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Original Article |

Effect on Oximetry of Dyes Used for Sentinel Lymph Node Biopsy:  Are There Differences? FREE

Antonio Piñero, MD, PhD; Julián Illana, MD, PhD; Carlos García-Palenciano, MD; Francisco Cañizares, MD; Manuel Canteras, PhD; Victoria Cañadillas, MD; Eugenia Durán, MD; Pascual Parrilla, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of General Surgery (Drs Pi[[ntilde]]ero, Illana, and Parrilla), Anaesthesia (Drs Garc[[iacute]]a-Palenciano, Ca[[ntilde]]adillas, and Dur[[aacute]]n), and Clinical Analysis (Dr Ca[[ntilde]]izares), [[ldquo]]Virgen de la Arrixaca[[rdquo]] University Hospital; and Department of Biostatistics, School of Medicine (Dr Canteras), Murcia, Spain.


Arch Surg. 2004;139(11):1204-1207. doi:10.1001/archsurg.139.11.1204.
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Hypothesis  There are differences between readings of peripheral blood oxygen saturation when the effect on saturation values of methylene blue is compared with that of isosulfan blue when used in sentinel lymph node biopsy in patients with breast cancer.

Design  Prospective randomized study.

Setting  University tertiary care center.

Patients  Thirty-two women undergoing surgery for breast cancer using sentinel lymph node biopsy.

Interventions  Sentinel lymph node biopsy usingmethylene blue (16 patients) and isosulfan blue (16 patients); there was also a control group of 6 surgicalpatients in whom dyes were not used.

Main Outcome Measures  Peripheral saturation of blood using pulse oximetry, oxygen saturation by blood-gas analysis, partial oxygen pressure by blood-gas analysis, and plasma dye levels, recorded before dye injection and 15, 30, and 60 minutes afterward.

Results  The 2 dyes interfered with the peripheral saturation reading, but only isosulfan blue showed significant differences. The differences in blood-gas analysis values between the 2 groups and with regard to the controls were not significant.

Conclusions  Methylene blue interferes less than isosulfan blue in the peripheral saturation reading. Desaturation is factitious in both cases, and does not correspond to alterations in blood-gas analysis values.

Figures in this Article

Selective sentinel lymph node biopsy represents a major milestone in the treatment of patients with breast cancer. This method can identify lymph nodes with a greater likelihood of being involved in the event of lymphatic spread of the disease and has the advantages of being able to avoid unnecessary lymphadenectomies and staging the process correctly; it has been regarded as even more accurate than standard lymphadenectomy, because it carries out a much more exhaustive study of the isolated lymph node or lymph nodes by also using immunohistochemical techniques.13

The agreed method for performing this technique combines the use of isotopic tracers and vital dyes, which yields a higher detection rate than the 2 methods used separately.46

Several vital dyes have been used, notably methylene blue, isosulfan blue, and patent blue. Each of them has its specific advantages and disadvantages, but generally one of the most common drawbacks is interference with the oxygen saturation readings taken intraoperatively by the anesthetist using photospectrometric techniques. The staining caused when these substances enter the bloodstream, and before they are eliminated by the kidneys, interferes with the data collected via these techniques; even if it is a factitious desaturation, it may cause monitoring problems in these patients.

This study compares the effect on saturation values of 2 of the vital dyes (methylene blue and isosulfan blue) most commonly used for sentinel lymph node biopsy in patients with breast cancer.

A prospective randomized study was conducted on 32 women undergoing consecutive operations for breast cancer in whom sentinel lymph node biopsy was indicated. Excluded were patients with anemia, cardiopathy, bronchopathy, and renal or hepatic insufficiency. The indications for sentinel lymph node biopsy included patients with single palpable tumors measuring less than 3 cm and those without clinically palpable adenopathies. All the patients were informed of the technique and gave their written consent. All of them underwent the mixed technique, with simultaneous use of an isotopic tracer (Nanocoll; Nicomed-Italia, Saluggia, Italy), injected around the tumor 2 to 12 hours before the operation, and a dye, injected around the areola after intubation of the patient and with a breast massage for at least 10 minutes. The patients were distributed consecutively in a 1:1 ratio to include 16 women in each of the following 2 groups: (1) 5 mL of 1% methylene blue and (2) 5 mL of 1% isosulfan blue (1% Lymphazurin; Ben Venue Laboratories Inc, Bedford, Ohio).

Six patients undergoing surgery under general anesthesia, without the use of dyes, were used as a control group; the same variables were recorded in these patients.

