Article

Adjusting D-dimer cutoffs: Brief literature summary and issues in clinical use

D-dimer cutoffs: Brief literat”>Correspondence / American Journal of Emergency Medicine 36 (2018) 21032128 2105

osteomyelitis more than SA, thus, it is questionable whether the 2 stud- ies should be included or not?

Fourthly, the retrieval strategy applied in the commented paper seems too simple, only two objective items (“Septic arthritis” and “procalcitonin”) were used as keywords and subject terms to search, ac- tually, “septic arthritis” was not very accurate, the terms like “infectious arthritis”, “bacterial arthritides”, “bacterial arthritis”, “viral arthritis”, “bacterial arthritides”, “bacterial arthritis”, “suppurative arthritis”, which are synonyms or homonyms of “septic arthritis” and should be retrieved as well, thus, we are afraid that the commented meta- analysis is not comprehensive and may miss some studies and make the final results unreliable.

Fifthly, the authors of this commented paper conclude that PCT is

more valuable than C-reactive protein (CRP) for distinguishing SA from non-SA, however this conclusion may be too simple. As shown in the Table 1, there are 4 cut-offs of CRP existed (18 mg/l, 30 mg/l, 50 mg/l, 120 mg/l), and no concrete information on the test methods of CRP had been extracted from any included studies, are the chosen cut-offs the best cut-offs? perhaps not, for example, in the study by Hugle et al. [6], the cut-off of 118 mg/l of CRP was superior to the value of 50 mg/l due to a higher Youden index (defined by sensitivity

+ specificity -1), thus the cut-off of 118 mg/l should be chosen rather

than 50 mg/l.

At last, we appreciate Zhao et al. for their innovative and meaningful study, but the interpretation of their work should be cautious and further rigorous studies are still warranted.

Abbreviations

PCT procalcitonin

SA septic arthritis

CRP C-reactive protein

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of supporting data

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

YY was supported by a grant from Guangdong Provincial Depart- ment of Science and Technology (Grant number: 2015A020210093). The funding sources had no role in the preparation, drafting, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Acknowledgements

None.

Simeng Wu

Chengdu University of Traditional Chinese Medicine, Chengdu 610075,

China

Xianshi Zhou*

Ye Ye

Emergency Department, Guangdong Provincial Hospital of Chinese

Medicine, Guangzhou 510120, China

*Corresponding author at: Department of Emergency, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Yuexiu District,

Guangzhou 510120, China.

E-mail address: [email protected].

https://doi.org/10.1016/j.ajem.2018.03.024

References

  1. Zhao J, Zhang S, Zhang L, et al. serum procalcitonin levels as a diagnostic marker for septic arthritis: a meta-analysis. Am J Emerg Med 2017 Aug;35(8):1166-71. https:// doi.org/10.1016/j.ajem.2017.06.014 (PMID:28623003).
  2. Butbul-Aviel Y, Koren A, Halevy R, Sakran W. Procalcitonin as a diagnostic aid in oste- omyelitis and septic arthritis. Pediatr Emerg Care 2005 Dec;21(12):828-32. https:// doi.org/10.1097/01.pec.0000190226.12610.24 (PMID:16340758).
  3. Maharajan K, Patro DK, Menon J, et al. Serum Procalcitonin is a sensitive and specific marker in the diagnosis of septic arthritis and acute osteomyelitis. J Orthop Surg Res 2013 Jul 4;8:19. https://doi.org/10.1186/1749-799X-8-19 (PMID:23826894).
  4. Wang C, Zhong D, Liao Q, Kong L, Liu A, Xiao H. Procalcitonin levels in fresh serum and fresh synovial fluid for the differential diagnosis of knee septic arthritis from rheuma- toid arthritis, osteoarthritis and gouty arthritis. Exp Ther Med 2014 Oct;8(4): 1075-80. https://doi.org/10.3892/etm.2014.1870 (PMID:25187799).
  5. Hassan AS, Rao A, Manadan AM, Block JA. Peripheral bacterial septic arthritis: review of diagnosis and management. J Clin Rheumatol 2017 Dec;23(8):435-42. https://doi. org/10.1097/RHU.0000000000000588 (PMID:28926460).
  6. Hugle T, Schuetz P, Mueller B, et al. Serum procalcitonin for discrimination between septic and non-septic arthritis. Clin Exp Rheumatol 2008 May-Jun;26(3):453-6 https://www.ncbi.nlm.nih.gov/pubmed/18578968 (PMID:18578968).

