What are the major changes in the definition of “sepsis” under the 3rd International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)?

Under Sepsis-3 [1], sepsis is defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection (suspected or confirmed)”. Systemic inflammatory response syndrome (SIRS) is no longer defined as part of the sepsis spectrum, and its criteria have been replaced by the Sequential Organ Failure Assessment (SOFA) with a change in score ≥2 (Table) having >10% in-hospital mortality. Septic shock is defined as hypotension requiring vasopressors to maintain a MAP ≥65 mm Hg and a lactate >2 mmol/L (18 mg/dL) despite adequate volume (>40% in-hospital mortality).

A bedside clinical tool “quickSOFA” (qSOFA), not meant to substitute for SOFA, is also proposed to identify patients primarily outside of the ICU who may be at high risk of adverse outcomes, based on the following criteria: systolic blood pressure ≤100 mmHg, respiratory rate ≥22/min, and altered mental status. A qSOFA score ≥2 is associated with poorer outcomes [1,2].

So what do these new guidelines mean for clinicians? Under the new terminology, “sepsis” now refers only to what was previously considered severe sepsis with or without shock, and those who may need more aggressive therapy, closer monitoring and possible transfer to an ICU [1,2]. As the guidelines stress, however, failure to meet qSOFA or SOFA criteria should by no means lead to a deferral or delay in evaluation or treatment of infection deemed necessary by clinicians, and SIRS criteria may still be useful in identification of infection [1]. It remains to be seen whether limiting the definition of sepsis to only patients with associated organ dysfunction will translate into an overall earlier diagnosis and improved prognosis for this condition. Stay tuned!

 

Table. Sequential (sepsis-related) organ failure assessment (SOFA) score (adapted from ref.1)____________________________________________________________________________________________________

                                                                                             Points

Parameter                                0                      1                      2                      3                      4

____________________________________________________________________________________________________

Pa02/Fi02                           ≥400                 <400                <300                 <200*          <100*

Platelets (no./mL)           >150,000         <150,000         <100,000         <50,000       <20,000

Bilirubin (mg/dL)            <1.2                  1.2-1.9              2.0-5.9             6.0-11.9       >12.0

MAP (mm Hg) or VP      MAP≥70         MAP<70          DPA≤5           DPA 5.1-15        DPA>15

Glascow Coma Scale       15                    13-14            10-12                    6-9                 3-6

Creatinine (mg/dL)        <1.2                 1.2-1.9           2.0-3.4                  3.5-4.9        >5.0

OR U.O.  (mL/dL)                                                                                              <500                <200

____________________________________________________________________________________________________

MAP= mean arterial pressure, VP=vasopressor (includes agents other than dopamine), DPA=dopamine (in mcg/kg/min for ≥1 hour);U.O.= urine output

*With respiratory support

References:

  1. Singer MS, Deutschman CS, Seymour CW, et al; The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315[8]:801-810.
  2. Jacob JA. New Sepsis Diagnostic Guidelines Shift Focus to Organ Dysfunction. JAMA. 2016;213[8]:739-740.

 

Contributed by Erik Kelly MD, Boston, MA

What are the major changes in the definition of “sepsis” under the 3rd International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)?

When should I consider ordering a coronary CT-angiogram (CCTA) in my patient with chest pain?

In patients at low-to-intermediate risk of coronary artery disease (CAD), CCTA is a viable alternative to functional stress tests and may facilitate triage decisions, as well as reduce the risk of missed myocardial infarctions and length of hospital stay (1,2). Although compared to conventional coronary angiography CCTA has lower specificity (64-90%), it has consistently been shown to have high sensitivity (>95%) and negative predictive values (>95%) for obstructive coronary stenosis, supporting its potential role in “ruling out” significant CAD in low-to-intermediate risk patients (1-2).

A coronary artery calcification (CAC) score is also commonly measured when CCTA is performed; a very high CAC score can interfere with proper interpretation of CCTA.  A negative CCTA combined with a CAC score of zero makes CAD-related chest pain extremely unlikely. The additional prognostic value of CAC score other than zero to CCTA is unclear (2).

References

  1. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52(21):1724.
  2. Villines TC,  Hullen EA, Shaw LJ, et al. Prevalence and severity of coronary artery disease and adverse events among symptomatic patients with coronary artery calcification scores of zero undergoing coronary computed tomography angiography results from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter) registry. J Am Coll Cardiol 2011;58:2533-2540.