Monitoring was done in all the patients by pulse oximetry using a monitor (model S/5) and an oxygen transducer (Oxisensor II D25; Datex-Ohmeda Inc, Andover, Mass), with a red and infrared light emission of between 660 and 910 nm. The radial artery was cannulated during the operation to obtain samples for determining oxygen saturation via blood-gas analysis, partial oxygen pressure, and serum dye levels before dye injection and 15, 30, and 60 minutes afterward. The anesthetist (C.G.-P., V.C., or E.D.) recording the data was unaware of which dye had been injected.

Eight patients from each dye group underwent determination of their serum dye levels at 15, 30, and 60 minutes after injection. The plasma was separated immediately by centrifugation (3000 rpm for 15 minutes), and the methylene blue and isosulfan blue levels were determined by the increase in absorbency at 666 and 638 nm, respectively, using a spectrophotometric sweep (Lambda 20; Perkin-Elmer, Torrance, Calif) between 570 and 720 nm, via the Allen method, correcting the absorbency of the plasma with the preoperative dye-free sample from each patient. The increase in absorbency was converted into concentration (milligrams per liter) using a standard curve for each dye.

All the patients maintained stable arterial tension values during surgery, with no significant fluctuations. There were no differences between the groups for age, serum creatinine levels, or fraction of inspired oxygen used during the operation (Table).

Table Graphic Jump LocationTable. Comparison of Groups With Regard to Age, FIO2, and Creatinine Levels*

Comparison of the between-group quantitative variables was done using a means comparison with the t test, regarding a value of P<.05 as significant. To compare the figures for oxygen saturation (in blood-gas analysis and pulse oximetry), partial oxygen pressure at each time between the 2 dye groups, and plasma dye level in each group, an analysis of variance was used of repeated measurements corresponding to a hierarchical factorial design; the between-group analysis, represented by the graphs, was done by comparison of measurements using the minimum significant difference criterion. Statistical calculations were performed using a software application (BMDP; Statistical Software Inc, Los Angeles, Calif). 

As can be seen in Figure 1, Figure 2, and Figure 3, pulse oximetry showed a desaturation process with both dyes, but it was not accompanied by a real desaturation in the blood-gas analysis readings.

Place holder to copy figure label and caption
Figure 1.

Evolution of oxygen saturation values recorded by peripheral pulse oximetry. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .14; for the control group vs the isosulfan blue group, P = .03; and for the methylene blue group vs the isosulfan blue group, P = .02.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Evolution of partial oxygen pressure values recorded by blood-gas analysis. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .47; for the control group vs the isosulfan blue group, P = .45; and for the methylene blue group vs the isosulfan blue group, P = .36.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Evolution of arterial oxygen saturation values recorded by blood-gas analysis. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .18; for the control group vs the isosulfan blue group, P = .18; and for the methylene blue group vs the isosulfan blue group, P = .14.

Graphic Jump Location

Differences were found in the pulse-oximetric saturation values 15 minutes after injection of the dye, the values being significantly lower when isosulfan blue was used (P<.001 at 15 minutes). Although the methylene blue group values were also lower than the control values, these differences were not statistically significant (Figure 1).

When differences by time in oxygen saturation values are considered for each group only, differences between values for isosulfan blue at 15 and 60 minutes were significant (P<.001), although a clear return toward baseline by time was registered in isosulfan blue readings (Figure 1).

The differences between the figures for gasometric saturation and gasometric partial oxygen pressure between the 2 groups and with regard to the controls were not significant (Figure 2 and Figure 3).

Determination of the plasma dye levels shows that the methylene blue values are at all times significantly lower than the isosulfan blue values (Figure 4).

Place holder to copy figure label and caption
Figure 4.

Evolution of plasma dye content in the 2 groups. Data are given as mean ± SE. P =.01 for the difference between the 2 groups.

Graphic Jump Location

The effects reported when using dyes for sentinel lymph node detection in patients with breast cancer include a desaturation in the pulse-oximetric reading taken by the anesthetist as part of the patient’s monitoring protocol.79 This desaturation is not a real problem but the result of the interference that dilution of the dye in the patient’s plasma causes in the photometric measurement of peripheral blood oxygen saturation. In other words, it does not reflect a decrease in oxygen saturation but an incorrect measurement of this saturation, which has generally been related to the use of different dyes, not only those studied herein.7,1017

Some previous series had already shown that, particularly for the patent blue V dye, there is no real alteration in oxygenation when the peripheral saturation reading is compared with that obtained in the blood-gas analysis.9 Our results corroborate these findings by showing that although there is desaturation in the pulse-oximetric reading, there are no significant differences in the figures for partial oxygen pressure and arterial saturation in the blood-gas analysis. To our knowledge, it has not been determined whether this factitious desaturation process occurring with the dyes occurred to the same extent with dyes that, while interfering with similar wavelengths in the photometric process, present differences in absorption and transport. This is the case of the 2 dyes studied herein.