    Adjusting D-dimer cutoffs: Brief literature summary and issues in clinical use

    Elevated D-dimer levels in patients presenting with pulmonary em- bolism (PE) were first reported in 1988 [1,2] and were subsequently in- corporated into Diagnostic strategies in evaluation of patients with potential PEs [3]. To decrease D-dimer testing, the PE rule-out criteria (PERC) were developed to exclude PE in patients younger than 50 who meet a set of low risk criteria [4]. In older patients or those not meeting low risk criteria, D-dimer testing remains part of risk stratifica- tion [5]. Using a cutoff of 500 ug/L, D-dimer has a high sensitivity (~95%) and a low specificity (~50%) for PE. Adjusting the cutoff for age and for pretest probability improves specificity without increasing the rate of false negative results. We offer a brief review of these strategies and offer some issues to consider when using adjusted cutoffs in practice.

    D-dimer levels increase with age (and also with trauma, surgery, in- fection, cancer). Above age 65, only 40% of patients have D-dimer levels below 500 ug/L [6]. In 2010, Douma et al. presented data that using an age-adjusted cutoff could decrease the number of patients needing pul- monary angiography with little change in sensitivity [7]. The cutoff of age x 10 in patients N50 years old increased the number of patients with a “negative” D-dimer by about 5% while maintaining a statistically equivalent False negative rate of 0.2%-0.3%. Since, multiple retrospective studies, several meta-analyses, and a prospective observational study of over 11,000 patients produced similar results [8-20]. The ADJUST-PE study prospectively demonstrated that using age-adjusted cutoffs with either the Revised Geneva or Wells score decreases the need for CTPA without an increase in missed PEs [21]. Of 2898 patients older than 50 who were low risk by Clinical scores, an additional 337 had D- dimer levels below the age-adjusted cutoff. Only one patient in the

    2106 Correspondence / American Journal of Emergency Medicine 36 (2018) 21032128

    age-adjusted group had a nonfatal PE in the 3 month follow up period. The American College of Physicians (ACP) issued a guideline supporting the use of age-adjusted cutoff [22] and an updated American College of Emergency Physicians (ACEP) clinical policy is currently under review. Kline et al. [23] suggested doubling the threshold (to 1000 ug/L) for patients under age 50 deemed low risk for PE. Retrospectively, this cut- off would have resulted in 98 less pulmonary angiograms on 678 patients. When compared to age-adjusted D-dimer and conventional cutoffs, using a risk-adjusted cutoff decreased the number of CTPAs by approximately 5% with no difference in negative predictive value between approaches [24- 26]. The YEARS study implemented a three question algorithm to stratify patients to either conventional or risk-adjusted cutoff [27]. If there is no sign of a DVT, no hemoptysis, and DVT is not the most likely diagnosis, a pa- tient was stratified to the higher (1000 ug/L) D-dimer cutoff. Utilizing this strategy, the authors report a significant reduction (14%) in the use of

    CTPA while maintaining an equivalent sensitivity and false negative rate.

    A recent article pointed out several issues for clinicians to keep in mind if using an adjusted cutoff, including a lack of Standardized reporting, lim- itations of available clinical studies, and lack of standard procedures for adopting age-adjusted cutoff [28]. To expand, D-dimer concentration is reported in either D-dimer Units (DDU) or Fibrinogen Equivalent Units , the difference based on the molecular structure of fibrin cross- links. The commonly used cutoff of 500 ug/L is reported in FEUs. DDUs can be converted by a factor of 1.8 based on molecular weight [29,30]. As an example, our institution uses an assay manufactured by Instrument Laboratories with a cutoff of 231 ng/mL, reported in D-dimer Units. Some data in the ADJUST-PE study was obtained with an assay from the same manufacturer, but includes only 185 patients and uses a cutoff of 500 ug/L. FEU/DDU ratios are not available in the text of the article.

    Either ELISA or immunoturbidometric assays are used to determine D-dimer concentration. Several different tests are commercially avail- able with different calibration and control recommendations. The corre- lation between different tests and laboratories can be fairly low [31], as demonstrated by Mullier et al. in which the authors report levels from a single patient’s plasma sample of 659, 590, 789, 1170, and 719 ng/mL from 5 different tests [32]. We could not find data from the manufac- turer of our institution’s test regarding recommendations or validity of age-adjusted cutoffs.