 

Contributed by Stephanie Meller, MD, Boston, MA.

 

When should I consider ordering a coronary CT-angiogram (CCTA) in my patient with chest pain?

My patient with chronic alcoholism is showing signs of alcohol withdrawal even though his blood alcohol level (BAL) is still elevated. Is this possible?

Absolutely! For patients with chronic alcohol dependence, any acute decline in their BAL may precipitate withdrawal (1). For example, if a patient typically drinks enough alcohol on a daily basis to sustain a BAL of 350 mg/dl, any significant drop in BAL (e.g. down to 125 mg/dl) may be associated with early signs of withdrawal such as nervousness, tachycardia and elevated blood pressure.

Another scenario that could lead to withdrawal symptoms despite an elevated BAL involves patients who use both alcohol and benzodiazepines chronically. In such patients— because the 2 substances have cross-reactive effects on the brain— a significant reduction in the dose or frequency of benzodiazepines may also lead to withdrawal despite an elevated BAL. 

 

Reference

  1. Roffman JL, Stern TA.  Alcohol withdrawal in the setting of elevated blood alcohol levels. Prim Care Companion J Clin Psychiatry. 2006; 8(3):170-173

 

Contributed by Stephanie Meller, MD, Boston, MA

 

 

My patient with chronic alcoholism is showing signs of alcohol withdrawal even though his blood alcohol level (BAL) is still elevated. Is this possible?

Is oral metronidazole (Flagyl®) effective in reducing the risk of recurrent Clostridium difficile infection (CDI)?

To date only 1 study has attempted to evaluate metronidazole’s role in preventing CDI1. This work, however,  has significant shortcomings including its retrospective nature, definition of metronidazole prophylaxis as any dose for reasons other than CDI starting 1-3 days before initiation of the primary antibiotic, undefined duration, less comorbidities in the metronidazole group, and surveillance period for CDI limited to only 7 days following initiation of the primary antibiotic. For these reasons, it is difficult to interpret the results of this study whose conclusion was that metronidazole may protective against CDI2.

In fact, there are several reasons why metronidazole prophylaxis may not be effective in CDI.   First, due to its very high bioavailability, concentrations of metronidazole in formed stool are often undetectable2,3 . Consequently, “preventive” metronidazole in patients at risk of CDI but with formed stools would not be expected to achieve high enough concentrations in the colon to be effective.  In additions, metronidazole itself may be associated with CDI4 and  vancomycin-resistant enterococci5,  and has several potential drug-interactions and adverse effects6 .

References

  1. Rodriguez S, Hernandez MB, Tarchini G, et al. Risk of Clostridium difficile infection in hospitalized patients receiving metronidazole for a non-C difficile infection. Clin Gastroenterol Hepatol 2014;12:1856-61. https://www.ncbi.nlm.nih.gov/pubmed/24681079
  2. Dupont HL. Chemoprophylaxis of Clostridium difficile infections in high-risk hospitalized patients. Clin Gastroenterol Hepatol 2014;12: 1862-63. https://www.ncbi.nlm.nih.gov/labs/articles/24768812/
  3. Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 1986;27:1169-1172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1433873/pdf/gut00370-0065.pdf
  4. Daly JJ, Chowdary KV. Pseudomembranous colitis secondary to metronidazole. Dig Dis Sci 1983;28:573-4.
  5.  Carmeli Y, Eliopoulos GM, Samore MH. Antecedent treatment with different antibiotic agents as a risk factor for vancomycin-resistant enterococcus. Emerg Infect Dis 2002;8:802-807. https://wwwnc.cdc.gov/eid/article/8/8/pdfs/01-0418.pdf
  6. Salvatore M, Meyers BR. Metronidazole. In Mandel, Douglas, Bennett’s Principles and Practice of Infectious Diseases-7th Ed. p. 419-426. 2010, Churchill Livingstone, Philadelphia.

 

 

Is oral metronidazole (Flagyl®) effective in reducing the risk of recurrent Clostridium difficile infection (CDI)?

My bed-bound, debilitated patient is being transferred to a long-term facility (LTF). Should I continue the venous thromboembolism (VTE) prophylaxis she has been receiving in the hospital?

