Continuous monitoring of haemoglobin concentration after in-vivo adjustment in patients undergoing surgery with blood loss*

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1 Anaesthesia 15, 7, doi:1.1111/anae.138 Original Article Continuous monitoring of haemoglobin concentration after in-vivo adjustment in patients undergoing surgery with blood loss* D. Frasca, 1 H. Mounios, B. Giraud, M. Boisson, B. Debaene 3 and O. Mimoz 1 Assistant Professor, Senior Anaesthetist, 3 Professor and Head of Department, Professor and Head of Surgical Intensive Care Unit, Department of Anaesthesia and Intensive Care, University Hospital of Poitiers, Poitiers, France Summary Non-invasive monitoring of haemoglobin concentration provides real-time measurement of haemoglobin concentration (SpHb) using multi-wavelength pulse co-oximetry. We hypothesised that in-vivo adjustment using the mean of three haemoglobinometer (HemoCue â ) measurements from an arterial blood sample at the first SpHb measurement (HCueART) would increase the accuracy of the monitor. The study included 1 adults for a total of 173 measurements of haemoglobin concentration. In-vivo adjusted SpHb was automatically calculated by the following formula: in-vivo adjusted SpHb = unadjusted SpHb (SpHb HCueART). The accuracy of in-vivo adjusted SpHb was compared with SpHb retrospectively adjusted using the same formula, except for haemoglobin level which was assessed at the central laboratory and then compared with all other available invasive methods of haemoglobin measurement (co-oximetry, HbSAT; arterial HemoCue, HCueART; capillary HemoCue, HCueCAP). Compared with laboratory measurement of haemoglobin concentration, bias (precision) for unadjusted SpHb, in-vivo adjusted SpHb, retrospectively adjusted SpHb, HbSAT, HCueART and HCueCAP were. (1.),.3 (1.1),.3 (1.1),. (.7),. (.) and.5 (1.) g.dl 1, respectively. In-vivo adjustment of SpHb values using the mean of three arterial HemoCue measurements improved the accuracy of the device similar to those observed after a retrospective adjustment using central laboratory haemoglobin level.... Correspondence to: O. Mimoz o.mimoz@chu-poitiers.fr *Presented in part to the Societe Francßaise d Anesthesie et de Reanimation, September 13, Paris, France. Accepted: January 15 Introduction Accuracy of haemoglobin measurement remains an important determinant for transfusion decisionmaking, and can be obtained in several ways. Haemoglobin measurement at the central laboratory (HbLAB) is the gold standard but requires a blood sample and involves a time delay in obtaining the results. Pointof-care devices such as co-oximeters and haemoglobinometers have been developed to reduce this time but they also require a blood sample, are time-consuming, and do not provide a real-time assessment of change during the acute phase of blood loss. A non-invasive haemoglobin device (SpHb monitor; Masimo TM, Irvine, CA, USA) which provides real-time measurement of haemoglobin concentration has been introduced recently. Its performance has been evaluated in emergency departments, intensive care units and in the operating theatre with conflicting results [1 1]. Thus, the utility of SpHb for transfusion decision-making remains unproven. Improved 15 The Association of Anaesthetists of Great Britain and Ireland 83

2 Anaesthesia 15, 7, Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment accuracy was observed when SpHb was adjusted retrospectively using a laboratory measurement, suggesting that part of the bias between SpHb and the reference value is related to the patient [11, 1]. An in-vivo method for adjusting SpHb has been proposed recently by the manufacturer, but there is as yet no published validation in clinical practice. We hypothesised that in-vivo adjustment using the mean of three haemoglobinometer (HemoCue â ; Hb1, Angelholm, Sweden; HCueART) measurements from arterial blood sampled at the first SpHb measurement would increase the accuracy of the monitor. We also hypothesised that the accuracy of SpHb in vivo, adjusted using arterial HemoCue, which is available within a few minutes, would be similar to those of SpHb retrospectively adjusted using haemoglobin concentration measured at the central laboratory, which requires 3 min before the result