Journal of Pediatric Urology (2015) 11, 74.e1e74.e7
Optical diagnosis of lower urinary tract infection: A pilot study in children Babak Shadgan a,b, Mark Nigro a,b, Andrew Macnab a, Mehdi Fareghi c, Lynn Stothers a,b, Lida Sharifi-Rad c, Abdol-Mohammad Kajbafzadeh c a
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
b Center for International Collaboration on Repair Discoveries (ICORD), Vancouver, Canada
c Pediatric Urology Research Center, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Iran
Correspondence to: B. Shadgan, ICORD, Blusson Spinal Cord Centre, 818 West 10th Ave., Vancouver, BC, V5Z1M9, Canada. Tel.: þ1 604 675 8846; fax: þ1 604 228 1158 [email protected] (B. Shadgan) [email protected] (M. Nigro) [email protected] (A. Macnab) [email protected] (M. Fareghi) [email protected] (L. Stothers) [email protected] (L. Sharifi-Rad) [email protected] (A.M. Kajbafzadeh)
Summary Conventionally, diagnosis of lower urinary tract infection (LUTI) is made on the basis of history, urine microscopy and culture. But there are limitations to this methodology especially in children and special populations where there is difficulty in obtaining a full history and details of clinical symptoms. The aim of this study was to determine if monitoring bladder wall oxygenation as a measure of bladder mucosal inflammation using transcutaneous near-infrared spectroscopy (NIRS) allows detection of the presence or absence of LUTI in children. Materials and methods A convenience sample of children referred to a pediatric urology clinic with an acute LUTI and a control group were studied. Diagnosis was confirmed by history, physical examination, laboratory investigations, and urine culture. Participants had transcutaneous measurement of an absolute measure of tissue oxygen saturation (TSI%) in their bladder wall, and a quadriceps muscle control site, using a spatially resolved (SR) wireless NIRS device. Average measures of bladder wall TSI% (B.TSI%) and
quadriceps TSI% (Q.TSI%) and their differences (TSI.diff) were calculated and compared between those with LUTI and controls by performing a twoway repeated analysis of variance. Results Thirty-four patients met the inclusion criteria (LUTI n Z 12 and controls n Z 22). Comparing LUTI to controls B.TSI% and TSI.diff values were significantly higher in the LUTI group (p < 0.0001), while Q.TSI% values were not significantly different. Conclusions Optical monitoring of bladder wall oxygenation is feasible in children. In this study a significant difference was evident in a SR NIRS-derived measure of absolute oxygen saturation in the bladder wall between children with UTI diagnosed by conventional testing methods, and those in a control group without infection. SR-NIRS monitoring of bladder wall oxygenation may offer a rapid and non-invasive means of bedside screening for LUTI where history and/or clinical signs are not available or adequate.
Keywords Near-infrared spectroscopy; Urinary bladder; Cystitis; Inflammation; Infection Received 22 April 2014 Accepted 27 August 2014 Available online 28 February 2015
Figure http://dx.doi.org/10.1016/j.jpurol.2014.08.017 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Optical diagnosis of urinary tract infection
Introduction Lower urinary tract infection (LUTI) is a common and potentially serious condition in both adult and pediatric populations [1]. LUTI is defined as infection of lower urinary tract with bacterial count 104 CFU/mL urine, which is accompanied by clinical signs and symptoms of lower urinary tract infection. In infants and young children as well as elderly adults and those affected by neuropathies and spinal cord injuries (SCI) the diagnosis is often complicated by difficulty obtaining the required history of the hallmark clinical symptoms on which diagnosis is based [2,3]. In additional to difficulties obtaining the required history, the diagnosis of LUTI can be complicated by issues related to urine analysis, as collecting urine samples suitable for definitive urinalysis and culture can be a challenge in both children and the elderly, and also patients with neurogenic bladder. The feasibility, reliability and usefulness of conventional tests for the diagnosis of UTI have been described [4e6]. Dipstick biochemical analysis for nitrites or leukocyte esterase is the easiest means of screening for UTI qualitatively, but requires collecting urine samples, does not detect all bacteria, and is subject to false-negative results, which may lead to failure of diagnosis [7]. These difficulties are relevant as early detection and management of LUTI is recognized as critical in the prevention of ascending upper urinary tract infections (UUTI) and its related complications [1,8]. A reliable and objective diagnostic and monitoring methodology to identify the presence of LUTI would be useful clinically. Near infrared spectroscopy (NIRS) is a non-invasive transcutaneous optical technique akin to oximetry that uses light in the near-infrared (NIR) spectrum to monitor changes in the concentration of oxygenated (O2Hb), deoxygenated (HHb) hemoglobin, and total hemoglobin (tHb) in a tissue of interest, including the bladder [9,10]. Changes in NIRS parameters are seen in real time in physiologic processes where tissue hemodynamics and/or oxygenation are altered [11]. Bacterial cystitis is recognized to cause inflammation of the bladder wall, and a physiologic increase in mucosal perfusion and local oxygen consumption is assumed to result [12]. Hence we hypothesized that a NIRS-derived measure of absolute tissue oxygenation would differ between subjects with and without LUTI, and consequently that NIRS could offer a non-invasive optical method of detecting changes in bladder perfusion and oxygenation resulting from the presence of infection. If proven, NIRS of the bladder might then be used as a screening method to detect the onset of LUTI and monitor for resolution of the resulting inflammation with effective treatment. NIRS uses principles of physics similar to those underlying oximetry. Photons of NIR light emitted from the device penetrate through skin and into living tissue; O2Hb and HHb are chromophores, compounds that absorb NIR light, and each has a different wavelength-dependent absorption peak [9,11]. A detector captures photons that return because they are neither absorbed nor scattered; softwarebased mathematical algorithms can determine from this raw optical data concentration changes from baseline for
74.e2 O2Hb and HHb using a modification of the BeereLambert law, from which real-time variations in tissue oxygenation and hemodynamics from baseline can be derived [13,14]. In addition, spatially resolved (SR) NIRS devices can provide an absolute measurement of tissue oxygen saturation [15]. The path of NIR photons though living tissue is “banana” shaped with penetration at the midpoint being equal to half the distance between the emitter and detector (interoptode distance) [9]. The feasibility of monitoring changes in detrusor blood volume and oxygen supply and demand in the bladder have been demonstrated [16], and also the measurement of bladder wall absolute tissue oxygen saturation, expressed as the tissue saturation index (TSI%) [17]. We describe a pilot study in children using a spatially resolved wireless NIRS device to non-invasively monitor children for physiological changes in bladder hemodynamics and oxygenation generated by LUTI, as measured by TSI%. We hypothesized that this measure of bladder wall oxygen saturation (TSI%) would be higher when the bladder is inflamed as a consequence of increased perfusion associated with having LUTI.
