PrimeCuts: This Week in the Journals

January 5, 2009

cold.jpgCommentary by Ramani Balu MD, PGY 1

Faculty Peer Reviewed

The beginning of the New Year is a time to reflect on our progress and look forward to developments yet to come. Here are a few articles from last week that highlight innovative approaches to old problems and force us to think in new ways about issues we face every day. Judging by these selections, it should be an exciting new year indeed for medical research.

New reasons to curtail polypharmacy
Patients on multiple medications must always be mindful of potential medication interactions. These interactions can have life-threatening consequences and represent a growing problem, especially in aging patients who have multiple chronic medical conditions. As clinicians, we routinely check for potential interactions between prescription medications that can cause adverse effects for patients. We rarely, however, check for possible interactions between prescription drugs and non-prescription medications despite the fact that many of our patients take a variety of over the counter medications, nutritional supplements and herbal remedies. A study in this week’s JAMA addressed the use of prescription drugs, over the counter medications and supplements in elderly adults in the United States. The authors found that multiple prescription and non-prescription medications were commonly taken together by older adults and that 1 in 25 individuals surveyed had the potential for a major, life threatening drug-drug interaction. These results underscore the importance of assessing all of a patient’s medications and always trying to limit polypharmacy.

New insights into the genesis of epilepsy
Because the precise mechanisms involved in seizure generation are still unclear, definitive treatment for epilepsy remains elusive. Despite our best efforts, status epilepticus (defined as a seizure lasting more than 30 minutes) carries a staggering 20-40% mortality rate. A study published in the current issue of Nature Medicine suggests that the inflammatory response in brain blood vessels may be critical for both initiating and maintaining epileptic seizures. The authors showed that experimentally inducing seizures in mice by treating them with pilocarpine (a muscarinic receptor agonist) is accompanied by the upregulation of cell adhesion molecules on endothelial cells which lead to leukocyte extravasation and a leaky blood brain barrier. Remarkably, pretreating mice with a selective antibody that blocks neutrophil adhesion to endothelial cells completely blocked the ability of pilocarpine to produce seizures. Giving mice the same antibody after a generalized seizure reduced the number of subsequent spontaneous seizures. It is unclear whether these results can be generalized to other experimental models of epilepsy, but it certainly represents a new and exciting potential target for treating seizure disorders.

A new way to fight hospital acquired infections: decontaminating the ICU
Despite advances in treatment, hospital acquired infections remain a significant source of mortality and morbidity in critically ill patients. Numerous infection control measures such as contact isolation, aspiration precautions in mechanically ventilated patients and strict guidelines for how central venous catheters can be placed have been implemented to reduce the rates of ICU infection. A different approach to infection control is to test whether changing the ecology of microbial flora present in the ICU by systematic decontamination can change rates of infection and infectious complications. A controlled, multi-center, crossover study of European ICU patients in this week’s New England Journal of Medicine tested this unique approach by assessing the effects of selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) on 28 day mortality. SDD involved systemic administration of cefotaxime during the first four days of ICU treatment along with topical application of tobramycin, colistin and amphotericin B to the oropharynx and stomach to hopefully prevent colonization of patients with gram-negative bacteria, S. aureus and yeasts. In addition, the administration of antibiotics with activity against anaerobes during the first four days was discouraged. SOD consisted of topical antibiotic application without administration of cefotaxime. This study had an overly complicated design; with cluster randomization, multiple cross-over periods and complicated statistical analyses. However, a small but significant reduction in 28 day mortality was seen with both SDD and SOD approaches relative to standard care. It will take further research to demonstrate whether this approach should be adopted widely, given the concerns for selecting for antibiotic resistant organisms with long-term use of any decontamination strategy.

