancouver, BC (J.A.R., K.R.W., J.S., A.C.G., M.M.S., D.A.); Ottawa Hospital, University of Ottawa, Ottawa (P.C.H.); Kelowna General Hospital, Kelowna, BC, and University of British Columbia, Vancouver (C.L.H.); Mount Sinai Hospital, Toronto (S.M.); Toronto General Hospital, Toronto Western Hospital, and University of Toronto, Toronto (J.T.G.); and St. Joseph’s Hospital and McMaster University, Hamilton, ON (D.J. Cook) — all in Canada; and Alfred Hospital and Monash University, Melbourne (D.J. Cooper); and Royal Melbourne Hospital and University of Melbourne (J.J.P.) — all in Melbourne, Australia.

Go into most doctor’s offices or clinics across the United States and you will see racks of messy files, patient charts, stacks of paper ready to be filed and lots of little messages and bits of paper that have no home. You could not differentiate if it is a chart room from 1943 or 2008, except that now there is 20 times the paper to be filed.

There is unanimous agreement from doctors, hospitals, patients, academics and Yes! our own government that Medicine is far behind other industries in automating with an electronic health record (EHR aka: electronic medical record). The push for the EHR has been around for 10+ years, continuing today from Pres. Bush and each of the presidential candidates in their “reform health care” platforms. Despite the unanimity around the benefits to society with a universal EHR, only 14% of doctors use a “minimally functional” EHR…one that captures clinical notes, orders for prescriptions, lab and radiology tests and results.

Roughly half of all practicing physicians are in solo or small partnership practices. They don’t have the resources, IT infrastructure, or development time to convert to the electronic health record. Large multi specialty groups (10 doctors or more) are the ones that are adopting this technology and generally they are very happy with the benefits to their practice lives and their patient care.

So when you hear the candidates talking about linking doctors, hospitals, all caregivers and patients electronically through an EHR and the wonderful savings that will be obtained by technology you should ask “Oh, yea, how do you think this is going to happen?” Despite billions of dollars invested in software development, we still do not have an interoperable EHR. The systems don’t talk to each other and the vendors are competitors and are unwilling to interface with each other.

A personal health record that the patient keeps is one thing and is valuable for both self-responsibility and control. But that is very different from a real time, complete, instantly accessible electronic chart that can be used by each of your doctors, whether it be the ER or the dermatologist. The privacy issues will disappear if we truly think of what is needed for best patient care (not data mining so you can be sold something or denied coverage for a condition).

Over time (lots of time), I think we will get there. The solo practitioner is a dying practice model and Medicine is going the way of big business and larger groups. It will take this type of capital investment for the EHR to be implemented everywhere. Making sure our technology goals have the “patient first” will go a long way in speeding up the process.

The answer is #3, Leprosy. Leprosy, also known as Hansen’s disease, is a chronic infectious bacteria that affects peripheral nerves, the respiratory tract lining and skin. Interestingly, only about 5% of people who are infected with the disease actually develop any symptoms. The mode of transmission is unknown, thought to be by respiratory droplets. Treatment with oral antibiotics is effective in treating Leprosy.

I’m back from Costa Rica with another New England Journal of Medicine challenge for you.

This patient is an immigrant from Pakistan. These lesions are not pruritic (itchy) or hypoesthetic (decreased sensation). What is the diagnosis? Click on the image for a better view. The answer will be posted tomorrow.
1. Granuloma annulare
2. Scrofula
3. Leprosy
4. Pityriasis rosea
5. Tinea Corporis (ringworm)

Oregon Health & Science University Cancer Institute researchers, in a first-of-its-kind study, have found that even men with advanced prostate cancer can take a much-needed safe break, or holiday, from chemotherapy.

The double-blind, randomized study, led by principal investigator Tomasz Beer, M.D., recently was published in the journal Cancer. Beer is the Grover C. Bagby Endowed Chair for Cancer Research, director of the OHSU Cancer Institute Prostate Cancer Program, and associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.

Beer and his team wanted to know if men with metastatic, androgen-independent prostate cancer cancer that has spread from the prostate and is not affected by the male hormone, androgen could take a break from docetaxel, an intravenous chemotherapy delivery drug that is the gold standard treatment for androgen-independent prostate cancer. Docetaxel works by killing cancer cells and slowing cell growth. However, the drug also can cause side effects, such as hair loss, nausea, loss of appetite and increased chance for infections. Chemo holidays can be a much-needed vacation from these side effects.

Prior to this study, it wasn’t known whether stopping chemotherapy would lead to treatment resistance.

“We wanted to see if we could improve the quality of life for these patients by giving them time away from chemotherapy and possibly extend the time their cancer is controlled. Essentially, what we proved is that in selected subjects, chemotherapy holidays are feasible and provided meaningful breaks from treatment,” said Beer.

This is the first multi-institutional trial to examine outcomes from intermittent chemotherapy. A total of 250 men participated. Of those, 18 percent entered the intermittent arm of the study. These men previously had responded well to chemotherapy.

The median duration of the first chemo holiday was 18 weeks. On resumption of chemotherapy, it the majority of subjects responded to treatment. Specifically, 45.5 percent of participants responded with a greater than 50 percent reduction in prostate specific antigen (PSA) from their post-holiday baseline; of those, 45.5 percent had stable PSAs for at least 12 weeks; and 9.1 percent developed disease progression. Prostate-specific antigen is a protein produced by the cells of the prostate gland and is present in small quantities in the serum of healthy men, and it often elevates when prostate cancer is present. Most men have less than 4 nanograms. Anything higher can indicate prostate cancer.