Materials and methods Subjects A convenience sample of children less than 16 years of age, referred to the urology clinic at a pediatric hospital during May 2013 participated. Inclusion criteria included: 1) children with a urogenital complaint, 2) with no history of bladder dysfunction, 3) with or without UTI, but with no other infections, 4) with no other major comorbidity, and 5) with suprapubic fat layer thickness of 74.5% as a potential diagnostic index for identifying a child as probably affected by UTI.
Figure 1 Wireless near-infrared spectroscopy measurements of bladder wall and quadriceps tissue oxygen saturation (TSI%) in a child with acute urinary tract infection.
Optical diagnosis of urinary tract infection Table 1 #
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 16 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
74.e4
Subject characteristics.
Gender
M F M M M M M M F M M M M M M M M M M F M M F F F F F F M F M M M F
Age (yrs)
3 4 3 3 6 5 2 2 8 1 6 1 8 1 3 7 5 2 2 11 1 4 5 5 6 4 6 2 2 9 6 12 7 6
Symptoms
Urine analysis
Fever
Dysuria
WBC
RBC
Bacteria
þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ
þ
þ þ þ þ þ þ þ þ þ þ þ þ þ
Urine culture
Q.TSI%
B.TSI%
TSI.diff
þ þ þ þ þ þ þ þ þ þ þ þ
58.8 64.1 59 72.3 64.8 75.9 69.2 65.2 64.8 75.8 56.2 58.5 73.9 74.9 78.9 65.6 70.4 69.3 70.4 69.9 60.8 74.6 68 68.1 75.6 75.4 74.7 65.8 75.3 74.8 74.2 60.7 62.2 70.2
58.3 64.5 60.9 67 62 73.7 67.8 59.4 66.3 77.1 58 49.1 75.3 73 75.6 63.1 72 71.9 69.3 71.1 59.4 74.5 80.1 81.9 89.9 84.9 79.9 82.5 80.7 80.9 88.7 70.5 70.6 78.9
0.5 0.4 1.9 5.3 2.8 2.2 1.4 5.8 1.5 1.3 1.8 9.4 1.4 1.9 3.3 2.5 1.6 2.6 1.1 1.2 1.4 0.1 12.1 13.8 14.3 9.5 5.2 16.7 5.4 6.1 14.5 9.8 8.4 8.7
TSI Z tissue oxygen saturation; B Z bladder; Q Z quadriceps.
Discussion In this study a significant difference was evident in an SR NIRS-derived measure of absolute oxygen saturation in the bladder wall between children with UTI diagnosed by conventional testing methods, and those in a control group without infection. The method we describe uses a noninvasive optical method akin to oximetry, where NIR light is introduced transcutaneously over the bladder to interrogate the bladder wall by measurement of NIR light absorption by the naturally occurring chromophores O2Hb and HHb. In other studies using NIRS to investigative the effects of inflammation at a surgical site, Govinda et al. [22] reported that NIRS-derived oxygen saturation (StO2) measurements might be able to predict surgical site infection, and thus allow earlier preventive measures to be implemented. These data compare to our findings of changes in bladder TSI% in patients affected by UTI.
In multiple prior studies, in a range of tissues, NIRS monitoring has been shown detect variations in oxygenation via changes in the concentration and trend data of the chromophores O2Hb and HHb, and hemodynamic variations via changes in the sum of O2Hb and HHb, total hemoglobin (tHb) [23,24]. In addition a number of absolute physiologic parameters can be measured by using variations on the basic NIRS monitoring technique. Absolute measurement of tissue oxygen saturation requires use of an SR NIRS device with optical geometry that incorporates two or more different NIR emitter to detector distances and specific software to derive the expressed value (tissue saturation index or TSI% in the case of the PortaMon device used in this study) free of motion artifact. Prior reports describing NIRS applications to monitor the bladder include: studies in health and where various bladder pathologies are present [19e21,25e30]; the methodologies applied [10,16,21,25]; and rationale for the data obtained representing
74.e5 Table 2
Q.TSI%
B.TSI%
TSI.diff
B. Shadgan et al. Groups comparison.
Mean SD () Range Mean SD () Range Mean SD () Range
Non-UTI group
UTI group
Significance
67.9 6.5 56.2e78.9 66.8 7.3 49.1e77.1 1.1 3 5.8 to 2.6
70.4 5.4 60.7e75.6 80.8 5.9 70.5e89.9 10.4 3.9 5.2e16.7
p Z 0.20
p < 0.0001
p < 0.0001
TSI Z tissue oxygen saturation; B Z bladder; Q Z quadriceps; UTI Z urinary tract infection.
