WORSENING OUTCOMES AND INCREASED RECURRENCE OF CLOSTRIDIUM DIFFICILE AFTER INITIAL TREATMENT WITH METRONIDAZOLE?
Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005;40:1591-1597; and Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.
Information on treatment of colitis caused by Clostridium difficile began to appear in the late 1970s and early 1980s. Since that time there have been a paucity of novel therapies. It has been well-established that both metronidazole and vancomycin can effectively treat this entity. Traditionally metronidazole has been the first-line agent for C. difficile-associated diarrhea (CDAD). The reasons for this are three:
- Randomized controlled trials have shown vancomycin and metronidazole to be equally efficacious;
- The cost of oral vancomycin is substantially more than oral metronidazole; and
- Many experts have cautioned that using vancomycin may contribute to the blooming number of bacteria that are resistant to vancomycin.
Indeed recommendations from the Centers for Disease Control and Prevention’s Healthcare Infection Control Practices Advisory Committee as well as the American Society for Health-System Pharmacists have supported using metronidazole as our initial agent of choice for CDAD (oral vancomycin is actually the only agent that is approved by the Food and Drug Administration for CDAD). Most of our earlier data claim initial response rates to be 88% or better and relapse rates to be somewhere between 5% and 12% when metronidazole is used.
Two new studies have been published raising a red flag on our current standard of practice. Musher, et al., designed a prospective, observational study in which they followed more 200 patients with CDAD that were initially treated with metronidazole. The patient pool came from a Veterans Affairs Medical Center. They all had a positive fecal ELISA for C. difficile toxin and were treated for seven or more days using at least 1.5 grams per day of metronidazole.
Records were reviewed six weeks prior to the diagnosis and then patients were followed for three months after cessation of therapy. Patients were assigned to four outcome groups:
- Complete responders who did not have recurrence over four months;
- Refractory-to-treatment where signs and symptoms of CDAD were present for 10 or more days;
- Recurrence after initial clinical response with signs and symptoms of CDAD and a positive toxin; and
- Clinical recurrence where there was an initial response but a recurrence of signs and symptoms of CDAD without a positive toxin (either the toxin was not present when tested or the test was not done).
Fifty percent were completely cured. Twenty-two percent were refractory to initial therapy. Twenty-eight percent had a recurrence of CDAD within the 90-day period. The mortality was 27%. This was higher among people who had failed to respond to initial therapy (31% versus 21%; p<.05).
Pepin, et al., retrospectively looked at more than 2,000 CDAD cases from one hospital between 1991 and 2004. To be included the patients needed either a positive toxin, endoscopic evidence of pseudomembranous colitis, or histopathologic evidence of pseudomembranous colitis on a biopsy specimen. Patients received at least 1 gram per day of metronidazole for 10 to 14 days. They were considered to have a recurrence if they had diarrhea within two months of the completion of therapy and either a positive toxin at that time or if the attending physician ordered a second course of antibiotics for C. difficile.
Between 1991 and 2002 the frequency of times that either therapy was changed to vancomycin or vancomycin was added to metronidazole was unchanged (9.6%). During 2003-2004 this more than doubled (25.7%). The number of patients experiencing recurrence over a two-month period comparing data from 1991-2002 to 2003- 2004 was staggering (20.8% versus 47.2%; p<.001). The authors noted that as patients aged the probabilities of recurrence increased.
They also found that a subgroup of patients with a white blood cell count over 20,000 cells/mm3 and an elevated creatinine had a high short-term mortality rate.
Why might we be seeing these results? Several theories exist. Patients are both older and sicker than they have been in the past. Our antibiotic choice is changing with an increase in using agents that provide a more broad-spectrum coverage. Immune responses vary with fewer antitoxin antibodies found in those patients with symptoms and/or recurrence. Metronidazole levels in stool decrease as inflammation and diarrhea resolve; this is not the case with vancomycin where fecal concentrations remain high throughout treatment.
