Implementing capnography for lactate- enhanced qSOFA scores: Sepsis diagnosis in the EMS setting

CRITICAL REVIEW

Implementing capnography for lactate-enhanced qSOFA scores: Sepsis diagnosis in EMS settings

ABSTRACT Sepsis is a life-threatening condition that occurs when the body produces a pro-inflammatory immune response to infection, leading to a decrease in blood flow that results in organ failure and death. Sepsis has the ability to kill within hours, and is responsible for 20% of deaths globally. However, current diagnostic techniques in the pre-hospital setting are limited by time and resources. It has recently been found that sepsis screening tools like qSOFA and lactate biomarkers used within the hospital could supplement diagnostic needs within the EMS setting. With research showing that lactate levels can be indirectly and instantaneously measured via capnography by EMS personnel, this technique may complement existing sepsis screening tools to achieve faster diagnosis. This article investigates the current flaws of sepsis diagnosis within the EMS setting and evaluates the benefits of the implementation of qSOFA and lactate technology.

INTRODUCTION There is inadequate emphasis on the importance of early sepsis diagnosis in the medical community. Defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection,” sepsis is responsible for almost 20% of deaths globally.1, 2 Current treatment effectiveness for sepsis depends heavily on how quickly treatment is initiated: broad-spectrum antibiotics should be administered within the first hour of diagnosis, followed by intravenous fluids within three hours, then the use of vasopressors to increase blood pressure.3

Given that patient survival depends on timely treatment, it is crucial for healthcare workers in the pre-hospital setting to detect sepsis prior to arrival at the emergency department (ED). Approximately 8–10% of patients who have an infection are diagnosed with sepsis by emergency medical services (EMS), yet approximately 50% of sepsis patients at the ED arrive via EMS, emphasizing the need for enhanced sepsis screening tools.4 Bayer et al. state that given the lack of sepsis-specific biomarkers, a practical scoring system could potentially improve patient outcomes.5 Although currently being used outside of the EMS setting, recent studies suggest that the quick Sequential Organ Failure Assessment (qSOFA) test and lactate markers can potentially improve sepsis detection rates.3 This article examines the shortcomings in current pre-hospital sepsis diagnostic methods and explores how qSOFA and lactate detection technologies may be used to promote early sepsis identification by EMS providers.

EXISTING SEPSIS SCREENING TOOLS The use of sepsis screening tools has been strongly advocated for by researchers and clinicians in the pre-hospital setting, with the goal of earlier initiation of fluid resuscitation and antibiotic administration. A variety of EMS screening tools have been proposed to date, but due to the lack of a Canadian EMS regulatory body, no standardized sepsis protocol exists. Rather, regional EMS centres design their operating procedures in collaboration with medical authorities at the provincial and federal levels.

While there lacks research on pre-hospital sepsis diagnosis, extensive research exists on the efficacy of existing inhospital screening tools. The main sepsis diagnostic tools include, Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), and qSOFA, with their specific criteria described in Table 1.6

LACTATE DETECTION IN SEPSIS DIAGNOSIS In recent years, a novel method of pre-hospital sepsis screening has been introduced that uses serum lactate levels to improve sepsis identification.17 Lactate is produced by hypoxic cells and tissues as a byproduct of anaerobic metabolism. Generally, lactate levels are tested in a hospital setting via blood sampling, whereby high concentrations of lactate are suggestive of sepsis. The biological system behind the correlation between sepsis and lactate levels is still unclear, but scientists suspect they are linked through four main mechanisms: (1) sepsis causes tissue hypoperfusion, resulting in an increase of anaerobic cell respiration and consequently elevated lactate levels;18 (2) cases of sepsis may result in liver and kidney dysfunction, resulting in lowered lactate clearance;17 (3) sepsis releases endogenous epinephrine, stimulating beta-2 receptors in skeletal muscle cells which promote the upregulation of glycolysis, generating excess pyruvate which is converted to lactate;19 and (4) tissue hypoperfusion from sepsis may lead to mitochondrial dysfunction, resulting in an upregulation of non-mitochondrial energy production.20