physiologic change in the bladder wall [16,20,27,28]. Also, the feasibility of monitoring bladder wall TSI% in patients with neurogenic bladder due to spinal cord injury and children [29,30]; two patient groups identified to represent a greater challenge than most other subjects in the context of detection and diagnosis of UTI. Conventionally, diagnosis of UTI is made on the basis of history, urine microscopy and culture. But there are limitations to this methodology especially in special populations where there is difficulty in obtaining a full history and details of clinical symptoms. Hence the potential of using a non-invasive monitoring technique that can detect the presence of bladder inflammation secondary to UTI to screen children, elderly people, and patients such as those with neurogenic bladder. NIRS could offer a means of
Figure 2 The difference between bladder wall and quadriceps tissue oxygen saturation (TSI.diff) is significantly higher in subjects affected by urinary tract infection (UTI) comparing non-UTI (NUTI) subjects.
screening for possible early infection, and if the technique is validated in further trials would provide the ability to identify the need to obtain a clean sample for microscopy and culture, and promptly initiate treatment. The effect of treatment could also be monitored via detection of the resolution of the inflammation generated in the bladder by active infection. In addition, home monitoring for patients at increased risk for UTI could be achieved in this way with a miniature wireless SR NIRS device used by the patient, with data collected as frequently as considered clinically desirable, and sent via secure wireless data link for interpretation at a urological center. Early detection and appropriate management of LUTI is an invaluable entity for prevention of ascending UUTI and consequent renal scar formation in children and high-risk individuals. Experimental studies confirm that the early administration of antibiotics and antioxidants result in a lower incidence of renal scaring [8]. Early recognition of LUTI by SR NIRS could pave the way for early detection of febrile UTI and rationalize administration of appropriate antibiotics prior to the receipt of the urine culture results 48e72 h later. NIRS offers a feasible method for early diagnosis of acute LUTI in children because it is an established noninvasive technology, and current devices are compact, low weight, relatively cheap, resistant to body motion and have the ability to achieve the depth of penetration through tissue for transcutaneous monitoring to interrogate the bladder wall. There are a number of limitations to this study. The sample size was small; subjects with a marked bladder dysfunction did not included; subjects did not undergo a comprehensive work-up to prove that in addition to UTI they were not affected by any other infection; bladder capacity, uroflow, and post-voiding residual were not measured in all subjects, and the application of SR NIRSderived TSI% measurement to detect inflammation due to UTI is novel. However, this same NIRS device has been used successfully to monitor bladder hemodynamics and oxygenation and detrusor oxygen saturation (TSI%) in children and adults, including those with neurogenic bladder due to spinal cord injury [29,30]. No early or late complications related to NIRS application were observed throughout the study. We also recognize that a number of important potential confounders exit in the context of NIRS monitoring of the bladder, including the depth of penetration of NIR photons, and the potential effect of light attenuation in subcutaneous tissue, changes in bladder volume, and movement on the chromophore data obtained. The reasons for confidence that NIRS does measure physiologic change and that diagnostic data are obtained have been discussed previously [11,16,18,21,25,27,28,31,32]. The current effective depth of penetrations of conventional NIRS systems is limited to a maximum of 25e30 mm in living tissues. This depth of penetration is enough to interrogate the bladder wall in children and adults, except in very overweight subjects with a suprapubic fat layer of more than 20 mm. For deeper measurements, NIRS systems need to have a higher interoptode distance, which requires using higher intensity light sources in a more complex setup. Prior bladder NIRS studies in children and adult subjects confirm access of transcutaneous near infrared lights to
Optical diagnosis of urinary tract infection interrogate bladder wall tissue [11,16,27,28]. Tissue movement during NIRS data collection can induce motion artifact on NIRS signals; however, with proper device placement and using different types of motion artifact removal techniques, the effect of movement on NIRS signals could be effectively controlled [31,32]. The statistical differences in the oxygen saturation parameters evident between the UTI and control groups show the significance of the findings in this pilot study, and also allow cut-off parameters for the presence and absence of UTI-derived bladder inflammation to be proposed. We suggest that further studies using NIRS as means of identifying UTI are warranted. To support this pilot study hypothesis a larger clinical trial is required to investigate the sensitivity and specificity of the SR NIRS TSI% method in subjects confirmed to have UTI based on conventional testing and a cohort of non-infected control subjects. Using a two-channel SR NIRS system for simultaneous measurement of bladder and control side TSI% values would reduce the time of testing to 1 min. Future studies could also include examination of the feasibility, diagnostic accuracy, and reliability of this method for early diagnosis and resolution of infection in response to treatment in people with SCI, because of the significant problem LUTI represents in this population.
Conclusion Non-invasive NIRS optical monitoring of an absolute measure of bladder oxygenation is feasible in children. In those with UTI proven by history, symptoms, and culture this measure differs significantly from asymptomatic controls. Further clinical trials with a larger sample size are required to confirm the findings of this pilot study.
Conflict of interest None.
Funding None.
Acknowledgments The authors would like to thank the Urology Foundation, Michael Smith Foundation for Health Research (MSFHR), Pediatric Urology Research Centre and Rick Hansen Institute (Postdoctoral Fellowship Award to Dr. Babak Shadgan: Trainee Award Number # ST-PDF-03096) for supporting this study.
References [1] Schardijn GH, Statius van Eps LW, Pauw W, Hoefnagel C, Nooyen WJ. Comparison of reliability of tests to distinguish upper from lower urinary tract infection. Br Med J (Clin Res Ed) 1984;289:284e7.