A survey of infectious disease physicians found that they believe antibiotic failure is on the rise in this setting. Before we take this as true, consider the following:
- We have no universally accepted clinical definition of what constitutes diarrhea for CDAD;
- Previous studies did not look for recurrence as far out from initial treatment as these two did; and
- These studies do not have the design to support arguments powerful enough to change our paradigm just yet.
The editorial comment acknowledged the Pepin, et al., report that patients with a high white blood cell count and worsening renal function are those that we should be particularly concerned about. The authors write that if the patient’s white blood cell count is increasing while on therapy that he changes his antibiotic choice to vancomycin. In addition, if someone has either ileus or fulminant CDAD he will use multiple antibiotics and consult the surgeons. At this time we have other agents being studied for CDAD, such as tinidazole. We now need a larger randomized prospective trial to better explore treatment outcomes in CDAD.
HYPERTONIC SALINE SOLUTION TO TREAT REFRACTORY CONGESTIVE HEART FAILURE
Paterna S, Di Pasquale P, Parrinello G, et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure. J Am Coll Cardiol. 2005;45:1997–2003.
CHF continues to increase in prevalence and incidence, despite our advances with therapies using ACE inhibitors, beta-blockers, and aldosterone antagonists. Refractory CHF accounts for a considerable portion of admissions to hospitalists’ services. Loop diuretics are part of the standard of arsenal we employ in these patients. Unfortunately, many patients fail to respond to initial diuretic doses. In this situation we might begin a constant infusion of diuretic or recruit diuretics from other classes in hope of synergism. Another typical approach in treating advanced CHF is restriction of sodium intake.
Paterna, et al., previously published four studies using small volume hypertonic saline solution and high-dose furosemide in refractory CHF, in which they demonstrated the safety and tolerability of these measures. They now present the first randomized double-blinded trial using this intervention. Ninety-four patients were included with NYHA functional class IV CHF on standard medical therapy and high doses of diuretics for at least two weeks. They had to have a left ventricular ejection fraction of <35%, serum creatinine <2 mg/dL, reduced urinary volume (<500 mL/24 h), and a low natriuresis (<60 mEq/24 h). They could not be taking NSAIDs.
Patients received either intravenous furosemide (500 to 1000 mg) plus hypertonic saline solution bid or the IV furosemide bid alone. Treatment lasted four to six days. Body weights were followed. Brain natriuretic peptide plasma levels were measured on hospital days one and six, as well as 30 days after discharge.
The group receiving hypertonic saline solution had brow-raising results. They had a significant increase in daily diuresis and natriuresis (p<0.05), a difference in brain natriuretic peptide levels on days six and 30, a reduction in their length of stay, and a decrease in their hospital readmission rate.
This is a provocative study. At this time the mechanism responsible for the results is unclear. Paterna, et al., offer multiple explanations. One possibility is through the osmotic action of hypertonic saline solution. It may hasten the mobilization of extravascular fluid into the intravascular space and then this volume is quickly excreted. Also, hypertonic saline solution may increase renal blood flow and perfusion alternating the handling of sodium and natriuresis while also allowing the concentration of furosemide in the loop of Henle to attain a more desirable level.
Should these results hold true in other investigations and the inclusion criteria loosen (measuring patients urine volume and sodium concentration for 24 hours prior to admission may not be easy or practical) then we might have a very inexpensive new method for treating refractory CHF.
PERIOPERATIVE BETA-BLOCKERS: HELPFUL OR HARMFUL FOR MAJOR NONCARDIAC SURGERY?
Lindenauer P, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. 2005;353:349–361.
Among the most common reasons that hospitalists are consulted is the “perioperative evaluation.” This is with good reason because 50,000 patients each year have a perioperative myocardial infarction. A statement by the Agency for Health Care Research and Quality proclaims that we have “clear opportunities for safety improvement” in regard to using beta-blockers for patients with intermediate and high risk for perioperative cardiovascular complications. The American Heart Association and the American College of Cardiology recommend using these medications in patients with either risk factors for or known coronary artery disease when undergoing high-risk surgeries. Despite all of this the efficacy of the class has not been proven by large randomized clinical studies.