is available. Finally, we compared the accuracy of SpHb adjusted in vivo with available invasive methods of haemoglobin measurements. Methods This prospective, observational study was conducted in the operating theatre at the University Hospital of Poitiers, France. After obtaining approval from the local ethics committee and written informed consent, adult patients undergoing elective major surgery with significant blood loss expected were recruited. Anaesthesia was induced with propofol.5 mg.kg 1 and sufentanil.3 mg.kg 1. Tracheal intubation was facilitated with rocuronium. mg.kg 1 and additional rocuronium administration was guided by neuromuscular monitoring during surgery. After induction of anaesthesia, an arterial catheter was placed in the radial artery to monitor blood pressure. Anaesthesia was maintained with isoflurane or desflurane and sufentanil. If necessary, a noradrenaline infusion was titrated to obtain a mean arterial pressure above 5 mmhg. Subjects were ventilated using volume-controlled mechanical ventilation (tidal volume: 8 ml.kg 1 ) with a mixture of oxygen and air (inspired oxygen fraction =.5). Respiratory rate was adjusted to maintain normocapnia. No patient received epidural or regional anaesthesia. Patients wore rainbow adult ReSposable sensors (R 5, Revision G) connected to a Radical-7 â Pulse co-oximeter, software version (Masimo), for continuous and non-invasive measurement of total haemoglobin concentration (SpHb), S p O, pulse rate and perfusion index (as an indicator of local perfusion). Sensors were applied to the patient following the directions for use provided by the manufacturer. This included the adequate application of the adhesive portion of the sensor so that the emitter and detector were precisely aligned on the finger. Sensors were covered with opaque shields to prevent optical interference per the manufacturer s directions for use. The sensor position was checked before every reading and readjusted if the adhesive portion became misaligned. If perfusion index was < 1%, the sensor was repositioned and recalibrated by switching the monitor off and on. For invasive assessment of haemoglobin level, arterial blood was drawn through a radial arterial catheter placed in the wrist contralateral to the SpHb sensor. Blood was collected into standard appropriate blood collection tubes. Reference haemoglobin values (HbLAB) were obtained by analysing arterial blood samples at the central laboratory using a Sysmex TM XT-1i automated haematology analyser (Roche TM Diagnostics, Paris, France). The confidence limits provided by the manufacturer for the Sysmex analyser are. g.dl 1. The same samples were also analysed with a satellite co-oximeter (Siemens TM RapidPoint 5, Siemens, Munich, Germany; HbSAT) and a HemoCue. Concomitantly, the fourth drop of blood after skin puncture on the ear was taken for testing of capillary blood with the same HemoCue point-ofcare device (HCueCAP). The anaesthetist was blinded to all haemoglobin values except those of HCueART that was used for clinical care. The Radical-7 is self-calibrating. The Sysmex measures haemoglobin concentration by colorimetry using the cyanide-free, sodium lauryl sulphate method, and is calibrated daily according to the manufacturer s instructions and good laboratory practice. The Rapid- Point is calibrated daily under the control of the central laboratory. The HemoCue point-of-care device is factory calibrated using the cyano-methaemoglobin method and does not require recalibration. The first SpHb ( first SpHb) measurement was recorded after the device had been reporting SpHb 8 15 The Association of Anaesthetists of Great Britain and Ireland