    In summary, multiple studies have demonstrated that the use of both age-adjusted and risk-adjusted cutoffs in combination with risk stratification tools can decrease the use of advanced imaging without an increase in missed PEs. Adjusting for risk may prove a more accurate strategy based on data from the YEARS study. Several issues exist with standardization of laboratory tests and unit reporting, which should be kept in mind but do not preclude the in- corporation of adjusted D-dimer cutoffs as part of a strategy to iden- tify patients at low risk for PE.

    Robert Solberg, MD, MS George Glass, MD?

    University of Virginia Health System, Department of Emergency Medicine,

    P.O. Box 800699, Charlottesville, VA 22908-0699, United States

    ?Corresponding author. E-mail address: [email protected] (R. Solberg), [email protected] (G. Glass).

    18 October 2017

    https://doi.org/10.1016/j.ajem.2018.03.027

    References

    Goldhaber SZ, Vaughan DE, Tumeh SS, Loscalzo J. Utility of cross-linked fibrin degrada- tion products in the diagnosis of pulmonary embolism. Am Heart J 1988 Aug;116:505-8.

  7. Bounameaux H, Slosman D, de Moerloose P, Reber G. Diagnostic value of plasma Ddimer in suspected pulmonary embolism. Lancet 1988 Sep 10;2(8611):628-9.
  8. Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000 Mar;83(3):416-20.
  9. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to pre- vent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost 2004 Aug;2(8):1247-55.
  10. Fesmire FM, Brown MD, Espinosa JA, Shih RD, Silvers SM, Wolf SJ, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med 2011 Jun;57 (6):628-652.e75.
  11. Sohne M, Kamphuisen PW, van Mierlo PJ, Buller HR. Diagnostic strategy using a modified clinical decision rule and D-dimer test to rule out pulmonary embolism in elderly in- and outpatients. Thromb Haemost 2005;94:206-10.
  12. Douma RA, le Gal G, Sohne M, Righini M, Kamphuisen PW, Perrier A, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary em- bolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010 Mar 30;340:c1475.
  13. van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost 2012 Jan;107(1):167-71.
  14. Leng O, Sitaraaman HB. Application of age-adjusted D-dimer threshold for exclusion thromboembolism (PTE) in older patients: a retrospective study. JACME 2012;11 (3):129-32.
  15. Verma N, Willeke P, Bicsan P, Lebiedz P, Pavenstadt H, Kumpers P. Age-adjusted Ddimer cut-offs to diagnose Thromboembolic events: validation in an emergency department. Med Klin Intensivmed Notfmed 2014 Mar;109(2):121-8.
  16. Sharp AL, Vinson DR, Alamshaw F, Handler J, Gould MK. An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications. Ann Emerg Med 2016 Feb;67(2):249-57.
  17. Han C, Zhao Y, Cheng W, Yang J, Yuan J, Zheng Y, et al. The performance of age-ad- justed D-dimer cut-off in Chinese outpatients with suspected venous thromboem- bolism. Thromb Res 2015 Oct;136(4):739-43.
  18. Flores J, Garcia de Tena J, Galipienzo J, Garcia-Avello A, Perez-Rodriguez E, Tortuero JI, et al. clinical usefulness and safety of an age-adjusted Ddimer cutoff levels to ex- clude pulmonary embolism: a retrospective analysis. Intern Emerg Med 2016 Feb;11 (1):69-75.
  19. Nobes J, Messow CM, Khan M, Hrobar P, Isles C. Age-adjusted D-dimer excludes pul- monary embolism and reduces unnecessary radiation exposure in older adults: ret- rospective study. Postgrad Med J 2017 Jul;93(1101):420-4.
  20. Jaconelli T, Eragat M, Crane S. Can an age-adjusted D-dimer level be adopted in man- aging venous thromboembolism in the emergency department? A retrospective co- hort study. Eur J Emerg Med 2017 Jan:10.
  21. Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA, et al. Diagnos- tic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ 2013 May 3;346:f2492.
  22. Adams D, Welch JL, Kline JA. Clinical utility of an age-adjusted D-dimer in the diag- nosis of venous thromboembolism. Ann Emerg Med 2014 Sep;64(3):232-4.
  23. Gallus A. Simplified and original wells rules plus age-adjusted D-dimer test were useful for ruling out suspected PE. Ann Intern Med 2017 Jun 20;166(12):JC71.
  24. Woller SC, Stevens SM, Adams DM, Evans RS, Lloyd JF, Snow GL, et al. Assessment of the safety and efficiency of using an age-adjusted D-dimer threshold to exclude suspected pulmonary embolism. Chest 2014 Dec;146(6):1444-51.
  25. Penaloza A, Roy PM, Kline J, Verschuren F, LE Gal G, Quentin-Georget S, et al. Perfor- mance of age-adjusted D-dimer cut-off to rule out pulmonary embolism. J Thromb Haemost 2012 Jul;10(7):1291-6.
  26. Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, et al. Age-ad- justed D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014 Mar 19;311(11):1117-24.
  27. Raja, et al, Clinical Guidelines Committee of the American College of Physicians. Eval- uation of patients with suspected acute pulmonary embolism: best practice advice from the clinical guidelines. Committee of the American College of Physicians. Ann Intern Med 2015;163:701-11.
  28. Kline JA, Hogg MM, Courtne DM, Miller CD, Jones AE, Smithline HA. D-dimer thresh- old increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary Computerized tomographic pulmonary angiography. J Thromb Haemost 2012 Apr;10(4):572-81.
  29. Takach Lapner S, Julian JA, Linkins LA, Bates S, Kearon C. Comparison of clinical prob- ability-adjusted D-dimer and age-adjusted D-dimer interpretation to exclude ve- nous thromboembolism. Thromb Haemost 2017 Aug 3;117(10).
  30. Kohn MA, Klok FA, van Es N. D-dimer interval likelihood ratios for pulmonary embo- lism. Acad Emerg Med 2017;24(7):832-7.
  31. Char S, Yoon HC. Improving appropriate use of pulmonary computed tomography angiography by increasing the serum D-dimer threshold and assessing clinical prob- ability. Perm J 2014;18(4):10-5.
  32. van der Hulle T, Cheung WY, Kooij S, et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, co- hort study. Lancet 2017 Jul 15;390(10091):289-97.
  33. Goodwin AJ, Higgins RA, Moser KA, Smock KJ, Chandler WL, Kottke-Marchant K, et al. Issues surrounding age-adjusted D-dimer cutoffs that practicing physicians need to know when evaluating patients with suspected pulmonary embolism. Ann Intern Med 2017 Mar 7;166(5):361-3.
  34. Riley RS, Gilbert AR, Dalton JB, Pai S, McPherson RA. Widely used types and clinical applications of D-dimer assay. Lab Med 2016 May;47(2):90-102.