74.e6 [2] National Institute for Health and Clinical Excellence. Urinary tract infection in children. London: NICE; 2007. Retrieved October 2013 from: http://guidance.nice.org.uk/CG054. [3] D’Hondt F, Everaert K. Urinary tract infections in patients with spinal cord injuries. Curr Infect Dis Rep 2011;13:544e51. [4] Hoffman JM, Wadhwani R, Kelly E, Dixit B, Cardenas DD. Nitrite and leukocyte dipstick testing for urinary tract infection in individuals with spinal cord injury. J Spinal Cord Med 2004; 27:128e32. [5] Aliyu SH, Ludlum H, Abubakar I, Bentley N. What is the role of urine dipstick testing in the management of UTI? Br J Gen Pract 2002;52:414e5. [6] Bitsori M, Galanakis E. Pediatric urinary tract infections: diagnosis and treatment. Expert Rev Anti Ther 2012;10: 1153e64. [7] Doley A, Nelligan M. Is a negative dipstick urinalysis good enough to exclude urinary tract infection in paediatric emergency department patients? Emerg Med (Fremantle) 2003 Feb;15:77e80. [8] Sadeghi Z, Kajbafzadeh AM, Tajik P, Monajemzadeh M, Payabvash S, Elmi A. Vitamin E administration at the onset of fever prevents renal scarring in acute pyelonephritis. Pediatr Nephrol 2008;23:1503e10. [9] Delpy DT, Cope M. Quantification in tissue near-infrared spectroscopy. Philos Trans R Soc Lond B 1997;352:649e59. [10] Pannek J. Editorial comment on: classification of male lower urinary tract symptoms using mathematical modeling and a regression tree algorithm of noninvasive near-infrared spectroscopy parameters. Eur Urol 2010;57:332e3. [11] Macnab AJ, Shadgan B. Biomedical applications of wireless continuous wave near infrared spectroscopy. Biomed Spectros Imaging 2012;1:205e22. [12] Echols RM, Tosiello RL, Haverstock DC, Tice AD. Demographic, clinical, and treatment parameters influencing the outcome of acute cystitis. Clin Infect Dis 1999;29:113e9. [13] Delpy DT, Cope M, van der Zee P, Arridge S, Wray S, Wyatt J. Estimation of optical pathlength through tissue from direct time of flight measurements. Phys Med Biol 1988;33: 1433e42. [14] Boushel R, Langberg H, Olesen J, Nowak M, Simonsen L, Bulow J, et al. Regional blood flow during exercise in humans measured by near-infrared spectroscopy and indocyanine green. J Appl Physiol 2000;89:1868e78. [15] Suzuki S, Takasaki S, Ozaki T, Kobayashi Y. A tissue oxygenation monitor using NIR spatially resolved spectroscopy. Proc SPIE 1999;3597:582e92. [16] Macnab AJ, Shadgan B, Stothers L. The evolution of wireless near infrared spectroscopy: applications in urology and rationale for clinical use. J NIRS 2012;20:57e73. [17] Shadgan B, Macnab, Stothers L. Optical diagnosis of interstitial cystitis/painful bladder syndrome. Proc SPIE 2013:856510. [18] van Beekvelt MCP, Borghuis MS, van Engelen BGM, Wevers RA, Colier WN. Adipose tissue thickness affects in vivo quantitative near-IR spectroscopy in human skeletal muscle. Clin Sci (London) 2001;101:21e8. [19] Shadgan B, Reid WD, Gharakhanlou R, Stothers L, Macnab A. Wireless near-infrared spectroscopy of skeletal muscle oxygenation and hemodynamics during exercise and ischemia. Spectroscopy 2009;23:233e41. [20] Macnab AJ, Friedman B, Shadgan B, Stothers L. Bladder anatomy physiology and pathophysiology: elements that suit near infrared spectroscopic evaluation of voiding dysfunction. Biomed Spectros Imaging 2012;1:223e35. [21] Macnab AJ, Stothers L, Shadgan B. Monitoring detrusor oxygenation and hemodynamics non-invasively during dysfunctional voiding. Adv Urol 2012:1e8. Article ID 676303. [22] Govinda R, Kasuya Y, Bala E, Mahboobi R, Devarajan J, Sessler DI, et al. Early postoperative subcutaneous tissue
74.e7
[23]
[24]
[25]
[26]
[27]
oxygen predicts surgical site infection. Anesth Analg 2010;111: 946e52. Ferrari M, Quaresima V. Near infrared brain and muscle oximetry: from the discovery to current applications. J NIRS 2012;20:1e14. Hamaoka T, McCully KK, Quaresima V, Yamamoto Y, Chance B. Near-infrared spectroscopy/imaging for monitoring muscle oxygenation and oxidative metabolism in healthy and diseased humans. J Biomed Opt 2007;12:062105. Macnab AJ, Stothers L. Near-infrared spectroscopy: validation of bladder-outlet obstruction assessment using non-invasive parameters. Can J Urol 2008;15:4241e8. Farag FF, Meletiadis J, Saleem MD, Feitz WF, Heesakkers JP. Near-infrared spectroscopy of the urinary bladder during voiding in men with lower urinary tract symptoms: a preliminary study. Biomed Res Int 2013;2013:452857. Farag FF, Martens FM, D’Hauwers KW, Feitz WF, Heesakkers JP. Near-Infrared Spectroscopy: a novel, noninvasive, diagnostic method for detrusor over activity in
B. Shadgan et al.
[28]
[29]
[30]
[31]
[32]
patients with overactive bladder symptoms e A preliminary and experimental study. Eur Urol 2011;50(5):757e62. Yurt M, Suer E, Gulpinar O, Telli O, Arikan N. Diagnosis of bladder outlet obstruction in men with lower urinary tract symptoms: comparison of near infrared spectroscopy algorithm and pressure flow studies. Urology 2012;80:182e6. Shadgan B, Afshar K, Stothers L, Macnab A. Near-infrared spectroscopy of the bladder: a new technique for studying lower urinary tract function in health and disease. Proc SPIE 2010;7548:75480U. Shadgan B, Macnab A, Nigro M, Stothers L. Monitoring of lower urinary tract function in patients with spinal cord injury using near infrared spectroscopy. Proc SPIE 2012;8207:820717. Molavi B, Dumont G, Shadgan B, Macnab A. Attenuation of motion artifact in near infrared spectroscopy signals using a wavelet based method. Proc SPIE 2011;7890:78900M. Molavi B, Dumont G, Shadgan B. Motion artifact removal from muscle NIR spectroscopy measurements. Electr Comput Eng 2010:1e4. http://dx.doi.org/10.1109/CCECE.2010.5575241.