3 Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 15, 7, values for at least 15 min. Concomitantly, a reference HbLAB value ( first HbLAB) and the mean of three HCue- ART ( first HCueART) were obtained from an arterial blood sample. In-vivo SpHb adjustment ( IVadjusted SpHb) was automatically done by the Radical-7 interface and the displayed SpHb value was obtained using the following formula: IVadjustedSpHb ¼ unadjusted SpHb ð first SpHb first HCueARTÞ where unadjusted SpHb is the unadjusted value obtained by the monitor at the time of reading. To validate our choice of using the mean of three HCueART as the reference value, the SpHb value was also retrospectively adjusted ( Radjusted SpHb) using the following formula: RadjustedSpHb ¼ unadjusted SpHb ð first SpHb first HbLABÞ Then, simultaneous recording of unadjustedsphb, IVadjustedSpHb, HbLAB, HbSAT, HCueART and HCue- CAP values were manually collected before surgical incision and when required by the anaesthesiologist. Measures ended after completion of the surgical procedure. The perfusion index and the use of vasopressors (noradrenaline and/or ephedrine) were also recorded. The primary objective of the study was to assess the influence of in-vivo adjustment using the mean of three arterial HemoCue on the accuracy of the SpHb monitor. Secondary objectives were to compare: (i) the accuracy of the monitor after in-vivo and retrospective adjustment using haemoglobin concentration measured at the central laboratory; and (ii) the accuracy of the monitor after in-vivo adjustment to those of several invasive methods of haemoglobin monitoring. The sample size was set to a minimum of 15 measurements ( patients each with 3 measurements) according to Bland and Altman [13 15] recommendations for a precision of.3 SD of the 95% CI of the limits of agreement. Agreement between HbLAB (reference method) and haemoglobin values provided by the test devices was assessed as described by Bland and Altman [13 15]. Multiple haemoglobin measurements per patient provided unequal numbers of replicated data in pairs. Therefore, Bland and Altman analysis for repeated measures per subject as reported earlier [1, 15] was performed to calculate test method bias (error), SD (precision) and limits of agreement with 95% CI. Multiple mixed effects regression analysis using a general linear model was performed to evaluate the association of patients characteristics to SpHb biases. Variables analysed were as follows: age; sex; blood loss; fluid expansion; and use of vasopressor (noradrenaline). In addition, outliers for all haemoglobin measurements were calculated as difference value with the reference method greater than 1 or g.dl 1. The differences in outliers were analysed by the chi-squared test. Statistical analysis was performed with R 3.. (R Foundation, Vienna, Austria) with a significance level for two-tailed tests at p <.5. Results The study enrolled patients, of whom one was excluded owing to the inability to obtain a SpHb signal with a PI 1%. The characteristics of the 1 remaining patients are shown in Table 1. There were no adverse events associated with the use of SpHb sensors and shields. At the time of SpHb adjustment, mean (SD) unadjustedsphb, HbLAB, HbSAT, HCueART and HCueCAP values were 1.7 (.9), 1. (.), 1. (.7), 1. (.5) and 1.9 (1.) g.dl 1, respectively. Mean (SD) difference between first HCueART and first HbLAB was. (.1) g.dl 1. A median (IQR [range]) of 3 ( Table 1 Characteristics of the 1 patients. Values are median (IQR [range]) or number (proportion). Age; years 5 (5 7 [3 83]) Male 9 (7%) Surgery Total hip or knee 1 (%) replacement (redux) Hepatectomy 9 (%) Spinal surgery 5 (1%) Aortic aneurysm repair 5 (1%) Nephrectomy 3 (7%) Prostatectomy (5%) Meningioma 1 (%) Blood loss; ml 5 (3 1 [1 3]) Red cell transfusion 1 (39%) Fluid expansion; ml.h 1 95 (75 15 [5 175]) Use of vasopressor 1 (%) during procedure 15 The Association of Anaesthetists of Great Britain and Ireland 85

4 Anaesthesia 15, 7, Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment [ 8]) measurements was carried out per patient, leading to a total of 173 haemoglobin measurements. During the surgical procedure, HbLAB values dropped below 1 g.dl 1 in % of measurements and below 8 g.dl 1 in < 1% of measurements. Of the 1 patients, 1 (%) received vasopressors during surgery for a total of 3 measurements (5% of all measurements). Compared to the HbLAB reference method, bias, precision and 95% limits of agreement for undajdustedsphb, IVadjustedSpHb, RajustedSpHb, HbSAT, HCueART and HCueCAP are given in Table and corresponding Bland and Altman plots are presented in Fig. 1. Using the first arterial HemoCue instead of the mean of three arterial HemoCue to adjust SpHb values resulted in a non-significant deterioration of bias (. g.dl 1 vs.3 g.dl 1 ) and precision (1. g.dl 1 vs 1.1 g.dl 1 ) of