In pulse oximetry, a sensor emits red and infrared light at a wavelength of between 660 and 910 nm. This light is partially absorbed by the blood, and the reflected part is picked up by the other sensor, which calculates peripheral arterial saturation based on the difference obtained. In physiological conditions, methylene blue and isosulfan blue have peak absorption at wavelengths of 666 and 638 nm, respectively. This implies that in the range of wavelengths used by the pulse oximeter, the dyes absorb much light and cause interference, leading to overestimation of the “desaturation” of hemoglobin.9,18

Besides the interference by both dyes in the saturation measurement, the differences between them must also be considered. For a dye—regardless of which—to enter and mark the lymph node, it must have an adequate molecular size and reach the lymphatic system from the injection site.19 Furthermore, binding with endogenous proteins in the lymphatic system, generally via sulfonation reactions, allows the dye to be accumulated and transported through the lymphatic system.20

Dyes also pass into the bloodstream, directly or after their migration through the lymphatic system, from where they are eliminated by renal clearing. It is in this migration that differences in molecular structure may explain the different behavior of dyes in the pulse-oximetric reading. Isosulfan blue is a widely used dye in selective sentinel lymph node biopsy. It is a patent blue isomer and, as such, has 2 sulfonic groups in its chemical structure, which, although to a small extent, allow protein binding in lymph and plasma.20,21 Conversely, methylene blue shows no affinity to proteins at a temperature of 37°C20; it circulates in dissolved form, diffuses passively, directly into lymphatic and blood capillaries, and is theoretically retained less and cleared more from the bloodstream through the kidneys. All the same, molecular reaction mechanisms have been reported, independent of protein sulfhydryl groups, for compounds such as methylene blue, via conjugation to ammonium groups; these mechanisms explain the retention capacity of the lymphatic system.20 This might explain the findings of our study: although the 2 dyes interfere with the pulse-oximetry readings, methylene blue would do so to a lesser extent because of a smaller accumulation in the bloodstream, and would at all times register lower serum levels than isosulfan blue.

The potential relationship between (factitious) hypoxia and plasma dye levels is suggested by their reversed curves (Figure 1 and Figure 4, respectively). The isosulfan blue reading’s return toward baseline (Figure 1) could be explained by differences between the dyes’ renal clearance.

The difference observed between methylene blue and isosulfan blue is because of the plasma dye level and its interference with pulse oximetry due to different peak absorptions.

We see, therefore, that although both dyes are similarly useful for detecting the sentinel lymph node,2224methylene blue interferes less in the peripheral monitoring of saturation by pulse oximetry. If to this we add the greater availability of methylene blue and its lower cost, we may consider that methylene blue is a valid and even advantageous alternative to isosulfan blue in selective sentinel lymph node biopsy.

Correspondence: Antonio Piñero, MD, PhD, Department of General Surgery, “Virgen de la Arrixaca”University Hospital, 30120 El Palmar, Murcia, Spain (apm.cg@ono.com).

Accepted for Publication: May 31, 2004.