Septic shock, being the most severe stage of sepsis, has been clinically noted to occur under two conditions: when hypotension is sustained even after fluid resuscitation, and when serum lactate levels are above 2 mmol/L.17 This claim is also supported by Shankar-Hari et al., who have also found that the combination of lactate levels above 2 mmol/L and low blood pressure may be a marker for sepsis.1 As a result, the lactate-enhanced qSOFA score (LqSOFA) has been developed as a novel in-hospital screening tool calculated by adding an additional point to qSOFA in patients who meet the lactate threshold above 2 mmol/L. LqSOFA has demonstrated better performance than SIRS, SOFA, and qSOFA prognostic tools, and increased qSOFA’s sensitivity from 47.6% to 65.5%.21-23

Currently, lactate testing is widely used in the hospital setting as laboratory testing is required to analyze the blood samples. However, a capnography test conducted by EMS personnel can also provide an indirect, but accurate measure of lactate levels. Capnography devices in ambulances can measure a patient’s end-tidal carbon dioxide (etCO2) levels —the amount of carbon dioxide released at the end of an exhaled breath.24 This functions on the basis that when glucose and oxygen are metabolized, carbon dioxide is diffused from

1. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Sepsis Definitions Task Force. Developing a new definition and assessing new clinical criteria for septic shock: For the third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):775-87. Available from: doi:10.1001/jama.2016.0289. 2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-11. Available from: doi:10.1016/S0140-6736(19)32989-7. 3. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock. Crit Care Med. 2016;43(3):304-77. Available from: doi:10.1007/s00134-017-4683-6. 4. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: A systematic review. BMJ Open. 2016;6(8). Available from: doi:10.1136/bmjopen-2016-011218. 5. Bayer O, Schwarzkopf D, Stumme C, Stacke A, Hartog CS, Hohenstein C, et al. An early warning scoring system to identify septic patients in the prehospital setting: The PRESEP score. Acad Emerg Med. 2015;22(7):868–71. Available from: doi:10.1111/acem.12707. 6. Koch C, Edinger F, Fischer T, Brenck F, Hecker A, Katzer C, et al. Comparison of qSOFA score, SOFA score, and SIRS criteria for the prediction of infection and mortality among surgical intermediate and intensive care patients. World J Emerg Surg. 2020;15(63). Available from: doi:10.1186/s13017-020-00343-y. 7. Chakraborty RK, Burns B. Systemic Inflammatory Response Syndrome. StatPearls Publishing; 2020. Available from https://www.ncbi. nlm.nih.gov/books/NBK547669/ [cited 2021 Jan 21]. 8. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-38. Available from: doi:10.1056/NEJMoa1415236. 9. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of clinical criteria for sepsis: For the third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):762-74. Available from: doi:10.1001/jama.2016.0288. 10. Kovach CP, Fletcher GS, Rudd KE, Grant RM, Carlbom DJ. Comparative prognostic accuracy of sepsis scores for hospital mortality in adults with suspected infection in non-ICU and ICU at an academic public hospital. PLoS One. 2019;14(9). Available from: doi:10.1371/ journal.pone.0222563. 11. Peng Y, Zhang W, Xu Y, Li L, Yu W, Zeng J, et al. Performance of SOFA, qSOFA and SIRS to predict septic shock after percutaneous nephrolithotomy. World J Urol. 2020. Available from: doi:10.1007/s00345-020-03183-2. 12. Costa RT, Nassar AP Jr, Caruso P. Accuracy of SOFA, qSOFA, and SIRS scores for mortality in cancer patients admitted to an intensive care unit with suspected infection. J Crit Care. 2018;45:52-7. Available from: doi:10.1016/j. jcrc.2017.12.024. 13. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score—development, utility and challenges of accurate assessment in clinical trials. Critical Care. 2019;23(1):74. Available from: doi:10.1186/s13054-019-2663-7. 14. Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. French Society of Emergency Medicine Collaborators Group. Prognostic accuracy of Sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317(3):301-8. Available from: doi:10.1001/jama.2016.20329. 15. Jiang J, Yang J, Mei J, Jin Y, Lu Y. Head-tohead comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: A meta-analysis. Scand J Trauma Resusc Emerg Med. 2018;26(1). Available from: doi:10.1186/ s13049-018-0527-9. 16. Critical Care Summit. New sepsis definitions and qSOFA - Craig Coopersmith MD, FACS, FCCM. [Video] 2016. Available from https:// www.youtube.com/watch?v=3kNbW_T-vrA [cited 2021 Jan 21]. 17. Lee SM, An WS. New clinical criteria for septic shock: serum lactate level as new emerging vital sign. J Thorac Dis. 2016;8(7):1388-90. Available from: doi:10.21037/jtd.2016.05.55. 18. Foucher CD, Tubben RE. Lactic Acidosis. Florida: StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK470202/ [cited 2021 Jan 21]. 19. Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through β2 stimulation is a common mechanism involved in lactate formation during shock states. Shock. 2008;30(4):417-21. Available from: doi:10.1097/SHK.0b013e318167378f. cells and into the blood as waste products.25 Decreased blood flow from sepsis results in elevated levels of metabolic waste in the bloodstream.26 As such, etCO2 levels are inversely proportional to lactate levels.26 Hunter et al. developed a general guideline for EMS personnel to follow, showing that etCO2 levels below 25 mmHg are strongly correlated with serum lactate levels above 4 mmol/L.27 Wiryana et al. further validate these findings, demonstrating a strong correlation between etCO2 and lactate levels.28