Using a large national registry of more than 300 U.S. hospitals, Lindenauer, et al., conducted a large observational study evaluating beta-blockade in the perioperative period in patients undergoing major noncardiac surgery. Looking at more than 700,000 patients, they found that 85% had no recorded contraindication to beta-blockers. Only 18% of eligible patients received beta-blockers (n=122, 338).
Patients were considered to have had a beta-blocker for prophylaxis if it was given within the first 48 hours of their hospitalization, though this may or may not have been the intended use (this information was not provided by the registry data base). Only in-hospital mortality was evaluated as postdischarge information was not available. All patients had a revised cardiac risk index configured. This index places risk on perioperative cardiac events by looking at the nature of the surgery as well as whether or not a history of congestive heart failure, ischemic heart disease, perioperative treatment with insulin, an elevated preoperative creatinine, and cerebrovascular disease are present. An increasing score means that major perioperative complications become more likely (scores range from 0–5).
Considering all patients, there was no risk reduction of in-hospital death for those receiving beta-blockers. If the revised cardiac risk index score was 0 or 1, the patients had an increase in the risk of death (43% and 13%, respectively). However, those patients whose scores were 2, 3, or 4 or higher had a reduction in the risk of death (from 10% to 43% as their score increased).
How are we to account for these results? In the high-risk patients we see benefit in treatment with beta-blockers. We suspect this drug class improves coronary filling time during diastole and/or prevents dangerous arrhythmias. In patients at low and intermediate risk, the results may be surprising. The study group did not have patient charts available. It is possible that these patients were given betablockers not for prophylaxis but in response to a postoperative ischemic event or infarction. If this misclassification took place, then the effectiveness of beta-blockers is underestimated and the suggestion that these drugs are harmful in this situation would be erroneous.
Given the data gleaned from this study and considering previous publications, we are justified—even obligated—in using betablockers in high-risk patients, without contraindications, who undergo major noncardiac surgery. Before using these drugs in patients at low or intermediate risk we need more information. Two large ongoing randomized trials (POISE and DECREASE–IV) should bring clarity to this issue. We expect results from these in the next four years.
A NEW CLINICAL ENTITY: THE HEPATOADRENAL SYNDROME
Marik PE, Gayowski T, Starzl TE, et al. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med. 2005;33:1254-1259.
It is not uncommon to see the temporary dysfunction of the hypothalamic-pituitary-adrenal axis while someone is critically ill. Many physicians who suspect this condition attempt to make a diagnosis using either a random total cortisol level or perform a cosyntropin stimulation test. End-stage liver disease and sepsis share some elements of their pathophysiology, such as endotoxemia and increased levels of mediators that influence inflammation.
A liver transplant intensive care unit has produced data on what they have coined the “hepatoadrenal syndrome.” Due to emerging evidence that severe liver disease is associated with adrenal insufficiency, this liver transplant intensive care unit began routinely testing all patients admitted to their unit for this condition. They presented their findings for 340 patients. This review will focus only on those patients with chronic liver failure and fulminant hepatic failure because transplant patients are often cared for by a multidisciplinary team. Patients were labeled as having adrenal insufficiency if the random total cortisol level was <20 micrograms (mcg)/dL in patients who were “highly stressed” (i.e., hypotension, respiratory failure). In all other patients a random total cortisol level of <15 mcg/dL or a 30-minute level <20 mcg/dL post-low-dose (1 mcg) cosyntropin established the diagnosis. Lipid profiles were also obtained from each patient. Those receiving glucocorticoids were excluded. It was left to the discretion of the treating physician whether or not to treat patients with steroids.
Eight patients (33%) with fulminant hepatic failure and 97 patients (66%) with chronic liver disease met their criteria for adrenal insufficiency. Of the patients with adrenal insufficiency the mortality rate was 46% for those not treated with glucocorticoids compared with 26% for those receiving glucocorticoid therapy. The HDL level was the only variable predictive of adrenal insufficiency (p<.0001).