Veronesi  UPaganelli  GViale  G  et al.  Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999;91368- 373
PubMed
Giuliano  AEHaigh  PIBrennan  MB  et al.  Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2001;191882- 1883
PubMed
Allweis  TMBadriyyah  MBar Ad  VCohen  TFreund  HR Current controversies in sentinel lymph node biopsy for breast cancer. Breast 2003;12163- 171
PubMed
Cox  CEPendas  SCox  JM  et al.  Guidelines for sentinel lymph node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998;227645- 653
PubMed
Linehan  DCHill  ADAkhurst  T  et al.  Intradermal radiocolloid and intraparenchymal blue dye injection optimise sentinel node identification in breast cancer patients. Ann Surg Oncol 1999;6450- 454
PubMed
Martin  RCEdwards  MJWong  SL  et al.  Practical guidelines for optimal gammaprobe detection of sentinel lymph nodes in breast cancer: results of a multi-institutional study. Surgery 2000;128139- 144
PubMed
Vokach-Brodsky  LJeffrey  SSLemmens  HJHBrock-Utne  JG Isosulfan blue affects pulse oximetry. Anesthesiology 2000;931002- 1003
PubMed
Hoskin  RWGranger  R Intraoperative decrease in pulse oximeter readings following injection of isosulfan blue. Can J Anaesth 2001;4838- 40
PubMed
Koivusalo  AMvon Smitten  KLundgren  L Sentinel node mapping affects intraoperative pulse oximetric recordings during breast cancer surgery. Acta Anaesthesiol Scand 2002;46411- 414
PubMed
Kessler  MREide  THumayun  BPoppers  PJ Spurious pulse oximeter desaturation with methylene blue injection. Anesthesiology 1986;65435- 436
PubMed
Scheller  MSUnger  RJKeldner  HJ Effect of intravenously administered dyes on pulse oximeter readings. Anesthesiology 1986;65550- 552
PubMed
Sidi  APaulus  DARush  WGravestein  NDavis  RF Methylene blue and indocyanine green artifactually lower pulse oximetry readings of oxygen saturation: studies in dogs. J Clin Monit 1987;3249- 256
Ralston  ACWebb  RKRunciman  WB Potential errors in pulse oximetry: effects of interferences, dyes, dyes-hemoglobin and other pigments. Anaesthesia 1991;46291- 295
PubMed
Morell  RCHeynecker  TKashtan  HIRippe  C False desaturation due to intradermal patent blue dye. Anesthesiology 1993;78363- 364
PubMed
Saito  SFukura  HShimada  HFujita  T Prolonged interference of blue dye “patent blue” with pulse oximetry readings. Acta Anaesthesiol Scand 1995;39268- 269
El Tamer  MKomenaka  IKCurry  STroxel  ABDitkoff  BASchnabel  FR Pulse oximeter changes with sentinel lymph node biopsy in breast cancer. Arch Surg 2003;1381257- 1260
PubMed
Heinle  EBurdumy  TRecabaren  J Factitious oxygen desaturation after isosulfan blue injection. Am Surg 2003;69899- 901
PubMed
Coleman  RLWhitten  CWO’Boyle  JSidhu  B Unexplained decrease in measured oxygen saturation by pulse oximetry following injection of Lymphazurin 1% (isosulfan blue) during a lymphatic mapping procedure. J Surg Oncol 1999;70126- 129
PubMed
Wong  JHCagle  LAMorton  DL Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 1991;214637- 640
PubMed
Tsopelas  CSutton  R Why certain dyes are useful for localizing the sentinel lymph node. J Nucl Med 2002;431377- 1382
PubMed
Kam  PCAThompson  JFUren  RF Microanatomy and physiology of the lymphatic system. Nieweg  OEEssner  RReintgen  DSThompson  JFedsLymphatic Mapping and Probe Applications in Oncology New York, NY MarcelDekker Inc2000;18- 21
Blessing  WDStolier  AJTeng  SCBolton  JSFuhrman  GM A comparison of methylene blue and Lymphazurin in breast cancer sentinel lymph node mapping. Am J Surg 2002;184341- 345
PubMed
Simmons  RThevarajah  SBrennan  HBChristos  POsborne  M Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization. Ann Surg Oncol 2003;10242- 247
PubMed
Piñero  AIllana  JGalindo  PJNicolás  FParrilla  P Comparación del azul de isosulfan y del azul de metileno en la localización del ganglio centinela en el cáncer de mama. Cir Esp 2004;7581- 84

Figures

Place holder to copy figure label and caption
Figure 1.

Evolution of oxygen saturation values recorded by peripheral pulse oximetry. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .14; for the control group vs the isosulfan blue group, P = .03; and for the methylene blue group vs the isosulfan blue group, P = .02.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Evolution of partial oxygen pressure values recorded by blood-gas analysis. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .47; for the control group vs the isosulfan blue group, P = .45; and for the methylene blue group vs the isosulfan blue group, P = .36.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Evolution of arterial oxygen saturation values recorded by blood-gas analysis. Data are given as mean ± SE. For the control group vs the methylene blue group, P = .18; for the control group vs the isosulfan blue group, P = .18; and for the methylene blue group vs the isosulfan blue group, P = .14.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Evolution of plasma dye content in the 2 groups. Data are given as mean ± SE. P =.01 for the difference between the 2 groups.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Comparison of Groups With Regard to Age, FIO2, and Creatinine Levels*