DISCUSSION As the severity of sepsis is exacerbated by delayed treatment, its early recognition in the pre-hospital setting is paramount to increasing patient survival rates. Current EMS sepsis protocols lack standardization and result in poor recognition of sepsis among EMS teams. Thus, the implementation of a pre-hospital screening tool that is simple, accurate, and timeefficient is crucial to patient survival.

Through evaluating the existing systems in place for sepsis identification, it should be underscored that the speed of qSOFA tests can be complemented by the accuracy provided by lactate measurements, thus making it an ideal candidate for pre-hospital sepsis screening. The qSOFA tool is heavily criticized for its poor sensitivity; yet, when measured in combination with lactate as a biomarker, its performance is improved. Research consistently demonstrates that LqSOFA scores can predict in-hospital mortality more accurately than qSOFA, SOFA, and SIRS.29-31 As discussed previously, capnography may serve as a novel lactate measuring technology for EMS personnel: they produce results instantaneously, are already part of ambulance equipment, and require minimal additional training to be applied in a sepsis context. Integrating lactate testing via capnography into the qSOFA criteria may thus be ideal for prehospital paramedic use.

Some EMS centres have already adopted sepsis protocols measuring lactate via etCO2 readings. Sepsis Alert —an EMS protocol that has been introduced in Denver, Colorado— is nearly identical to qSOFA apart from the additional criterion of etCO2 levels less than or equal to 25 mmHg. When Sepsis Alert was initiated in Denver, the overall mortality for severe sepsis patients transported by EMS was nearly halved, from 26.7% to 13.6%.32 While LqSOFA tests may serve as a promising tool, it is essential that EMS centres reinforce training to improve sepsis detection rates.22 As EMS personnel treat patients in emergency situations, the identification of immediate injuries may be prioritized over the diagnosis of later-onset sepsis.33 Studies by Green et al. show that three-hour training sessions for EMS clinicians on identifying sepsis in patients increase early-diagnosis of sepsis in 40%–50% of emergency cases.32 However, the introduction of qSOFA and lactate technologies are more efficient to use and provide ambulatory clinicians with greater time and opportunity to identify sepsis. Hence, strengthening training on sepsis diagnosis, particularly the use of qSOFA and etCO2 technologies, may assist EMS personnel in improving the identification of sepsis.