Optical diagnosis of lower urinary tract infection: A pilot study in children Babak Shadgan a,b, Mark Nigro a,b, Andrew Macnab a, Mehdi Fareghi c, Lynn Stothers a,b, Lida Sharifi-Rad c, Abdol-Mohammad Kajbafzadeh c a
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
b Center for International Collaboration on Repair Discoveries (ICORD), Vancouver, Canada
c Pediatric Urology Research Center, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Iran
Correspondence to: B. Shadgan, ICORD, Blusson Spinal Cord Centre, 818 West 10th Ave., Vancouver, BC, V5Z1M9, Canada. Tel.: þ1 604 675 8846; fax: þ1 604 228 1158 [email protected] (B. Shadgan) [email protected] (M. Nigro) [email protected] (A. Macnab) [email protected] (M. Fareghi) [email protected] (L. Stothers) [email protected] (L. Sharifi-Rad) [email protected] (A.M. Kajbafzadeh)
Summary Conventionally, diagnosis of lower urinary tract infection (LUTI) is made on the basis of history, urine microscopy and culture. But there are limitations to this methodology especially in children and special populations where there is difficulty in obtaining a full history and details of clinical symptoms. The aim of this study was to determine if monitoring bladder wall oxygenation as a measure of bladder mucosal inflammation using transcutaneous near-infrared spectroscopy (NIRS) allows detection of the presence or absence of LUTI in children. Materials and methods A convenience sample of children referred to a pediatric urology clinic with an acute LUTI and a control group were studied. Diagnosis was confirmed by history, physical examination, laboratory investigations, and urine culture. Participants had transcutaneous measurement of an absolute measure of tissue oxygen saturation (TSI%) in their bladder wall, and a quadriceps muscle control site, using a spatially resolved (SR) wireless NIRS device. Average measures of bladder wall TSI% (B.TSI%) and
quadriceps TSI% (Q.TSI%) and their differences (TSI.diff) were calculated and compared between those with LUTI and controls by performing a twoway repeated analysis of variance. Results Thirty-four patients met the inclusion criteria (LUTI n Z 12 and controls n Z 22). Comparing LUTI to controls B.TSI% and TSI.diff values were significantly higher in the LUTI group (p < 0.0001), while Q.TSI% values were not significantly different. Conclusions Optical monitoring of bladder wall oxygenation is feasible in children. In this study a significant difference was evident in a SR NIRS-derived measure of absolute oxygen saturation in the bladder wall between children with UTI diagnosed by conventional testing methods, and those in a control group without infection. SR-NIRS monitoring of bladder wall oxygenation may offer a rapid and non-invasive means of bedside screening for LUTI where history and/or clinical signs are not available or adequate.
Keywords Near-infrared spectroscopy; Urinary bladder; Cystitis; Inflammation; Infection Received 22 April 2014 Accepted 27 August 2014 Available online 28 February 2015
Figure http://dx.doi.org/10.1016/j.jpurol.2014.08.017 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Optical diagnosis of urinary tract infection
Introduction Lower urinary tract infection (LUTI) is a common and potentially serious condition in both adult and pediatric populations [1]. LUTI is defined as infection of lower urinary tract with bacterial count 104 CFU/mL urine, which is accompanied by clinical signs and symptoms of lower urinary tract infection. In infants and young children as well as elderly adults and those affected by neuropathies and spinal cord injuries (SCI) the diagnosis is often complicated by difficulty obtaining the required history of the hallmark clinical symptoms on which diagnosis is based [2,3]. In additional to difficulties obtaining the required history, the diagnosis of LUTI can be complicated by issues related to urine analysis, as collecting urine samples suitable for definitive urinalysis and culture can be a challenge in both children and the elderly, and also patients with neurogenic bladder. The feasibility, reliability and usefulness of conventional tests for the diagnosis of UTI have been described [4e6]. Dipstick biochemical analysis for nitrites or leukocyte esterase is the easiest means of screening for UTI qualitatively, but requires collecting urine samples, does not detect all bacteria, and is subject to false-negative results, which may lead to failure of diagnosis [7]. These difficulties are relevant as early detection and management of LUTI is recognized as critical in the prevention of ascending upper urinary tract infections (UUTI) and its related complications [1,8]. A reliable and objective diagnostic and monitoring methodology to identify the presence of LUTI would be useful clinically. Near infrared spectroscopy (NIRS) is a non-invasive transcutaneous optical technique akin to oximetry that uses light in the near-infrared (NIR) spectrum to monitor changes in the concentration of oxygenated (O2Hb), deoxygenated (HHb) hemoglobin, and total hemoglobin (tHb) in a tissue of interest, including the bladder [9,10]. Changes in NIRS parameters are seen in real time in physiologic processes where tissue hemodynamics and/or oxygenation are altered [11]. Bacterial cystitis is recognized to cause inflammation of the bladder wall, and a physiologic increase in mucosal perfusion and local oxygen consumption is assumed to result [12]. Hence we hypothesized that a NIRS-derived measure of absolute tissue oxygenation would differ between subjects with and without LUTI, and consequently that NIRS could offer a non-invasive optical method of detecting changes in bladder perfusion and oxygenation resulting from the presence of infection. If proven, NIRS of the bladder might then be used as a screening method to detect the onset of LUTI and monitor for resolution of the resulting inflammation with effective treatment. NIRS uses principles of physics similar to those underlying oximetry. Photons of NIR light emitted from the device penetrate through skin and into living tissue; O2Hb and HHb are chromophores, compounds that absorb NIR light, and each has a different wavelength-dependent absorption peak [9,11]. A detector captures photons that return because they are neither absorbed nor scattered; softwarebased mathematical algorithms can determine from this raw optical data concentration changes from baseline for
74.e2 O2Hb and HHb using a modification of the BeereLambert law, from which real-time variations in tissue oxygenation and hemodynamics from baseline can be derived [13,14]. In addition, spatially resolved (SR) NIRS devices can provide an absolute measurement of tissue oxygen saturation [15]. The path of NIR photons though living tissue is “banana” shaped with penetration at the midpoint being equal to half the distance between the emitter and detector (interoptode distance) [9]. The feasibility of monitoring changes in detrusor blood volume and oxygen supply and demand in the bladder have been demonstrated [16], and also the measurement of bladder wall absolute tissue oxygen saturation, expressed as the tissue saturation index (TSI%) [17]. We describe a pilot study in children using a spatially resolved wireless NIRS device to non-invasively monitor children for physiological changes in bladder hemodynamics and oxygenation generated by LUTI, as measured by TSI%. We hypothesized that this measure of bladder wall oxygen saturation (TSI%) would be higher when the bladder is inflamed as a consequence of increased perfusion associated with having LUTI.
