Monday, June 23, 2014

Dip the Tap? - Diagnosis of Spontaneous Bacterial Peritonitis at the Bedside

The Gist:  Study results of urine reagent strips for the bedside diagnosis of spontaneous bacterial peritonitis (SBP) are highly variable with sensitivities from 45-100%.  Some suggest that certain dipsticks, if at least Grade 3 positive, have a great positive predictive value and positive likelihood ratio; thus, initiating treatment for SBP is likely a good idea.  A negative result, however, cannot rule out SBP, and this test is subject to limitations such as which reagent strip one has, what qualifies as "positive," and the prevalence of SBP at that location.  Suspect SBP or sick patient? Give antibiotics.

Why the enthusiasm in the Emergency Department (ED)?
A bedside test for diagnosis of SBP is neat and could potentially help identify an infective source earlier than standard laboratory tests (ascitic fluid cell count of >1000 WBCs or >250 polymorphonuclear neutrophils (PMNs) [1].  This laboratory endeavor takes time and reagent test strips commonly referred to as "urine dipsticks" have surfaced as a candidate.  Some studies cite a time "savings" of 2-3 hours using these strips as one may start targeted antibiotics after the bedside test [6].  In an era of source control and "time to antibiotics" measures in sepsis, early diagnosis of SBP has potential benefit.
Photo: Nottingham Vet School
Typical reagent strips, like the one above, demonstrate different grades of positivity, indicated by the color of the individual block.  Here, the leukocytes are indicated by the box on the far left of the image in which presence of leukocytes is quantified by reaction via leukocyte esterase.  These are read at the bedside after a certain period of time elapses (often 1-2 minutes), either by a person or machine. The pictured stick has a negative (off white), Grade 1 (slightly less off white), Grade 2 (lavender), Grade 3 (darker lavender/purple).

One important lesson that Free Open Access Medical education (FOAM) has hammered home, however, is the importance of understanding how to use a test prior to adoption.  On a recent episode of FOAMcast, we discovered that the core text, Rosen's Emergency Medicine references the positive correlation between SBP and a "positive" dipstick [1].  Unfortunately, the text doesn't go into how specifically to use the test or limitations, which could potentially lead to misapplication.  As an excited resident, I might opt to test this trick of the trade out without investigating exactly how it could or should change my practice. Furthermore, major societies currently recommend against the use of these test strips [2,3].

The Early Literature Hype
The initial studies were promising and cited sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Values (NPV) of 100% [4].  These studies also had relatively small numbers (n=31-257) and were conducted in a variety of settings with limited ED patients [4].  A positive test, in the majority of studies, was any result other than negative.  Some authors, including Gaya et al, called for the ability to rule out SBP based on a negative dipstick (Multistix 10SG) [5].

The Shifting Tide:  The many studies that subsequently followed had varied results and few were conducted in the Emergency Department (ED).  These studies used a variety of strips (Multistix - most commonly tested, Nephur, Combur, Uriscan, Aution Combina, and Choiceline) and demonstrated widely variable predictive scores with sensitivities of approximately 65% in nearly half of the studies and one study with a sensitivity of merely ~45%.  The specificity in these studies, however, remained quite high at >90% [4].  This literature is summarized nicely in a meta-analysis by Nguyen-Khac et al.
  • Multistix (n=12 studies): Sensitivities ranged from 45.3-100%, with higher sensitivities when a lower grade was used as "positive" (64.7-100%) [4].
A more recent study that was not included in this analysis posed a head-to-head ED based comparison between Uri-Quick Clini 10SG and MultistixSG10 in a population with a relative high incidence of SBP - 21.9% (49/223 samples).  Both strips had comparable specificities in the ~98% range.  This study more accurately depicts the way in which one might use reagent test strips, the importance of understanding which strip one has access to and its test characteristics, and the authors emphasize that the test does not rule out or replace the cell count [7].
  • Uri-Quick Clini 10SG Sensitivity 79.6% (64-87); + LR 33.7 (13-90); - LR 0.22 (0.13-0.38)
  • MultistixSG10: Sensitivity 77.5% (64-88%); + LR 33.6 (12.66-89.91); -LR 0.23 (0.14-0.39)
Why the variation?
  • Strips calibrated for urine so they don't match up to the PMN threshold for SBP.  As a result, what qualifies as a "positive" test varies - some studies used any level of positivity as "positive" and some specified a particular "Grade." 
  • Reading times of reagent strips varies and may impact results.
  • Different types of strips - the matrix and enzymes in strips varies based on manufacturer which may affect performance.  The strips used (ex: Aution sticks with high sensitivity) are not universally available [4,7].
  • Subjective interpretation of strips - This is a potential problem; however, the interrater reliability (kappa) was 0.8-0.94 (excellent!) in the studies in which it was calculated [6,7].  This is also dependent on whether the stick is read by a human or a machine (spectrophotometry).  
  • Varying prevalence of SBP in studied population (7-20%) [4,6].
What Now?
  • A 2012 study out of Mexico by Uribe et al demonstrates the utility of reagent strip testing as a rapid rule in diagnosis for SBP in low resource settings, with the caution that it is not a "rule out" test [7].  
  • SBP is associated with great mortality indicative of a very sick population, with an estimated survival after a patient's first episode of 68.1% at 1 month and 30.8% at 6 months [8].  As a result, it's probably best to suspect SBP in any sick cirrhotic, understand the limitations of the clinical exam, and administer antibiotics early in these patients.  Even if these patients get a non-targeted dose of piperacillin-tazobactam, this antibiotic still covers most SBP (although agents of choice are typically cefotaxime 2 grams IV Q4-8 hours or ceftriaxone 2 grams IV Q24 hours) [8].
  • Look for use of reagent strips at the bedside in the future for SBP but, like any test, understand the variability, the limitations, and the ways that the test is usable in one's own ED. 
References
1.  Oyama L.  Chapter 90:  Disorders of the Liver and Biliary Tract.  Rosen's Emergency Medicine, 8e (2014).  pp 1186-1204.
2.  European Association for the Study of the Liver.  EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417.
3.  Runyon BA.  Management of Adult Patients with Ascites  Due to Cirrhosis: Update 2012.  (2013) doi: 10.1002/hep.00000
4.  Nguyen-Khac E1, Cadranel JF, Thevenot T, Nousbaum JB. Review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients. Aliment Pharmacol Ther. 2008 Aug 1;28(3):282-8.
5. Gaya Dr, Lyon DB, Clarke J et al. Bedside leucocyte esterase reagent strips with spectrophotometric analysis to rapidly exclude spontaneous bacterial peritonitis: a pilot study. Eur J Gastroenterol Hepatol. 2007 Apr;19(4):289-95.
6.  Nousbaum JB, Cadranel JF, Nahon P, et al. Diagnostic accuracy of the Multistix? 8 SG reagent strip in diagnosis of spontaneous bacterial peritonitis. Hepatology 2007; 45: 1275–81.
7.  Uribe M, Vargas-vorackova F. Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in Emergency. 2012;11(5):696–699.
8.  O’Mara SR, Gebreyes K.  Chapter 83. Hpeatic Disorders, Jaundice, and Hepatic Failure. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. p 566-574

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