The association between HDL levels and cortisol is as follows: The adrenal glands do not store cortisol. Cholesterol is a precursor for the synthesis of steroids—80% of cortisol arises from it. The lipoprotein of choice to use as substrate in steroid production is HDL. Because a major protein component of HDL is synthesized by the liver, those with liver disease have low levels of serum HDL.
Recently our current method of diagnosing adrenal insufficiency during acute illness has been challenged in the literature. Measuring free cortisol rather than total cortisol has been suggested as proteins that bind cortisol decrease in this setting while free cortisol levels actually rise. Similar to the picture we see in sepsis, there are low levels of these same proteins in liver disease.
At this time testing for free cortisol is not widely available nor do we have good information on what an “appropriate” free cortisol level should be during acute illness. Therefore, given the frequency in which Marik, et al., report encountering this condition and the effect that treatment had on mortality it seems as though this is a diagnosis worth consideration.
TREATMENT OPTIONS FOR ATRIAL FIBRILLATION
Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation. JAMA. 2005;293(21):2634-2640.
Atrial fibrillation affects millions of people. This diagnosis has a significant mortality associated with it, causes strokes, and influences quality of life. Therapy has been less than satisfying. Both rate control and rhythm control have multiple potential adverse consequences. Pulmonary vein isolation is performed in the electrophysiology laboratory using an ablation catheter. The goal of this procedure is to completely disconnect the electrical activity between the pulmonary vein antrum and the left atrium. This is a potentially curable procedure for atrial fibrillation.
In a multicenter prospective randomized pilot study Wazni, et al., studied 70 patients with highly symptomatic atrial fibrillation. Patients were between 18 and 75 years old. They could not have undergone ablation in the past, had a history of open-heart surgery, been previously treated with antiarrhythmic drugs, or had a contraindication to long-term anticoagulation. Patients were randomized to antiarrhythmic therapy or pulmonary vein isolation. Those receiving medical treatment were given flecainide, propafenone, or sotalol. Amiodarone was used for patients who had failed at least two or more of these medications. Drugs were titrated to the maximum tolerable doses. The other arm of the group underwent pulmonary vein isolation. This group also received anticoagulation with warfarin beginning the day of the procedure, and this was continued for at least three months. Anticoagulation was extended beyond this time if atrial fibrillation recurred or the pulmonary vein was narrowed by 50% or more (as seen on a three-month post-procedure CT scan). Follow-up was at least one year. A loop event-recorder was worn for one month by all patients and event recorders were used for patients who were symptomatic beyond the first three months of therapy initiation.
After one year, symptomatic atrial fibrillation recurred in 63% of the antiarrhythmic group versus 13% in the pulmonary vein isolation group (p<.001). Fifty-four percent of those medically treated were hospitalized versus 9% of pulmonary vein isolation patients (p<.001). There were no thromboembolic events in either group. Bleeding rates were similar in both groups. For those who underwent pulmonary vein isolation 3% had mild pulmonary vein stenosis and 3% had moderate stenosis (all of which were asymptomatic). Five of the eight measures of quality of life were significantly improved in the pulmonary vein isolation arm versus those receiving antiarrhythmic drugs.
Recently data from multiple trials such as AFFIRM and RACE confirm that rhythm control does not confer significant benefits over rate-control for atrial fibrillation. In fact rate control seems to be a more attractive approach to many patients given the side-effect profile of the antiarrhythmia medications. This study was initiated prior to the release of the information gained from RACE and AFFIRM, thus no rate-control arm was included. This trial also differed from previous studies by using a younger population that was highly symptomatic in comparison with other recent studies using older patients who had recurrent persistent atrial fibrillation.
The biggest concerns about pulmonary vein isolation are the complication rates (death in 0.05% and stroke in 0.28%). We also don’t know if this procedure will translate into long-term cures. Until we have larger studies this should not be a first-line modality for treating all patients. Quite often we find patients where neither rate nor rhythm control is a particularly attractive option, especially in regard to long-term anticoagulation. Pulmonary vein isolation provides us with a new viable option for these people as well as something to consider for carefully selected highly symptomatic patients. TH