Materials and methods Subjects A convenience sample of children less than 16 years of age, referred to the urology clinic at a pediatric hospital during May 2013 participated. Inclusion criteria included: 1) children with a urogenital complaint, 2) with no history of bladder dysfunction, 3) with or without UTI, but with no other infections, 4) with no other major comorbidity, and 5) with suprapubic fat layer thickness of 74.5% as a potential diagnostic index for identifying a child as probably affected by UTI.
Figure 1 Wireless near-infrared spectroscopy measurements of bladder wall and quadriceps tissue oxygen saturation (TSI%) in a child with acute urinary tract infection.
Optical diagnosis of urinary tract infection Table 1 #
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 16 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
74.e4
Subject characteristics.
Gender
M F M M M M M M F M M M M M M M M M M F M M F F F F F F M F M M M F
Age (yrs)
3 4 3 3 6 5 2 2 8 1 6 1 8 1 3 7 5 2 2 11 1 4 5 5 6 4 6 2 2 9 6 12 7 6
Symptoms
Urine analysis
Fever
Dysuria
WBC
RBC
Bacteria
þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ
þ
þ þ þ þ þ þ þ þ þ þ þ þ þ
Urine culture
Q.TSI%
B.TSI%
TSI.diff
þ þ þ þ þ þ þ þ þ þ þ þ
58.8 64.1 59 72.3 64.8 75.9 69.2 65.2 64.8 75.8 56.2 58.5 73.9 74.9 78.9 65.6 70.4 69.3 70.4 69.9 60.8 74.6 68 68.1 75.6 75.4 74.7 65.8 75.3 74.8 74.2 60.7 62.2 70.2
58.3 64.5 60.9 67 62 73.7 67.8 59.4 66.3 77.1 58 49.1 75.3 73 75.6 63.1 72 71.9 69.3 71.1 59.4 74.5 80.1 81.9 89.9 84.9 79.9 82.5 80.7 80.9 88.7 70.5 70.6 78.9
0.5 0.4 1.9 5.3 2.8 2.2 1.4 5.8 1.5 1.3 1.8 9.4 1.4 1.9 3.3 2.5 1.6 2.6 1.1 1.2 1.4 0.1 12.1 13.8 14.3 9.5 5.2 16.7 5.4 6.1 14.5 9.8 8.4 8.7
TSI Z tissue oxygen saturation; B Z bladder; Q Z quadriceps.
Discussion In this study a significant difference was evident in an SR NIRS-derived measure of absolute oxygen saturation in the bladder wall between children with UTI diagnosed by conventional testing methods, and those in a control group without infection. The method we describe uses a noninvasive optical method akin to oximetry, where NIR light is introduced transcutaneously over the bladder to interrogate the bladder wall by measurement of NIR light absorption by the naturally occurring chromophores O2Hb and HHb. In other studies using NIRS to investigative the effects of inflammation at a surgical site, Govinda et al. [22] reported that NIRS-derived oxygen saturation (StO2) measurements might be able to predict surgical site infection, and thus allow earlier preventive measures to be implemented. These data compare to our findings of changes in bladder TSI% in patients affected by UTI.
In multiple prior studies, in a range of tissues, NIRS monitoring has been shown detect variations in oxygenation via changes in the concentration and trend data of the chromophores O2Hb and HHb, and hemodynamic variations via changes in the sum of O2Hb and HHb, total hemoglobin (tHb) [23,24]. In addition a number of absolute physiologic parameters can be measured by using variations on the basic NIRS monitoring technique. Absolute measurement of tissue oxygen saturation requires use of an SR NIRS device with optical geometry that incorporates two or more different NIR emitter to detector distances and specific software to derive the expressed value (tissue saturation index or TSI% in the case of the PortaMon device used in this study) free of motion artifact. Prior reports describing NIRS applications to monitor the bladder include: studies in health and where various bladder pathologies are present [19e21,25e30]; the methodologies applied [10,16,21,25]; and rationale for the data obtained representing
74.e5 Table 2
Q.TSI%
B.TSI%
TSI.diff
B. Shadgan et al. Groups comparison.
Mean SD () Range Mean SD () Range Mean SD () Range
Non-UTI group
UTI group
Significance
67.9 6.5 56.2e78.9 66.8 7.3 49.1e77.1 1.1 3 5.8 to 2.6
70.4 5.4 60.7e75.6 80.8 5.9 70.5e89.9 10.4 3.9 5.2e16.7
p Z 0.20
p < 0.0001
p < 0.0001
TSI Z tissue oxygen saturation; B Z bladder; Q Z quadriceps; UTI Z urinary tract infection.
