We review approaches and challenges in developing chemical sensor-based methods to accurately and continuously monitor levels of key analytes in blood related directly to the status of critically ill hospitalized patients. Electrochemical and optical sensor-based technologies have been pursued to measure important critical care species in blood [i.e., oxygen, carbon dioxide, pH, electrolytes (K+, Na+, Cl, etc.), glucose, and lactate] in real-time or near real-time. The two main configurations examined to date for achieving this goal have been intravascular catheter sensors and patient attached ex vivo sensors with intermittent blood sampling via an attached indwelling catheter. We discuss the status of these configurations and the main issues affecting the accuracy of the measurements, including cell adhesion and thrombus formation on the surface of the sensors, sensor drift, sensor selectivity, etc. Recent approaches to mitigate these nagging performance issues that have prevented these technologies from clinical use are also discussed.


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Literature Cited

  1. Bakker E. 1.  2004. Electrochemical sensors. Anal. Chem. 76:3285–98 [Google Scholar]
  2. Wolfbeis OS. 2.  2008. Fiber-optic chemical sensors and biosensors. Anal. Chem. 80:4269–83 [Google Scholar]
  3. Córcoles EP, Boutelle MG. 3.  2013. Biosensors and Invasive Monitoring in Clinical Applications New York: Springer [Google Scholar]
  4. Frost MC, Wolf AK, Meyerhoff ME. 4.  2013. In vivo sensors for continuous monitoring of blood gases, glucose and lactate: biocompatibility challenges and potential solutions. Detection Challenges in Clinical Diagnosis P Vadgama, S Peteu 129–55 Cambridge: RSC Publ. [Google Scholar]
  5. Gifford R. 5.  2013. Continuous glucose monitoring: 40 years, what we've learned and what's next. Chem. Phys. Chem. 14:2032–44 [Google Scholar]
  6. Frost MC, Meyerhoff ME. 6.  2002. Indwelling chemical sensors for real-time clinical monitoring: progress and challenges. Curr. Opin. Chem. Biol. 6:633–41 [Google Scholar]
  7. Frost MC, Meyerhoff ME. 7.  2006. In vivo chemical sensors: tackling biocompatibility. Anal. Chem. 78:7370–77 [Google Scholar]
  8. Ganter M, Zollinger A. 8.  2003. Continuous intravascular blood gas monitoring: development, current techniques, and clinical use of a commercial device. Brit. J. Anaesth. 91:397–407 [Google Scholar]
  9. Coule LW, Truemper EJ, Steinhart CM, Lutin WA. 9.  2001. Accuracy and utility of a continuous intra-arterial blood gas monitoring system in pediatric patients. Crit. Care Med. 29:420–26 [Google Scholar]
  10. Shapiro BA. 10.  1992. In-vivo monitoring of arterial blood gases and pH. Resp. Care 37:165–69 [Google Scholar]
  11. Wahr JA, Tremper KK. 11.  1994. Continuous intravascular blood gas monitoring. J. Cardiothorac. Vasc. Anesth. 8:342–53 [Google Scholar]
  12. Meyerhoff ME. 12.  1993. In vivo blood-gas and electrolyte sensors: progress and challenges. Trends Anal. Chem. 12:257–66 [Google Scholar]
  13. Collison ME, Meyerhoff ME. 13.  1990. Chemical sensors for bedside monitoring of critically ill patients. Anal. Chem. 62:425A–37 [Google Scholar]
  14. Mahutte CK, Sasson CSH, Muro JR, Hansmann DR, Maxwell TP. 14.  et al. 1990. Progress in the development of a fluorescent intravascular blood gas system in man. J. Clin. Monitoring 6:147–57 [Google Scholar]
  15. Divers S, Marshall W, Foster-Smith R. 15.  1992. Advances in intra-arterial blood gas sensors. Proc. Conf. Electrolytes, Blood Gases and Other Critical Analytes MS Burritt, SF Sena, P D'Orazio 1–9 Washington, DC: AACC [Google Scholar]