There are no randomized-controlled studies that examine the effectiveness of VTE prophylaxis in debilitated patients following discharge from the hospital, and currently  the literature does not recommend prophylaxis for chronic immobility as a single risk factor for VTE (1). However, given the expected morbidity, potential mortality and hospital readmission associated with VTE,  prophylaxis should be considered in residents of LTFs with the following comorbidities (2):

  • Acute exacerbation of congestive heart failure
  • Acute exacerbation of chronic obstructive pulmonary disease
  • Acute infection (e. g. pneumonia, urosepsis, skin and soft tissue infections, infectious diarrhea)
  • Acute exacerbation of inflammatory/autoimmune diseases
  • Active malignancy
  • Immobility and prior VTE

 

Unless contraindicated, patients should receive prophylactic doses of unfractionated heparin, enoxaparin, or other approved drugs. Mechanical VTE prophylaxis should be used only when the risk of bleeding is considered unacceptably high or when there are drug intolerances or adverse effects.

The need for VTE prophylaxis should be reassessed regularly taking into account patient’s overall health status, mobility, drug tolerance and goals of care.

 

References

  1. Pai M, Douketis JD. Preventing venous thromboembolism in long-term care residents: Cautious advice based on limited data. Cleveland Clin J Med 2010;77: 123-130
  2. Robinson Am. Venous thromboembolism prophylaxis for chronically immobilized long-term care residents. Ann Long-Term Care 2013;10:30.
My bed-bound, debilitated patient is being transferred to a long-term facility (LTF). Should I continue the venous thromboembolism (VTE) prophylaxis she has been receiving in the hospital?

How do I interpret serum ammonia levels in hospitalized patients with altered mental status?

The primary source of ammonia in the blood is the intestine, where bacterial break down of urea leads to ammonia which is converted back to urea by the liver before it is excreted by the kidneys and colon. Besides hepatic dysfunction and inborn errors of metabolism, portosystemic shunts, urinary diversion, parenteral nutrition, multiple myeloma, distal renal tubular acidosis, drugs (e.g. sodium valproate), and convulsive seizures may also be associated with elevated serum ammonia levels (1).

In end-stage liver disease (ESLD), elevated serum ammonia level is neither very sensitive nor specific for the presence or the degree of hepatic encephalopathy (HE). In fact, over 2/3 of patients with ESLD without encephalopathy may have elevated serum ammonia levels (2).

In contrast, in patients with acute liver failure, an elevated serum ammonia level may be of prognostic value, with arterial ammonia levels >200 ug/dL associated with cerebral herniation in such patients (2).

In patients without suspected liver disease, measuring serum ammonia levels as part of a broader workup for mental status changes is reasonable, but just as in patients with ESLD, hyperammonia-related altered mental status should remain a diagnosis of exclusion.

 

References

  1. Hawkes ND, Thomas GAO, Jurewicz A, et al. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J 2001;77:717-722.
  2. Elgouhari HM, O’Shea R. What is the utility of measuring the serum ammonia level in patients with altered mental status? Cleveland Clin J Med 2009;76: 252-4.
How do I interpret serum ammonia levels in hospitalized patients with altered mental status?

Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?

Although the sooner NAIs are initiated the more likely the odds of a favorable impact on the course of influenza, the FDA approval of these drugs was based on study in relatively healthy ambulatory patients not those who require hospitalization and are generally much sicker. There are no randomized studies but several observational studies support  the benefit of NAIs even when initiated after 48 h of onset of the disease.  One study reported improvement in survival even when treatment was delayed for 4-5 days after symptom onset (1), while others have reported more rapid viral clearance and clinical benefit in severe infections even when antivirals were initiated after 48 h (2).  

Collectively , these data suggest that in the presence of ongoing symptoms and likely active viral replication, NAI treatment should be seriously considered in hospitalized patients who are likely to have more severe disease. CDC recommends  “initiation of antiviral treatment as early as possible” in hospitalized patients, and states that “antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until >48 hours after onset of illness.” (3)  

 

References

  1. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1) pdm09. Clin Infect Dis 2012;44:1198-1204.
  2. Lee N, Ison MG. “Late” treatment with neuraminidase inhibitors for severely ill patients with influenza: better late than never?
  3. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR 2011;60 (RR01):1-24.
Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?