The next step, said Beer, is to study the addition of immunotherapy, treating the cancer by working with the immune system, during the chemotherapy holidays.

“Because we know holidays are a good thing, we want to find ways to make them even longer,” Beer said. OHSU and Beer have significant financial interest in Novacea, Inc., a company that has a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.

A new test that examines large sections of the sentinel lymph node for genes expressed by breast cancer could reduce the risk of recurrence and multiple surgeries, doctors say.

The GeneSearch Breast Lymph Node Assay, manufactured by Veridex, L.L.C., a Johnson & Johnson company, is being used at the Medical College of Georgia to examine half of the tissue in the sentinel lymph node, the first place breast cancer typically spreads. The sample represents more than 10 times the amount of tissue examined in traditional biopsies.

And because the test examines the tissue with molecular tools, it is more sensitive, says Dr. Zixuan (Zoe) Wang, molecular biologist and scientific director of MCG’s Georgia Esoteric and Molecular Diagnostic Labs, L.L.C.

“When we look at the tissue with the GeneSearch test, we are looking for excessive amounts of mamoglobin and cytokeratin 19, both genes that are expressed more in breast cancer tissue,” Dr. Wang says. “If those genes are present in excessive amounts, we know the cancer has metastasized.”

MCG is the first place in Georgia to offer the test, which Time Magazine named one of the top-10 medical breakthroughs of 2007.

Done during a lumpectomy, the GeneSearch test uses molecular diagnostic methods to examine more tissue than traditional sentinel node biopsies, reducing the chance of false negative results, says Dr. Stephen Peiper, chair of the MCG Department of Pathology and Georgia Cancer Coalition Distinguished Cancer Clinician and Scientist.

The sentinel node, located in the armpit, filters fluid from the breast.

“During a traditional sentinel node biopsy, a surgeon would remove a node, then the pathologist would cut that section in half and cut that section to a quarter of the original sample size,” Dr. Peiper says. “They then would cut wafer-thin slices from those sections, freeze and stain them, and look for cancer cells under a microscope. This technique, called frozen section, would be done during the lumpectomy surgery. If the tissue is positive for cancer cells, the surgeon removes more nodes from the patient, but if it is negative, the surgery is over.”

The problem with that type of test, he says, can come when pathologists review more tissue slices during a confirmatory second test, called a permanent section and done a day later.

Permanent section tests are done the day after surgery because the tissue is set with a fixative that causes proteins in cells to harden for better examination.

“The cancer cells may not have been present in the part of the node that we looked at the day before in the frozen section,” Dr. Peiper says. “But on the second day, we may find them in the other section. We perform both the traditional test and the new GeneSearch molecular test in parallel to provide the best care for our patients.”

The larger the sample, he says, the better the chance of catching the cancer during the intraoperative test.

“If there are small amounts of cancer cells in the whole node, we may or may not see those with the traditional tests, because we only examine a small section of tissue,” he says. “With this technology, we increase the chance of detecting them.”

Nearly 20 percent of women with negative nodes confirmed by a traditional biopsy end up having a recurrence and metastasis, Dr. Peiper says.

“There is a higher false-negative rate with traditional sentinel node biopsies,” says Dr. Scott Lind, professor and chief of the MCG Section of Surgical Oncology. “If that happens, the patient has to come back in for another surgery to take out more lymph nodes that have likely harbored the breast cancer cells.”

In clinical trials, the new test correctly identified more than 95 percent of patients whose cancer had spread to their lymph nodes, according to Veridex, L.L.C.

“This will help us provide better care to patients and better overall treatment,” Dr. Lind says.

A new study published today in PLoS Medicine suggests that antidepressants only benefit some, very severely depressed patients.

“New generation” antidepressants, such as fluoxetine (Prozac) are widely prescribed for the treatment of clinical depression. However some studies have suggested that these drugs do not help the majority of depressed people get better by very much. Irving Kirsch, from the University of Hull, and his colleagues, studied this question in closer detail, looking at whether a patient’s response to antidepressant therapy depends on how badly depressed they are to start out with.

Kirsch and colleagues used a technique called “meta-analysis”, where they put together data on clinical benefit from all the trials submitted to the US Food and Drug Administration for four drugs: fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat / Paxil). (The researchers also wanted to include sertraline and citalopram, but couldn’t find all the relevant data for those two drugs). By including data from unpublished as well as published trials, the researchers set out to avoid bias that might come from non-publication of disappointing findings.

When the data from all of these trials had been put together, the improvement in depression amongst patients receiving the trial drug, as compared to those receiving placebo (dummy tablets), was not clinically significant in mildly depressed patients or even in most patients who suffer from very severe depression. The benefit only seemed to be clinically meaningful for a small group of patients who were the most extremely depressed to start out with. This improvement seemed to come about because these patients did not respond as well as less depressed patients to placebo, rather than responding better to the drug.

Irving Kirsch, summarising the paper, says: “Although patients get better when they take antidepressants, they also get better when they take a placebo, and the difference in improvement is not very great. This means that depressed people can improve without chemical treatments.”

Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective