Use of ultraviolet, near-ultraviolet and near infrared resonance raman spec-troscopy and fluorescence spectroscopy fro tissue interrogation of shock states, critical illnesses, and other disease states

• US 20040039269A1
• Filed: 07/29/2003
• Published: 02/26/2004
• Est. Priority Date: 07/13/2000
• Status: Active Grant

• Current Assignee: Virginia Commonwealth University
• Original Assignee: Virginia Commonwealth University
• Inventors: Ivatury, Rao R, Ward, Kevin R., Hawkridge, Fred, Barbee, R. Wayne, Terner, James
• Granted Patent: US 7,113,814 B2
• Time in Patent Office: Days
• US Class Current: 600/312
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/0086 using infrared radiation
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/14551 for measuring blood gases
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/445 Evaluating skin irritation or skin trauma, e.g. rash, eczema, wound, bed sore
• CPC Class Codes: G01N 21/65 Raman scattering

Abstract

In an emergency medicine patient, accurate measurement of change or lack thereof from non-shock, non-ischemic, non-inflammation, non-tissue injury, non-immune dysfunction conditions is important and is provided, as practical, real-time approaches for accurately characterizing a patient'"'"'s condition, using Raman (3) and/or fluorescence (30) spectroscopy with a high degree of accuracy. Measurement times are on the order of seconds. High-accuracy measurement is achieved with Raman spectroscopy interrogation of tissue. Simultaneous interrogation by NADH fluorescence spectroscopy may he used. Measurements may be non-invasive to minimally invasive. Preclinical (ultra-early) states of shock can be detected (5), severity can be determined, effectiveness of various treatments can be determined.

Claims

1. A tissue analysis method, comprising:

interrogating a biological tissue with Raman spectroscopy and fluorescence spectroscopy to obtain spectroscopy results.

2. The tissue analysis method of claim 1, wherein the obtained spectroscopy results are for at least one mediator or marker associated with a shock state and/or tissue injury.

3. The method of claim 1, including diagnosing and/or following progression or resolution of shock states and/or tissue injury, and/or tissue ischemia.

4. The method of claim 3, wherein the tissue injury includes inflammatory or immune dysfunction.

5. The method of claim 2, wherein the obtained spectroscopy results are for presence and/or proportions for the at least one shock state and/or tissue injury mediator or marker.

6. The method of claim 1, wherein the tissue interrogating is noninvasive.

7. The method of claim 1, wherein the tissue is in vivo and in situ.

8. The method of claim 1, wherein the tissue is removed from a patient before the tissue interrogation.

9. The method of claim 1, including measuring tissue hemoglobin oxygen saturation including amount of oxyhemoglobin and deoxyhemoglobin by Raman spectroscopy.

10. The method of claim 1, including measuring NADH presence and/or accumulation by fluorescence spectroscopy.

11. The method of claim 1, including measuring tissue hemoglobin oxygen saturation by Raman spectroscopy and measuring NADH presence and/or accumulation by fluorescence spectroscopy.

12. The method of claim 1, including determining whether the tissue has insufficient oxygen delivery to meet metabolic demands of the tissue while simultaneously determining whether mitochondrial dysfunction or injury exists.

13. The method of claim 1, including measuring myoglobin oxygenation saturation.

14. The method of claim 1, including determining cytochrome oxidase redox status.

15. The method of claim 1, including determining absolute concentration of hemoglobin in the tissue.

16. The method of claim 9, including determining absolute concentration of hemoglobin in the tissue.

17. The method of claim 1, including determining pH of the tissue.

18. The method of claim 9, including determining pH of the tissue.

19. The method of claim 2 including determining the concentration of at least one mediator or marker.

20. The method of claim 19, including determining absolute concentration.

21. The method of claim 19, including determining relative concentration.

22. The method of claim 2 including determining the presence of at least one mediator or marker.

23. The method of claim 2, wherein the obtained spectroscopy results are selected from the group consisting of at least one mediator associated with a shock state, tissue injury or tissue ischemia, inflammation or immune dysfunction, and at least one marker of tissue perfusion or injury.

24. The method of claim 23, wherein the marker may be within intracellular, interstitial or intravascular space or within exhaled air from a patient.

25. The method of claim 23, wherein the marker is selected from the group consisting of lactate, pyruvate, ATP, Pcr, AMP, ADP, Pi, NAD, NADH, albumin, endotoxin, exotoxin, microbes, cytokines-chemokines, procalcitonin, hormones, myeloperoxidase, elastase, xanthine oxidase, xanthine dehydrogenase, fatty acid binding proteins, catecholamines and vasoactive peptides.

26. The method of claim 23, wherein the marker or mediator is a metabolic or pro or anti-inflammatory marker or mediator.

27. The method of claim 1, including intermittently or continuously interrogating the tissue of a patient.

28. The method of claim 27, including monitoring for appearance of one or more tissue markers specific for a specific disease state.

29. The method of claim 1, including determining tissue viability.

30. The method of claim 1, including diagnosing shock.

31. The method of claim 1, including diagnosing tissue injury, tissue inflammation or tissue immune dysfunction.

32. A method of diagnosing shock, tissue ischemia, tissue injury, tissue inflammation, or tissue immune dysfunction, comprising:

(A) for a target molecule population, taking a sample Raman spectroscopy, and/or fluorescence spectroscopy, profile for a patient;

(B) comparing the sample spectroscopy profile with a pre-established Raman spectroscopy and/or fluorescence spectroscopy profile for the target molecule population under baseline conditions.

33. The method of claim 32, wherein the method is non-invasive.

34. The method of claim 32, wherein the target molecule population comprises oxygenated hemoglobin, deoxygenated hemoglobin and/or NADH.

35. The method of claim 32, wherein the profiles are of relative amounts.

36. The method of claim 32, wherein the profiles are of absolute amounts.

37. The method of claim 35, wherein the profiles are of relative amounts of NAD/NADH;

lactate/pyruvate;

Pcr-ATP;

ATP-ADP;

Pcr-Pi;

oxidized cytochrome oxidase to reduced cytochrome oxidase, and/or oxyhemoglobin with deoxyhemoglobin.

38. The method of claim 32, including taking the profiles by Raman spectroscopy.

39. The method of claim 38, including signal enhancement at a resonant frequency for a target molecule of the target molecule population.

40. The method of claim 35, including operating an electromagnetic radiation generator at a range of selectable wavelengths from about 270 nm to about 20,000 nm.

41. The method of claim 32, including monitoring a specific tissue bed in the patient.

42. The method of claim 41, wherein the specific tissue bed is a brain, heart, lung, liver, eye, intestines, stomach, pancreas, kidney, bladder, urethra, skin, nailbed, cervix, uterus, oropharynx, nasopharynx, esophagus or blood.

43. The method of claim 41, including detecting exhaled markers or mediators of organ injury.

44. The method of claim 43, wherein exhaled markers or mediators of lung injury are detected.

45. The method of claim 43, wherein a detector is placed at the airway of the patient.

46. The method of claim 43, wherein the exhaled markers indicate organ injury.

47. The method of claim 43, wherein the exhaled markers or mediators are isoprostanes and/or myeloperoxidase.

48. The method of claim 32, including calculating pH. of blood and/or tissue.

49. The method of claim 32, including minimally invasively probing the patient by a fiber optic probe or probe array inserted into a tissue bed.

50. The method of claim 49, wherein the probe or probe array is inserted into a muscle.

51. The method of claim 32, including analysis of interstitial fluid.

56. The method of claim 32, including cellular analysis.

57. The method of claim 32, including placing a probe on or near any mucosal or epithelial covered surface of a body or an organ.

58. The method of claim 32, including simultaneously performing fluorescence spectroscopy probing of NADH while performing Raman spectroscopy.

59. The method of claim 32, wherein spectroscopy is performed for multiple wavelengths.

52. The method of claim 52, including Raman spectroscopy.

53. The method of claim 52, including resonance Raman spectroscopy at 390 to 420 m wavelength.

54. The method of claim 53, wherein the sample profile is taken from a tissue or a space in a body.

55. The method of claim 53, wherein the sample profile is taken from a tissue or a space out of the body.

60. A spectroscopy comparative profile, comprising:

a pre-established Raman spectroscopy and fluorescence spectroscopy profile for a target molecule population under baseline conditions; and

a sample Raman spectroscopy and fluorescence spectroscopy profile for the target molecule population.

61. The comparative profile of claim 61, including a pre-established fluorescence spectroscopy profile for NADH under baseline conditions and a sample fluorescence profile for NADH.

62. A method of diagnosing abnormalities in vivo and in situ, comprising:

(A) for a target molecule population, taking a sample Raman spectroscopy and/or fluorescence spectroscopy profile for a patient;

(B) comparing the sample Raman spectroscopy or fluorescence spectroscopy profile with a pre-established Raman spectroscopy or fluorescence spectroscopy profile for the target molecule population under baseline conditions;

(C) using differences identified in said comparing step to identify an abnormality.

63. The method of claim 62, including continuously interrogating the patient for appearance of abnormal tissue markers specific for a suspected disease state.

64. The method of claim 63, wherein the markers are cardiac biomarkers, GI markers, cerebral markers, skin markers, lung markers, blood markers, and/or eye markers.

65. The method of claim 62, including, while taking the Raman spectroscopy profile, also performing fluorescence spectroscopy measurement on the patient.

66. A medical measurement device comprising:

a spectrometer with multiple wavelength settings for resonance Raman spectroscopy; and

a biological probe electrically connected to the spectrometer.

67. The medical measurement device of claim 66, including a fluorescence spectrometer electrically connected to the biological probe.

68. The medical measurement device of claim 66 including a laser source and a charge coupled device.

69. The medical instrument of claim 66 including a laser tunable to multiple wavelengths.

70. A computer system comprising:

a database of stored baseline Raman spectroscopy and/or fluorescence spectroscopy profiles and

a means to store patient Raman spectroscopy and/or fluorescence spectroscopy profiles.

71. The computer system of claim 70, including a computing system for comparing patient profiles to baseline profiles.

72. A biological material analysis method, comprising:

interrogating a biological material with Raman spectroscopy and fluorescence spectroscopy to obtain spectroscopy results.

73. The biological material analysis method of claim 72, wherein the biological material is bodily fluid.

74. The biological material analysis method of claim 72, wherein the biological material is tissue.

75. The biological material analysis method of claim 72, wherein the obtained spectroscopy results are for at least one mediator or marker associated with a shock state and/or tissue injury.

76. The method of claim 75, wherein the markers are contained in a biological material selected from the group consisting of urine, saliva, wound exudates, vitreous humor, aqueous humor, tissue exudate, gastric contents, and fecal matter.