    Correspondence / American Journal of Emergency Medicine 36 (2018) 21032128

    Olson JD. D-dimer: an overview of hemostasis and fibrinolysis, assays, and clinical

    2107

    Talha Sarigoz

    applications. Adv Clin Chem 2015;69:1-46.

    Olson JD, Cunningham MT, Higgins RA, Eby CS, Brandt JT. D-dimer: simple test, tough problems. Arch Pathol Lab Med 2013;137(8):1030-8.

  35. Mullier F, Vanpee D, Jamart J, Dubuc E, Bailly N, Douxfils J, et al. Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of ve- nous thromboembolism in emergency department. Blood Coagul Fibrinolysis 2014 Jun;25(4):309-15.

    The use of computed tomography tractography in anterior abdominal Stab wounds

    Dear Editor,

    Clinical approach to penetrating abdominal trauma has changed considerably over the years. With the aid of new diagnostic tech- niques, reduced number of negative laparotomies and shortened du- ration of hospital stay were reported. In the same group of patients, role of computed tomography tractography has been the topic of recent debate. In this regard, we read the article “Is computed to- mography tractography reliable in patients with anterior abdominal stab wounds?” published in your journal with great interest and we want to share our opinions on this subject [1]. Despite quite impres- sive study results, we have thought several points need clarification before disapproving CT tractography in anterior abdominal Stab wounds.

    local wound exploration (LWE) is an effective method in evaluat- ing the peritoneal penetration but the method has some limitations especially for patients with obesity or heavy muscle. And also it is difficult to explore the oblique wound tracts. The mean body mass index of the related study was 25.2 +- 4.9, and this might be the rea- son why LWE was so successful. Theoretically tractography may have a better role in obese patients rather than LWE but the litera- ture lacks research in this setting [2,3]. Also, we are wondering why the authors applied all 3 methods -LWE, CT, and CT tractography- in the LWE positive patients. Their method puts pa- tient at risk for excessive radiation and additional trauma. In the work of Ertan et al., all patients were evaluated by CT tractography and they pointed out that this procedure helped abstain from LWE [4]. In a later study, again highly successful results were reported for CT tractography in determination of peritoneal violation [5]. Also performing LWE in prior to tractography may have disrupted trajectory and can be blamed for final results, and we are wondering the authors’ opinion about this subject. Furthermore, the main pur- pose of a CT tractography in patients with anterior stab wound should be to differ cases that need surgical exploration from can be followed as outpatient and treated with simple intervention. But the authors preferred to hospitalize patients with negative perito- neal penetration. We think this is not cost-effective, and need to know the rationale for their preference.