A new paradigm: can upper GI bleeds be managed as an outpatient?
The large spectrum in the severity of upper GI bleeds presents a difficult challenge for the allocation of clinical resources. One the one hand, a patient may present with florid exsanguination and hemodynamic compromise and require rapid, emergent endoscopy and monitoring in an ICU setting. On the other hand, a patient with mild coffee-ground emesis and stable hemoglobin can be treated conservatively. These patients are usually admitted for observation and often get endoscopy a day or more after admission depending on urgency. Often, no lesion is found on the EGD and we are left wondering whether it would have been better to send the patient home from the ER with close outpatient follow up. A new study published in Lancet tested whether a scoring system for GI bleed severity—the Glasgow-Blatchford bleeding scale (GBS)—which uses simple clinical and laboratory values can identify low risk patients who can be followed as an outpatient after their initial ER presentation. The study found that none of the low risk patients identified by the GBS subsequently needed intervention with endoscopy. More research needs to be done, but such a scoring system may be a useful method for determining who needs inpatient treatment for an upper GI bleed.

New approaches to curtail the spread of HIV and mosquito-borne diseases
A variety of approaches have been proposed to reduce the spread of HIV. A new paper in this week’s Lancet uses a mathematical model to show that universal annual screening for HIV with immediate initiation of anti-retroviral therapy for individuals who test positive could eradicate the spread of HIV. The authors premise rests on the fact that early initiation of ART can reduce viral load and therefore dramatically reduce the number of subsequent infections generated by a single HIV infected person. In their model, when early ART is coupled with universal screening a threshold can be reached where no subsequent infections are generated from a person who tests positive; effectively halting the spread of the disease. This marks a new way to view HIV control, and could have a dramatic impact on policy and funding for HIV prevention.

A different approach to infection control was taken in a study in this week’s issue of Science to investigate how the spread of mosquito borne illnesses can be reduced. These authors introduced a strain of the obligate intracellular bacterium Wolbachia pipiens that reduces insect life-span into the Aedes aegypti mosquito (the mosquito vector for Dengue fever). These mosquitos were able to reproduce but had a markedly shortened lifespan that stably passed through multiple generations. The lifespan was on average shorter than the incubation time needed for dengue virus to replicate and enter the mosquito salivary gland. These engineered mosquitos could be introduced into the wild, where they can compete with wild mosquitos and reduce the spread of Dengue fever. A similar strategy could be used for malaria control. One problem with this approach however, is that populations engineered with shorter lifespans will likely have a reduced reproductive fitness which will make introduction into the wild difficult.

A new approach to manage post-MI ventricular tachycardia
Myocardial infarction puts patients at risk for subsequent sustained ventricular tachycardia (VT). Ventricular tachycardias are effectively aborted by implantable cardioverter-defibrillators (ICDs), but ICDs do not prevent VT. In addition, despite proper ICD functioning, VT episodes continue to increase a patient’s risk of sudden cardiac death and heart failure. Another approach to treating VT in post-MI patients is to use radiofrequency catheter ablation. A new multicenter prospective trial in the current issue of Circulation tested whether catheter ablation helped prevent the occurrence of post-MI VT. This approach has been used in prior smaller studies, but because patients often have multiple inducible VT foci these re-entrant circuits are particularly difficult to map. The present combined radiofrequency catheter ablation with an electroanatomic mapping system that facilitated substrate mapping. The authors showed that ablation abolished recurrent VT in about half of the patients and that the frequency of VT was reduced in the other patients. While this approach certainly does not obviate the need for an ICD, it may represent a new strategy for treating patients with difficult to control ventricular tachycardias.

New reasons to curtail polypharmacy
Qato DM et al (2008) Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 300(24): 2867-2878

New insights into the genesis of epilepsy
Fabene PF et al (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nature Medicine 14(12):1377-1383

Decontaminating the Intensive Care Unit
de Smet AMGA et al (2009) Decontamination of the digestive tract and oropharynx in ICU patients. NEJM 360(1): 20-31

Can upper GI bleeds be managed as an outpatient?
Stanley AJ et al (2009) Outpatient management of patients with low risk upper-gastrointestinal hemorrhage: multicenter validation and prospective evaluation. Lancet 373: 42-47

New approaches to curtail the spread of HIV and mosquito-borne diseases
Granich RM et al (2009) Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for the elimination of HIV transmission: a mathematical model. Lancet 373:48-57

McMeniman CJ et al (2009) Stable introduction of a life-shortening Wolbachia infection into the mosquito Aedes aegypti. Science 323:141-144

Radiofrequency ablation of post-MI ventricular tachycardia
Stevenson WG et al. (2008) Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation 118: 2773-2782.

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