Though current studies suggest that LqSOFA criteria may significantly improve rates of patient diagnosis, there are limitations to this proposal. Few studies have clinically tested the effectiveness of qSOFA paired with etCO2 levels. Research by Guerra et al. demonstrated that the Sepsis Alert protocol could reduce mortality for sepsis patients arriving via EMS. These benefits are challenged by Daniel J. Lane, who suggested that this hybrid criteria yields no significant improvements in sensitivity or specificity compared to qSOFA alone.30,34 Green et al. explains that different clinical settings may benefit from different technologies to varying extents. In summary, additional research needs to be conducted to assess the validity of using etCO2 measurements to enhance qSOFA screening.34

CONCLUSION Of existing in-hospital sepsis screening tools, qSOFA demonstrates the greatest potential for practical usage in an EMS setting. While qSOFA’s simplicity impacts its accuracy, the addition of a novel lactate biomarker may significantly improve test sensitivity. Research presents capnography devices as a promising alternative for existing lactate laboratory tests that, when used in combination with qSOFA and effective training, may improve early diagnosis of sepsis by EMS providers. Further research is needed to assess the accuracy of an LqSOFA score in a pre-hospital setting.

TABLE 1: Criteria for SIRS, qSOFA, and SOFA sepsis screening tests.7 There is a variety of screening tools used by healthcare professionals to identify septic patients in an inhospital setting. The criteria for SIRS, qSOFA, and SOFA are illustrated in the table below.

SIRS

Criteria for SIRS are met if at least two of four clinical findings are present. Presence of at least two out of three clinical criteria. Scores on a scale of zero to four are given for the following six systems based on the provided parameters.

Tachycardia:

Heart rate >90 beats/min qSOFA

Low blood pressure:

SBP ≤100 mmHg SOFA

Respiratory:

PO2/FiO2 mmHg

Tachypnea:

Respiratory rate >20 breaths/min

High respiratory rate:

≥22 breaths/min

Coagulation:

Platelets in 103/mm3

Fever/hypothermia:

Temperature >38 or <36 ºC

Altered mentation:

Glasgow coma scale <15

Liver:

Bilirubin in mg/dL

Leukocytosis, leukopenia, bandemia:

White blood cells >1,200/mm3 , <4,000/mm3 or bandemia ≥10%

Cardiovascular:

Mean Arterial Pressure (MAP) in mmHg and doses of dopamine, epinephrine, norepinephrine given in mcg/kg/min

Renal:

Creatinine in mg/dL

Neurological:

Glasgow coma score

SIRS is an exaggerated immune response to external stressors that characterizes sepsis when combined with suspected infection.7 Although still in use clinically, the SIRS criteria has been criticized for its inability to predict organ dysfunction.7,8 SOFA has since repeatedly outperformed SIRS in predicting mortality rates and length of stay in the intensive care unit (ICU), but is significantly more time-consuming due to the weighted scoring system and the greater number of tests required.9-13 These concerns led to the creation of qSOFA— a quicker and more sensitive iteration of SOFA and SIRS. The qSOFA tool has been recommended in the Sepsis-3 criteria for its simplicity and increased predictive validity.9,14 Jiang et al. conclude that a qSOFA score of two or higher is more accurate in predicting mortality than a SIRS score of two or more.15 Similarly, Koch et al. found that qSOFA predicts negative patient outcomes in 97.8% of positive cases, while SOFA is accurate in 26.7% of those outcomes.6 Despite the simplicity of the qSOFA criteria, it consistently performs well in settings outside the ICU.16

PEER REVIEWED BY: DR. GEORGE FARJOU

Dr. George Farjou is an infectious disease physician at Fraser Health Authority and Assistant Clinical Professor of Medicine in the Faculty of Health Sciences at McMaster University. Aside from Farjou’s clinical work, his research has involved analytical surveys on evidence-based medical textbooks, as well as examining the role of community hospitals in trials of treatments for COVID-19.