References

Veronesi  UPaganelli  GViale  G  et al.  Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999;91368- 373
PubMed
Giuliano  AEHaigh  PIBrennan  MB  et al.  Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2001;191882- 1883
PubMed
Allweis  TMBadriyyah  MBar Ad  VCohen  TFreund  HR Current controversies in sentinel lymph node biopsy for breast cancer. Breast 2003;12163- 171
PubMed
Cox  CEPendas  SCox  JM  et al.  Guidelines for sentinel lymph node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998;227645- 653
PubMed
Linehan  DCHill  ADAkhurst  T  et al.  Intradermal radiocolloid and intraparenchymal blue dye injection optimise sentinel node identification in breast cancer patients. Ann Surg Oncol 1999;6450- 454
PubMed
Martin  RCEdwards  MJWong  SL  et al.  Practical guidelines for optimal gammaprobe detection of sentinel lymph nodes in breast cancer: results of a multi-institutional study. Surgery 2000;128139- 144
PubMed
Vokach-Brodsky  LJeffrey  SSLemmens  HJHBrock-Utne  JG Isosulfan blue affects pulse oximetry. Anesthesiology 2000;931002- 1003
PubMed
Hoskin  RWGranger  R Intraoperative decrease in pulse oximeter readings following injection of isosulfan blue. Can J Anaesth 2001;4838- 40
PubMed
Koivusalo  AMvon Smitten  KLundgren  L Sentinel node mapping affects intraoperative pulse oximetric recordings during breast cancer surgery. Acta Anaesthesiol Scand 2002;46411- 414
PubMed
Kessler  MREide  THumayun  BPoppers  PJ Spurious pulse oximeter desaturation with methylene blue injection. Anesthesiology 1986;65435- 436
PubMed
Scheller  MSUnger  RJKeldner  HJ Effect of intravenously administered dyes on pulse oximeter readings. Anesthesiology 1986;65550- 552
PubMed
Sidi  APaulus  DARush  WGravestein  NDavis  RF Methylene blue and indocyanine green artifactually lower pulse oximetry readings of oxygen saturation: studies in dogs. J Clin Monit 1987;3249- 256
Ralston  ACWebb  RKRunciman  WB Potential errors in pulse oximetry: effects of interferences, dyes, dyes-hemoglobin and other pigments. Anaesthesia 1991;46291- 295
PubMed
Morell  RCHeynecker  TKashtan  HIRippe  C False desaturation due to intradermal patent blue dye. Anesthesiology 1993;78363- 364
PubMed
Saito  SFukura  HShimada  HFujita  T Prolonged interference of blue dye “patent blue” with pulse oximetry readings. Acta Anaesthesiol Scand 1995;39268- 269
El Tamer  MKomenaka  IKCurry  STroxel  ABDitkoff  BASchnabel  FR Pulse oximeter changes with sentinel lymph node biopsy in breast cancer. Arch Surg 2003;1381257- 1260
PubMed
Heinle  EBurdumy  TRecabaren  J Factitious oxygen desaturation after isosulfan blue injection. Am Surg 2003;69899- 901
PubMed
Coleman  RLWhitten  CWO’Boyle  JSidhu  B Unexplained decrease in measured oxygen saturation by pulse oximetry following injection of Lymphazurin 1% (isosulfan blue) during a lymphatic mapping procedure. J Surg Oncol 1999;70126- 129
PubMed
Wong  JHCagle  LAMorton  DL Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 1991;214637- 640
PubMed
Tsopelas  CSutton  R Why certain dyes are useful for localizing the sentinel lymph node. J Nucl Med 2002;431377- 1382
PubMed
Kam  PCAThompson  JFUren  RF Microanatomy and physiology of the lymphatic system. Nieweg  OEEssner  RReintgen  DSThompson  JFedsLymphatic Mapping and Probe Applications in Oncology New York, NY MarcelDekker Inc2000;18- 21
Blessing  WDStolier  AJTeng  SCBolton  JSFuhrman  GM A comparison of methylene blue and Lymphazurin in breast cancer sentinel lymph node mapping. Am J Surg 2002;184341- 345
PubMed
Simmons  RThevarajah  SBrennan  HBChristos  POsborne  M Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization. Ann Surg Oncol 2003;10242- 247
PubMed
Piñero  AIllana  JGalindo  PJNicolás  FParrilla  P Comparación del azul de isosulfan y del azul de metileno en la localización del ganglio centinela en el cáncer de mama. Cir Esp 2004;7581- 84

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