physiologic change in the bladder wall [16,20,27,28]. Also, the feasibility of monitoring bladder wall TSI% in patients with neurogenic bladder due to spinal cord injury and children [29,30]; two patient groups identified to represent a greater challenge than most other subjects in the context of detection and diagnosis of UTI. Conventionally, diagnosis of UTI is made on the basis of history, urine microscopy and culture. But there are limitations to this methodology especially in special populations where there is difficulty in obtaining a full history and details of clinical symptoms. Hence the potential of using a non-invasive monitoring technique that can detect the presence of bladder inflammation secondary to UTI to screen children, elderly people, and patients such as those with neurogenic bladder. NIRS could offer a means of
Figure 2 The difference between bladder wall and quadriceps tissue oxygen saturation (TSI.diff) is significantly higher in subjects affected by urinary tract infection (UTI) comparing non-UTI (NUTI) subjects.
screening for possible early infection, and if the technique is validated in further trials would provide the ability to identify the need to obtain a clean sample for microscopy and culture, and promptly initiate treatment. The effect of treatment could also be monitored via detection of the resolution of the inflammation generated in the bladder by active infection. In addition, home monitoring for patients at increased risk for UTI could be achieved in this way with a miniature wireless SR NIRS device used by the patient, with data collected as frequently as considered clinically desirable, and sent via secure wireless data link for interpretation at a urological center. Early detection and appropriate management of LUTI is an invaluable entity for prevention of ascending UUTI and consequent renal scar formation in children and high-risk individuals. Experimental studies confirm that the early administration of antibiotics and antioxidants result in a lower incidence of renal scaring [8]. Early recognition of LUTI by SR NIRS could pave the way for early detection of febrile UTI and rationalize administration of appropriate antibiotics prior to the receipt of the urine culture results 48e72 h later. NIRS offers a feasible method for early diagnosis of acute LUTI in children because it is an established noninvasive technology, and current devices are compact, low weight, relatively cheap, resistant to body motion and have the ability to achieve the depth of penetration through tissue for transcutaneous monitoring to interrogate the bladder wall. There are a number of limitations to this study. The sample size was small; subjects with a marked bladder dysfunction did not included; subjects did not undergo a comprehensive work-up to prove that in addition to UTI they were not affected by any other infection; bladder capacity, uroflow, and post-voiding residual were not measured in all subjects, and the application of SR NIRSderived TSI% measurement to detect inflammation due to UTI is novel. However, this same NIRS device has been used successfully to monitor bladder hemodynamics and oxygenation and detrusor oxygen saturation (TSI%) in children and adults, including those with neurogenic bladder due to spinal cord injury [29,30]. No early or late complications related to NIRS application were observed throughout the study. We also recognize that a number of important potential confounders exit in the context of NIRS monitoring of the bladder, including the depth of penetration of NIR photons, and the potential effect of light attenuation in subcutaneous tissue, changes in bladder volume, and movement on the chromophore data obtained. The reasons for confidence that NIRS does measure physiologic change and that diagnostic data are obtained have been discussed previously [11,16,18,21,25,27,28,31,32]. The current effective depth of penetrations of conventional NIRS systems is limited to a maximum of 25e30 mm in living tissues. This depth of penetration is enough to interrogate the bladder wall in children and adults, except in very overweight subjects with a suprapubic fat layer of more than 20 mm. For deeper measurements, NIRS systems need to have a higher interoptode distance, which requires using higher intensity light sources in a more complex setup. Prior bladder NIRS studies in children and adult subjects confirm access of transcutaneous near infrared lights to
Optical diagnosis of urinary tract infection interrogate bladder wall tissue [11,16,27,28]. Tissue movement during NIRS data collection can induce motion artifact on NIRS signals; however, with proper device placement and using different types of motion artifact removal techniques, the effect of movement on NIRS signals could be effectively controlled [31,32]. The statistical differences in the oxygen saturation parameters evident between the UTI and control groups show the significance of the findings in this pilot study, and also allow cut-off parameters for the presence and absence of UTI-derived bladder inflammation to be proposed. We suggest that further studies using NIRS as means of identifying UTI are warranted. To support this pilot study hypothesis a larger clinical trial is required to investigate the sensitivity and specificity of the SR NIRS TSI% method in subjects confirmed to have UTI based on conventional testing and a cohort of non-infected control subjects. Using a two-channel SR NIRS system for simultaneous measurement of bladder and control side TSI% values would reduce the time of testing to 1 min. Future studies could also include examination of the feasibility, diagnostic accuracy, and reliability of this method for early diagnosis and resolution of infection in response to treatment in people with SCI, because of the significant problem LUTI represents in this population.
Conclusion Non-invasive NIRS optical monitoring of an absolute measure of bladder oxygenation is feasible in children. In those with UTI proven by history, symptoms, and culture this measure differs significantly from asymptomatic controls. Further clinical trials with a larger sample size are required to confirm the findings of this pilot study.
Conflict of interest None.
Funding None.
Acknowledgments The authors would like to thank the Urology Foundation, Michael Smith Foundation for Health Research (MSFHR), Pediatric Urology Research Centre and Rick Hansen Institute (Postdoctoral Fellowship Award to Dr. Babak Shadgan: Trainee Award Number # ST-PDF-03096) for supporting this study.
References [1] Schardijn GH, Statius van Eps LW, Pauw W, Hoefnagel C, Nooyen WJ. Comparison of reliability of tests to distinguish upper from lower urinary tract infection. Br Med J (Clin Res Ed) 1984;289:284e7.