  16. Weiss IK, Fink S, Harrison R, Feldman JD, Brill JE. 16.  1999. Clinical use of continuous arterial blood gas monitoring in the pediatric intensive care unit. Pediatrics 10:440–45 [Google Scholar]
  17. Wilson GS, Gifford R. 17.  2005. Biosensors for real-time in vivo measurement. Biosens. Bioelectron. 20:2388–403 [Google Scholar]
  18. Mo JW, Smart W. 18.  2004. Lactate biosensors for continuous monitoring. Front. Biosci. 9:3384–91 [Google Scholar]
  19. Yan Q, Major TC, Bartlett RH, Meyerhoff ME. 19.  2011. Intravascular glucose/lactate sensors prepared with nitric oxide releasing poly(lactide-co-glycolide)-based coatings for enhanced biocompatibility. Biosens. Bioelectron. 26:4276–82 [Google Scholar]
  20. Dyson A, Singer M. 20.  2011. Tissue oxygen tension monitoring: will it fill the void?. Curr. Opin. Crit. Care 17:281–89 [Google Scholar]
  21. Hartmann M, Montgomery A, Jönsson K, Haglund U. 21.  1991. Tissue oxygenation in hemorrhagic shock measured as transcutaneous oxygen tension, subcutaneous oxygen tension, and gastrointestinal intramucosal pH in pigs. Crit. Care Med. 19:205–10 [Google Scholar]
  22. Yassin J, Singer M. 22.  2007. Fundamental of oxygen delivery. Acute Kidney Injury C Romnco, R Bellomo, JA Kellum 119–32 Basel: S. Kager AG [Google Scholar]
  23. Bakker J, Vincent JL, Gris P, Leon M, Coffernils M, Kahn RJ. 23.  1992. Veno-arterial carbon dioxide gradient in human septic shock. Chest 101:509–15 [Google Scholar]
  24. Luft FC. 24.  2001. Lactic acidosis update for critical care clinicians. J. Am. Soc. Nephrol. 12:S15–19 [Google Scholar]
  25. Kraut JA, Madias NE. 25.  2007. Serum anion gap: its uses and limitations in clinical medicine. Clin. J. Am. Soc. Nephrol. 2:162–74 [Google Scholar]
  26. Fletcher S, Dhrampal A. 26.  2003. Acid-base balance and arterial blood gas analysis. Surgery 21:61–65 [Google Scholar]
  27. Ali R, Lang T, Saleh SM, Meier RJ, Wolfbeis OS. 27.  2011. Optical sensing scheme for carbon dioxide using solvatochromic probe. Anal. Chem. 83:2846–51 [Google Scholar]
  28. Morf WE, Mostert IA, Simon W. 28.  1985. Time response of potentiometric gas sensors to primary and interfering species. Anal. Chem. 57:1122–26 [Google Scholar]
  29. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. 29.  2005. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am. J. Health Syst. Pharm. 62:1665–82 [Google Scholar]
  30. Z'Graggen WJ, Lin CSY, Howard RS, Beale RJ, Bostock H. 30.  2006. Nerve excitability changes in critical illness polyneuropathy. Brain 129:2461–70 [Google Scholar]
  31. Lindner G, Schwarz C, Grüssing H, Kneidinger N, Fazekas A, Funk GC. 31.  2013. Rising serum sodium levels are associated with a concurrent development of metabolic alkalosis in critically ill patients. Intensive Care Med. 39:399–405 [Google Scholar]
  32. Kondepati VR, Heise HM. 32.  2007. Recent progress in analytical instrumentation for glycemic control in diabetic and critically ill patients. Anal. Bioanal. Chem. 388:545–563 [Google Scholar]
  33. Valenza F, Aletti G, Fossali T, Chevallard G, Sacconi F. 33.  et al. 2005. Lactate as a marker of energy failure in critically ill patients: hypothesis. Crit. Care 9:588–93 [Google Scholar]
  34. Facchinetti A. 34.  2013. Real-time improvement of continuous glucose monitoring accuracy. Diabetes Care 36:793–900 [Google Scholar]
  35. Tubiana-Rufi N, Riveline JP, Dardari D. 35.  2007. Real-time continuous glucose monitoring using Guardian® RT: from research to clinical practice. Diabetes Metab. 33:415–420 [Google Scholar]
  36. McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH. 36.  et al. 2001. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am. J. Surgery 182:481–85 [Google Scholar]