    Finally, due to technical variety and lack of randomized study, it is too early to make a judgment on CT tractography. We believe continued pursuit of research will clarify appropriate approach to this group of patients.

    Financial disclosure

    We declare that this study has received no financial support.

    Conflict of interest disclosure

    We declare that we do not have any commercial or associative inter- est that represents a conflict of interest in connection with the work submitted.

    Batman Sason State Hospital, General Surgery, Batman, Turkey

    Corresponding author at: Asagi Mahalle, Eski Tekel Caddesi, Sason

    Devlet Hastanesi, 72500 Batman, Turkey.

    E-mail address: [email protected].

    Yusuf Sevim Ankara Numune Training and Research Hospital, Department of General Surgery, Division of Colorectal Surgery, Ankara, Turkey

    9 March 2018

    https://doi.org/10.1016/j.ajem.2018.03.028

    References

    Sarici IS, Kalayci MU. Is computed tomography tractography reliable in patients with anterior abdominal stab wounds? Am J Emerg Med 2018. https://doi.org/10.1016/j. ajem.2017.12.065 [in press].

  36. Henneman PL. Penetrating abdominal trauma. Emerg Med Clin North Am 1989;7(3): 647-66.
  37. Tsikitis V, Biffl WL, Majercik S, Harrington DT, Cioffi WG. Selective clinical manage- ment of anterior abdominal stab wounds. Am J Surg 2004;188(6):807-12.
  38. Ertan T, Sevim Y, Sarigoz T, Topuz O, Tastan B. Benefits of CT tractography in evalua- tion of anterior abdominal stab wounds. Am J Emerg Med 2015;33(9):1188-90.
  39. Uzunosmanoglu H, Corbacioglu SK, Cevik Y, Akinci E, Hacifazlioglu C, Yavuz A, et al. What is the diagnostic value of computed tomography tractography in patients with abdominal stab wounds? Eur J Trauma Emerg Surg 2017;43(2):273-7.

    Is computed tomography tractography reliable in patients with anterior abdominal stab wounds?

    Dear Editor,

    Penetrating traumas are still common traumas encountered in trauma and emergency departments. Determination peritoneal violation is to be done first with local wound exploration in cases of anterior abdomi- nal stab wounds [1]. According to the current literature and guidelines recommendations, local wound exploration is the method with the highest accuracy to determine peritoneal violation [1,2]. Advances in ra- diologic imaging have shown that high-resolution CTs and CT tractography in the recent period are used for the evaluation of these patients and this imaging is preferred by Emergency doctors. In our study protocol, tomography performed a low-dose radiation even lower than the dosing routinely the patient received. The maximum dose that an adult person can receive per year is 0.1 Sv. We calculate our computed tomography scan protocol with the effective dose esti- mate for abdominal tomography (dose-length product (251 mGy-cm)

    * k (0.015): 3.7 mSV).

    CT tractography is reported in two ways that peritoneal violation positive or negative. In the presence of positive peritoneal penetration, the emergency physician consults the patient to general surgeon. How- ever, there are different situations that need to be addressed by the gen- eral surgeon, who responsible the patient after this stage. Are there any intraabdominal Organ injuries in the patient? Should the patient followed conservatively or surgery be performed? The surgeon will have to give the decision to do it. As it is known, 55% of the positive peri- toneal violation with anterior abdominal stab wounds doesn’t cause organ injury [1,2]. How the CT tractography may affect the surgeon in making these decisions at this stage is discussed in detail in the last two paragraphs in the Discussion section and in Table 5 of the article [5]. The second result of CT tractography is negative peritoneal violation. What should be done when peritoneal penetration is not detected? Can we discharge the patient safely when CT tractography is negative? There are two papers on CT tractography in anterior abdominal stab wounds patients. In the study performed by Ertan et al., 20 patients

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