74.e6 [2] National Institute for Health and Clinical Excellence. Urinary tract infection in children. London: NICE; 2007. Retrieved October 2013 from: http://guidance.nice.org.uk/CG054. [3] D’Hondt F, Everaert K. Urinary tract infections in patients with spinal cord injuries. Curr Infect Dis Rep 2011;13:544e51. [4] Hoffman JM, Wadhwani R, Kelly E, Dixit B, Cardenas DD. Nitrite and leukocyte dipstick testing for urinary tract infection in individuals with spinal cord injury. J Spinal Cord Med 2004; 27:128e32. [5] Aliyu SH, Ludlum H, Abubakar I, Bentley N. What is the role of urine dipstick testing in the management of UTI? Br J Gen Pract 2002;52:414e5. [6] Bitsori M, Galanakis E. Pediatric urinary tract infections: diagnosis and treatment. Expert Rev Anti Ther 2012;10: 1153e64. [7] Doley A, Nelligan M. Is a negative dipstick urinalysis good enough to exclude urinary tract infection in paediatric emergency department patients? Emerg Med (Fremantle) 2003 Feb;15:77e80. [8] Sadeghi Z, Kajbafzadeh AM, Tajik P, Monajemzadeh M, Payabvash S, Elmi A. Vitamin E administration at the onset of fever prevents renal scarring in acute pyelonephritis. Pediatr Nephrol 2008;23:1503e10. [9] Delpy DT, Cope M. Quantification in tissue near-infrared spectroscopy. Philos Trans R Soc Lond B 1997;352:649e59. [10] Pannek J. Editorial comment on: classification of male lower urinary tract symptoms using mathematical modeling and a regression tree algorithm of noninvasive near-infrared spectroscopy parameters. Eur Urol 2010;57:332e3. [11] Macnab AJ, Shadgan B. Biomedical applications of wireless continuous wave near infrared spectroscopy. Biomed Spectros Imaging 2012;1:205e22. [12] Echols RM, Tosiello RL, Haverstock DC, Tice AD. Demographic, clinical, and treatment parameters influencing the outcome of acute cystitis. Clin Infect Dis 1999;29:113e9. [13] Delpy DT, Cope M, van der Zee P, Arridge S, Wray S, Wyatt J. Estimation of optical pathlength through tissue from direct time of flight measurements. Phys Med Biol 1988;33: 1433e42. [14] Boushel R, Langberg H, Olesen J, Nowak M, Simonsen L, Bulow J, et al. Regional blood flow during exercise in humans measured by near-infrared spectroscopy and indocyanine green. J Appl Physiol 2000;89:1868e78. [15] Suzuki S, Takasaki S, Ozaki T, Kobayashi Y. A tissue oxygenation monitor using NIR spatially resolved spectroscopy. Proc SPIE 1999;3597:582e92. [16] Macnab AJ, Shadgan B, Stothers L. The evolution of wireless near infrared spectroscopy: applications in urology and rationale for clinical use. J NIRS 2012;20:57e73. [17] Shadgan B, Macnab, Stothers L. Optical diagnosis of interstitial cystitis/painful bladder syndrome. Proc SPIE 2013:856510. [18] van Beekvelt MCP, Borghuis MS, van Engelen BGM, Wevers RA, Colier WN. Adipose tissue thickness affects in vivo quantitative near-IR spectroscopy in human skeletal muscle. Clin Sci (London) 2001;101:21e8. [19] Shadgan B, Reid WD, Gharakhanlou R, Stothers L, Macnab A. Wireless near-infrared spectroscopy of skeletal muscle oxygenation and hemodynamics during exercise and ischemia. Spectroscopy 2009;23:233e41. [20] Macnab AJ, Friedman B, Shadgan B, Stothers L. Bladder anatomy physiology and pathophysiology: elements that suit near infrared spectroscopic evaluation of voiding dysfunction. Biomed Spectros Imaging 2012;1:223e35. [21] Macnab AJ, Stothers L, Shadgan B. Monitoring detrusor oxygenation and hemodynamics non-invasively during dysfunctional voiding. Adv Urol 2012:1e8. Article ID 676303. [22] Govinda R, Kasuya Y, Bala E, Mahboobi R, Devarajan J, Sessler DI, et al. Early postoperative subcutaneous tissue
74.e7
[23]
[24]
[25]
[26]
[27]
oxygen predicts surgical site infection. Anesth Analg 2010;111: 946e52. Ferrari M, Quaresima V. Near infrared brain and muscle oximetry: from the discovery to current applications. J NIRS 2012;20:1e14. Hamaoka T, McCully KK, Quaresima V, Yamamoto Y, Chance B. Near-infrared spectroscopy/imaging for monitoring muscle oxygenation and oxidative metabolism in healthy and diseased humans. J Biomed Opt 2007;12:062105. Macnab AJ, Stothers L. Near-infrared spectroscopy: validation of bladder-outlet obstruction assessment using non-invasive parameters. Can J Urol 2008;15:4241e8. Farag FF, Meletiadis J, Saleem MD, Feitz WF, Heesakkers JP. Near-infrared spectroscopy of the urinary bladder during voiding in men with lower urinary tract symptoms: a preliminary study. Biomed Res Int 2013;2013:452857. Farag FF, Martens FM, D’Hauwers KW, Feitz WF, Heesakkers JP. Near-Infrared Spectroscopy: a novel, noninvasive, diagnostic method for detrusor over activity in
B. Shadgan et al.
[28]
[29]
[30]
[31]
[32]
patients with overactive bladder symptoms e A preliminary and experimental study. Eur Urol 2011;50(5):757e62. Yurt M, Suer E, Gulpinar O, Telli O, Arikan N. Diagnosis of bladder outlet obstruction in men with lower urinary tract symptoms: comparison of near infrared spectroscopy algorithm and pressure flow studies. Urology 2012;80:182e6. Shadgan B, Afshar K, Stothers L, Macnab A. Near-infrared spectroscopy of the bladder: a new technique for studying lower urinary tract function in health and disease. Proc SPIE 2010;7548:75480U. Shadgan B, Macnab A, Nigro M, Stothers L. Monitoring of lower urinary tract function in patients with spinal cord injury using near infrared spectroscopy. Proc SPIE 2012;8207:820717. Molavi B, Dumont G, Shadgan B, Macnab A. Attenuation of motion artifact in near infrared spectroscopy signals using a wavelet based method. Proc SPIE 2011;7890:78900M. Molavi B, Dumont G, Shadgan B. Motion artifact removal from muscle NIR spectroscopy measurements. Electr Comput Eng 2010:1e4. http://dx.doi.org/10.1109/CCECE.2010.5575241.