EDITED BY: SHADI SADEGHIAN & SHANZEY ALI

20. Ruggieri AJ, Levy RJ, Deutschman CS. Mitochondrial dysfunction and resuscitation in sepsis. Crit Care Clin. 2010;26(3):567-75. Available from: doi:10.1016/j.ccc.2010.04.007. 21. Liu S, He C, He W, Jiang T. Lactate-enhancedqSOFA (LqSOFA) score is superior to the other four rapid scoring tools in predicting in-hospital mortality rate of the sepsis patients. Ann Transl Med. 2020;8(16). Available from: doi: 10.21037/atm-20-5410. 22. Zhou H, Lan T, Guo S. Prognostic prediction value of qSOFA, SOFA, and admission lactate in septic patients with community acquired pneumonia in emergency department. Emerg Med Int. 2020;2020. Available from: doi:10.1155/2020/7979353. 23. Shetty A, MacDonald S, Williams J, Bockxmeer J, de Groot B, Cuevas L, et al. Lactate ≥2 mmol/L plus qSOFA improves utility over qSOFA alone in emergency department patients presenting with suspected sepsis. EMA. 2017;29(6):626-34. Available from: doi:10.1111/1742-6723.12894. 24. Richardson M, Moulton K, Rabb D, Kindopp S, Pishe T, Yan C, Akpinar I, et al. Capnography for Monitoring End-Tidal CO2 in Hospital and Pre-hospital Settings: A Health Technology Assessment. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK362376/ [cited 2021 Jan 21]. 25. Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, PazosGarcía C. Liver glucose metabolism in humans. Biosci Rep. 2016;36(6). Available from: doi:10.1042/BSR20160385. 26. Safari E, Torabi M. Relationship between endtidal CO2 (ETCO2) and lactate and their role in predicting hospital mortality in critically ill trauma patients: A cohort study. Bull Emerg Trauma. 2020;8(2):83-8. Available from: doi:10.30476/BEAT.2020.46447. 27. Hunter CL, Silvestri S, Dean M, Falk JL, Papa L. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. Am J Emerg Med. 2013;31(1):6471. Available from: doi:10.1016/j. ajem.2012.05.034. 28. Wiryana M, Sinardja K, Budiarta G, Widnyana I, Wayan A, Paramasari A. A correlation of end tidal CO2 (ETCO2) level with hyperlactatemia om patient with hemodynamic disturbance. J Clin Anesth. 2016;08(07). Available from: doi:10.4172/2155-6148.1000741. 29. Sinto R, Suwarto S, Lie KC, Harimurti K, Widodo D, Pohan HT. Prognostic accuracy of the quick Sequential Organ Failure Assessment (qSOFA)lactate criteria for mortality in adults with suspected bacterial infection in the emergency department of a hospital with limited resources. Emerg Med J. 2020;37(6):363-9. Available from: doi:10.1136/emermed-2018-208361. 30. Baumann BM, Greenwood JC, Lewis K, Nuckton TJ, Darger B, Shofer FS, et al. Combining qSOFA criteria with initial lactate levels: Improved screening of septic patients for critical illness. Am J Emerg Med. 2020;38(5):883-9. Available from: doi:10.1016/j.ajem.2019.07.003. 31. Guerra WF, Mayfield TR, Meyers MS, Clouatre AE, Riccio JC. Early detection and treatment of patients with severe sepsis by prehospital personnel. J Emerg Med. 2013;44(6):111625. Available from: doi:10.1016/j.jemermed.2012.11.003. 32. Green R, Travers A, Cain E, Campbell S, Jensen J, Petrie D, Erdogan M, et al. Recognition of sepsis in the prehospital setting: A prospective observational study. Emerg Med Int . 2016;2016. Available from: doi:10.1155/2016/6717261. 33. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: A systematic review. BMJ Open. 2016;6(8). Available from: doi: 10.1136/bmjopen-2016-011218. 34. Lane DJ. The identification and management of sepsis in the prehospital setting. PhD thesis. Institute of Health Policy, Management and Evaluation University of Toronto; 2018. Available from: http://hdl.handle.net/1807/91963 [cited 2021 Jan 21].