Susan Jeffrey

November 14, 2011

November 14, 2011 (Orlando, Florida) — New-onset atrial fibrillation (AF) in patients with severe sepsis is associated with a significant increase in stroke and death in hospital compared both with patients with sepsis who do not develop AF and with those who have preexisting AF.

"Our findings suggest that new-onset AF during severe sepsis is associated with especially high short-term nosocomial stroke and mortality risks; most patients with new-onset AF during a hospitalization with severe sepsis did not survive," Allan J. Walkey, MD, from the Pulmonary Center at the Boston University School of Medicine in Massachusetts, and colleagues conclude.

Current guidelines do not address AF that occurs during severe sepsis or an acute infection, the authors note, suggesting this may be an underrecognized public health issue.

Dr. Allan J. Walkey

If their findings are replicated in other data sets, "then it will be important to examine management strategies that might diminish the risk of adverse outcomes associated with AF during severe sepsis."

Their report was published online November 13 in JAMA to coincide with presentation here at the American Heart Association (AHA) 2011 Scientific Sessions. Dr. Walkey is a finalist for an American Heart Association Council Early Career Investigator Award, the Cournand and Comroe Young Investigator Prize in Cardiopulmonary and Critical Care.

Prognosis Unclear

It is estimated that new-onset AF occurs in 6% to 20% of patients with severe sepsis, the authors note. Although new AF appears relatively common in severe sepsis, they write, "data are sparse to risk stratify or prognosticate these often complicated and critically ill patients."

Previous small studies have linked new-onset AF with higher mortality and prolonged hospitalization for patients with sepsis, but there has been no population-based assessment of this risk.

Dr. Walkey and colleagues used administrative claims data from the Agency for Healthcare Research and Quality to take a retrospective look at outcomes for these patients in nonfederal acute care hospitals between January 1 and December 31, 2007.

They chose to use the California State Inpatient Database because the California International Classification of Diseases, 9th Revision, (ICD-9) codes have a "present on admission" modifier to discriminate between diagnoses present at the outset from those established during the hospitalization, Dr. Walkey noted.

Data were available on more than 3 million hospitalized adults, of whom 49,082 had severe sepsis according to ICD-9–Clinical Modification code 995.92.

New-onset AF was defined as AF that occurred during hospital admission, excluding patients in which AF was present at admission. Outcome measures were in-hospital stroke, including ICD-9–Clinical Modification codes 43, 434, or 436, or death.

New-onset AF was significantly more common in patients with severe sepsis than in hospitalized patients without severe sepsis. Severe sepsis was present in 14% of all new cases of AF among hospitalized adults.

"Extrapolating to the US population, we estimate that 60,000 patients a year in the United States with severe sepsis experience new-onset [AF]," Dr. Walkey said.

Table 1. New-Onset AF With Severe Sepsis vs No Sepsis

Endpoint Severe Sepsis No Sepsis Odds Ratio (95% Confidence Interval) P
New-onset AF (%) 5.9 0.65 6.82 (6.54 - 7.11) < .001

Consistent with previous reports linking infection with increased stroke risk, "our study demonstrates that patients with severe sepsis had a 6-fold increased risk of in-hospital stroke compared with hospitalized patients without severe sepsis," the researchers note.

"As far as we are aware," they add, "the increased risk of ischemic stroke in patients with severe sepsis and new-onset AF has not been previously reported."

In-hospital mortality was also significantly increased with new-onset AF.

Table 2. In-Hospital Stroke Risk With Severe Sepsis and New-Onset AF

Endpoint Severe Sepsis With New-Onset AF Severe Sepsis Without New-Onset AF Odds Ratio (95% Confidence Interval) P
In-hospital stroke (%) 2.6 0.6 2.70 (2.05 - 3.57) < .001

Table 3. In-Hospital Mortality Risk With Severe Sepsis and New-Onset AF

Endpoint Severe Sepsis With New-Onset AF Severe Sepsis Without New-Onset AF Odds Ratio (95% Confidence Interval) P
In-hospital mortality (%) 56 39 1.07 (1.04 - 1.11) < .001

Their findings remained robust across 2 definitions of severe sepsis, multiple methods of addressing possible confounding, and multiple sensitivity analyses, they add.

Factors associated with new-onset AF during severe sepsis included demographic factors such as increasing age, male sex, and white race; comorbidities such as a history of heart failure, obesity, malignancy, and stroke; and acute factors such as increasing number of organ failures, respiratory failure, and renal failure.

The researchers speculated on potential mechanisms that might explain the increased risk. "Severe sepsis alone may be associated with an increased risk of stroke through hemodynamic collapse, increased systemic inflammation, and coagulopathy," they write. Alternatively, new-onset AF "may simply be a marker for greater severity of illness and, thus, greater stroke risk."

"It really is a call to action that we need to look into this in more detail," Dr. Walkey told Medscape Medical News. "There may be a subgroup of [AF] that requires more study."

"Whether the risk stratification for stroke applied at the community level can apply to critically ill patients with severe sepsis is unclear," he added. Further studies are needed to look at further risk stratifying these patients, and potentially to inform clinical trials of therapies to help reduce stroke risk or death risk in these patients.

Important Finding

Christopher H. Goss, MD, from the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, and the Division of Pulmonary Medicine, Department of Pediatrics, Seattle Children's Hospital, and Shannon S. Carson, MD, from the Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, wrote an editorial accompanying the publication.

In their commentary, Dr. Goss and Dr. Carson point out some of the weaknesses of administrative data sets and suggest that the results should therefore be interpreted cautiously.

Still, they write: "Given the limitations of the data analyzed, Walkey et al have shown that the association of new-onset [AF] with both in-hospital stroke and death persisted through a number of key sensitivity analyses. This association is plausible and represents an important finding (particularly in relation to the association with stroke) that is potentially relevant to intensivists."

An important question raised by the findings is whether clinicians should try to intervene to reduce the apparent increased risk with acute cardioversion, anticoagulation, or both, they note. However, maintaining successful cardioversion in severe sepsis is difficult, perhaps because acute risk factors such as high catecholamine states have not been resolved, they point out, and anticoagulation would carry additional risk for patients with severe sepsis because of coagulation abnormalities and frequent invasive procedures.

"Given the limitations of these observational data, current practice should not change in favor of interventions that could involve additional risk," they write. Although randomized trials might be difficult with the small event rates, they add, further studies in large databases looking at how different interventions might modify stroke risk may provide useful information.

"If these findings are replicated in another large cohort study of patients with severe sepsis that could also assess potential interventions, the next step would be to conduct a clinical trial to evaluate different approaches to management. As survival in sepsis continues to improve, clinical investigators must look for potentially modifiable factors that influence long-term patient-centered outcomes," they conclude. "New-onset [AF] may represent one of those factors."

The study was supported by grants from the Boston University Clinical Translational Research Institute and by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University; the National Heart, Lung, and Blood Institute; the National Cancer Institute; and the Department of Veterans Affairs. The authors have disclosed no relevant financial relationships. Dr. Goss reports receiving grants from Transave Inc, Vertex Pharmaceuticals, the National Institutes of Health, the US Food and Drug Administration, and the Cystic Fibrosis Foundation; lecture fees from Roche and Johns Hopkins University, Baltimore, Maryland; and participating in advisory board activities for Transave Inc, and KaloBios Pharmaceuticals. Dr. Carson reports receiving consulting fees from Research Triangle Institute.

American Heart Association (AHA) 2011 Scientific Sessions: Abstract 8688. Presented November 13, 2011.

JAMA. Published online November 13, 2011. Article full text, Editorial

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