  37. Ramdomski MW, Moncada S. 37.  1993. The biological and pharmocological role of nitric oxide in platelet function. Mechanisms of Platelet Activation and Control KS Authi, SP Watson, VV Kakkar 251–64 Plenum Press New York: [Google Scholar]
  38. Yim JB, Hubbard TW, Melkerson LD, Sexton MA, Fieggen BM. 38.  1991. Configuration fiber-optic blood gas sensor bundle and method of making. US Patent No. 5,047,627
  39. Amao Y. 39.  2003. Probes and polymers for sensing oxygen. Microchim. Acta 143:1–12 [Google Scholar]
  40. Yeh TS, Chu CS, Lo Y. 40.  2006. Highly sensitive optical fiber oxygen sensor using Pt(II) complex embedded in sol-gel matrices. Sens. Actuators B 119:701–12 [Google Scholar]
  41. Chu CS, Lo YL. 41.  2010. Optical finer dissolved oxygen sensors based on Pt(II) complex and core-shell silica nanoparticles incorporated in sol-gel matrix. Sens. Actuators B 151:83–89 [Google Scholar]
  42. Severinghaus JW. 42.  1968. Measurement of blood gases: PO2 and PCO2. Ann. N. Y. Acad. Sci. 148:115–32 [Google Scholar]
  43. Jin W, Jiang J, Song Y, Bai C. 43.  2012. Real-time monitoring of blood carbon dioxide tension by fluorosensor. Res. Physiol. Neurobiol. 180:141–46 [Google Scholar]
  44. Nivens DA, Schiza MV, Angel M. 44.  2002. Multilayer sol-gel membranes for optical sensing applications: single layer pH and dual layer CO2 and NH3 sensors. Talanta 58:543–50 [Google Scholar]
  45. Jin W, Jiang J, Wang X, Zhu X, Wang G. 45.  et al. 2011. Continuous intra-arterial blood pH monitoring in rabbits with acid-base disorders. Res. Physiol. Neurobiol. 177:183–88 [Google Scholar]
  46. Offenbacher H, Wolfbeis OS, Furlinger E. 46.  1986. Fluorescence optical sensors for continuous determination of near-neutral pH values. Sens. Actuators 9:73–84 [Google Scholar]
  47. Tusa JK, He H. 47.  2005. Critical care analyzer with fluorescent optical chemosensors for blood analytes. J. Mater. Chem. 15:2640–47 [Google Scholar]
  48. Clark LC, Wolf R, Granger D, Taylor Z. 48.  1953. Continuous recording of blood oxygen tensions by polarography. J. Appl. Physiol. 6:189–93 [Google Scholar]
  49. Kinlen PJ, Heider JE, Hubbard DE. 49.  1994. A solid-state pH sensor based on a Nafion-coated iridium oxide indicator electrode and a polymer-based silver chloride reference electrode. Sens. Actuators B 22:13–25 [Google Scholar]
  50. Meyerhoff ME. 50.  1990. New in vitro analytical approaches for clinical chemistry measurements in critical care. Clin. Chem. 36:1567–72 [Google Scholar]
  51. Meruva RK, Meyerhoff ME. 51.  1998. Catheter-type sensor for potentiometric monitoring of oxygen, pH and carbon dioxide. Biosens. Bioelectron. 13:201–12 [Google Scholar]
  52. Makos MA, Omiatek DM, Ewing AG, Heien ML. 52.  2010. Development and characterization of a voltammetric carbon-fiber microelectrode pH sensor. Langmuir 26:10386–91 [Google Scholar]
  53. Huang WD, Cao H, Deb S, Chiao M, Chiao JC. 53.  2011. A flexible pH sensor based on the iridium oxide sensing film. Sens. Actuators A 169:1–11 [Google Scholar]
  54. Kennedy CD. 54.  1990. Ionic strength and the dissociation of acids. Biochem. Ed. 18:35–40 [Google Scholar]
  55. Oesch U, Ammann D, Simon W. 55.  1986. Ion-selective membrane electrodes for clinical use. Clin. Chem. 32:1448–59 [Google Scholar]
  56. Dimeski G, Badrick T, St John A. 56.  2010. Ion selective electrodes (ISEs) and interferences—a review. Clin. Chim. Acta 411:309–17 [Google Scholar]
  57. Kondepati VR, Heise HM. 57.  2007. Recent progress in analytical instrumentation for glycemic control in diabetic and critically ill patients. Anal. Bioanal. Chem. 388:545–63 [Google Scholar]
  58. Wilson GS, Gifford R. 58.  2005. Biosensors for real-time in vivo measurements. Biosens. Bioelectron. 20:2388–403 [Google Scholar]
  59. Mo JW, Smart W. 59.  2004. Lactate biosensors for continuous monitoring. Front. Biosci. 9:3384–91 [Google Scholar]
  60. Ward WK, Jansen LB, Anderson E, Reach G, Klein JC, Wilson GS. 60.  2002. A new amperometric glucose microsensor: in vitro and short-term in vivo evaluation. Biosens. Bioelectron. 17:181–89 [Google Scholar]
  61. Wang J. 61.  2001. Glucose biosensors: 40 years of advances and challenges. Electroanalysis 13:983–88 [Google Scholar]
  62. Koschinsky T, Heinemann L. 62.  2001. Sensors for glucose monitoring: technical and clinical aspects. Diabetes Metab. Res. Rev. 17:113–23 [Google Scholar]
  63. Choleau C, Klein JC, Reach G, Aussedat B, Demaria-Pesce V. 63.  et al. 2002. Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients: Part 2. Superiority of the one-point calibration method. Biosens. Bioelectron. 17:647–54 [Google Scholar]
  64. Waeger P, Hummel M. 64.  2008. Latest developments in continuous glucose monitoring. Diabetes Metab. Heart 17:385–91 [Google Scholar]
  65. Tubiana-Rufi N, Riveline JP, Dardari D. 65.  2007. Real-time continuous glucose monitoring using Guardian® RT: from research to clinical practice. Diabetes Metab. 33:415–20 [Google Scholar]
  66. Hirsch IB, Armstrong D, Bergenstal RM, Buckingham B, Childs BP. 66.  et al. 2008. Clinical application of emerging sensor technologies in diabetes management: consensus guidelines for continuous glucose monitoring (CGM). Diabetes Technol. Ther. 10:232–46 [Google Scholar]
  67. Gough DA, Kumosa LS, Routh TL, Lin JT, Lucisano JY. 67.  2010. Function of an implanted tissue glucose sensor for more than 1 year in animals. Sci. Transl. Med. 2:42–53 [Google Scholar]
  68. McNichols RJ, Cote GL. 68.  2000. Optical glucose sensing in biological fluids: an overview. J. Biomed. Opt. 5:5–16 [Google Scholar]
  69. Wang J. 69.  2008. In vivo glucose monitoring: towards “sense and act” feedback-loop individualized medical systems. Talanta 75:636–41 [Google Scholar]
  70. Heller A. 70.  2006. Electron-conducting redox hydrogels: design, characteristics and synthesis. Curr. Opin. Chem. Biol. 6:664–72 [Google Scholar]
  71. Marvin JS, Hellinga HW. 71.  1998. Engineering biosensors by introducing fluorescent allosteric signal transducers: construction of a novel glucose sensor. J. Am. Chem. Soc. 120:7–11 [Google Scholar]
  72. Mansouri S, Schultz JS. 72.  1984. A miniature optical glucose sensor based on affinity binding. Biotechnology 2:885–90 [Google Scholar]
  73. Tipnis R, Vaddiraju M, Jain F, Burgess D, Papadimitrakopoulos F. 73.  2007. Layer-by-layer assembled semipermeable membranes for amperometric glucose sensors. J. Diabetes Sci. Technol. 2:193–200 [Google Scholar]
  74. Lin Y, Taylor S, Li H, Fernando KAS, Qu L. 74.  et al. 2004. Advances toward bioapplications of carbon nanotubes. J. Mater. Chem. 14:527–41 [Google Scholar]
  75. Lin YH, Lu F, Tu Y, Ren ZF. 75.  2004. Glucose biosensors based on carbon nanotube nanoelectrode ensembles. Nano Lett. 4:191–95 [Google Scholar]
  76. Zhu Z, Song W, Burugapalli K, Moussy F, Li YL, Zhong XH. 76.  2010. Nano-yarn carbon nanotube fiber based enzymatic glucose biosensor. Nanotechnology 21:165501 [Google Scholar]
  77. Tierney S, Falch BMH, Hjelme DR, Stokke BT. 77.  2009. Determination of glucose levels using a functionalized hydrogel-optical fiber biosensor: toward continuous monitoring of blood glucose in vivo. Anal. Chem. 81:3630–36 [Google Scholar]
  78. Paek SH, Cho IH, Kim DH, Jeon JW, Lim GS, Paek SH. 78.  2013. Label-free, needle-type biosensor for continuous glucose monitoring based on competitive binding. Biosens. Bioelectron. 40:38–44 [Google Scholar]

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