the device. In multivariate analysis, there was no influence of tested covariates (including perfusion index and use of vasopressors) on unadjustedsphb and IVadjusted SpHb bias. Percentages of outliers are indicated in Table 3. Discussion This study is the largest one to assess the influence of in-vivo adjustment using the mean of three arterial HemoCue measurements on the accuracy of SpHb measurements in patients requiring elective surgery with a high risk of bleeding. This method of in-vivo adjustment was associated with an improvement of SpHb accuracy similar to those obtained after retrospective adjustment using haemoglobin assessment at the central laboratory. In-vivo adjustment is a new feature available on the Radical-7 monitor. It allows the clinician to adjust the initial SpHb measurement manually to match a value of his/her preferred reference device. Thereafter, the SpHb value is automatically adjusted by the user-entered bias. In a study conducted in surgical patients requiring 9 haemoglobin measurements, SpHb values were adjusted by subtracting the difference between the first SpHb and the first laboratory value from all subsequent SpHb values. SpHb bias (precision) was. (1.5) g.dl 1 before and.7 (1.) g.dl 1 after retrospective adjustment [11]. In a second study including 19 adult surgical patients requiring 73 measurements, both the bias (.8 g.dl 1 vs.1 g.dl 1 ) and precision (1. g.dl 1 vs.77 g.dl 1 ) improved after in-vivo adjustment [1]. In this latter study, adjustment was made using haemoglobin concentration measured with an automated gas analyser. These devices may be subject to significant intra-device and inter-device variability, greater than those of central laboratory analyser. Furthermore, the observed improvement in terms of coefficient of linear correlation (from.8 to.95) was not statistically tested. In this study, in-vivo adjustment improved SpHb precision to.3 g.dl 1 without significant impact on SpHb bias, which remained close to g.dl 1. The absence of significant effect on bias may be explained by the random changing direction of the difference between SpHb and the reference value. To expedite calibration of the monitor, we demonstrated that using the average of three values of HCueART allows the equivalent accuracy to the use of the laboratory value in < min. The use of Table Bias, precision and 95% limits of agreement for tested methods compared to reference method (based on 173 measurements). Values are number (95% CI). Bias; g.dl 1 Precision; g.dl 1 95% limits of agreement*; g.dl 1 unadjustedsphb. (.5 to.3) 1. (1. 1.5) 3. ( 3. to 3.) to. (..5) IVadjustedSpHb.3 (.3 to.3) 1.1 (.9 1.). (.5 to.) to 1.8 ( ) RadjustedSpHb.3 (.3 to.3) 1.1 (.9 1.). (.5 to.) to 1.8 ( ) HbSAT. (. to.).7 (..8). (. to.) to.7 (.7.7) HCueART. (..). (.3.).8 (.8 to.8) to.8 (.8.8) HCueCAP.5 (. to.) 1. (1. 1.5).9 ( 3. to.8) to 1.9 (1.8.1) unadjustedsphb, unadjusted continuous non-invasive haemoglobin measurement; IVadjustedSpHb, SpHb adjusted in vivo; RadjustedSpHb, SpHb adjusted retrospectively; HbSAT, satellite co-oximeter; HCueART, haemoglobinometer (arterial); HCueCAP, haemoglobinometer (capillary). * Adjusted for multiple measurements per patient The Association of Anaesthetists of Great Britain and Ireland

5 Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 15, 7, (a) (b) HbLAB - unadjusted SpHb (g.dl 1 ).. 3. HbLAB - IVadjusted SpHb (g.dl 1 ) Mean of HbLAB and unadjusted SpHb (g.dl 1 ) Mean of HbLAB and IVadjusted SpHb (g.dl 1 ) (c) (d) HbLAB - Radjusted SpHb (g.dl 1 ) HbLAB - HbSAT (g.dl 1 ).7.. (e) Mean of HbLAB and Radjusted SpHb (g.dl 1 ) (f) Mean of HbLAB and HbSAT (g.dl 1 ) HbLAB - HCueART (g.dl 1 ).8..8 HbLAB - HCueCAP (g.dl 1 ) Mean of HbLAB and HCueART (g.dl 1 ) Mean of HbLAB and HCueCAP (g.dl 1 ) Figure 1 Bland and Altman plot for (a) unadjusted continuous non-invasive haemoglobin measurement ( unadjusted SpHb), (b) SpHb adjusted in vivo ( IVadjusted SpH) or (c) retrospectively ( Radjusted SpHb), (d) satellite co-oximeter (HbSAT), (e) arterial haemoglobinometer (HCueART), and (f) capillary haemoglobinometer (HCueCAP), vs haematology analyser (HbLAB). Limits of agreement are adjusted for repeated measures from the same subject. Each point stands for one measurement. Mean bias is represented by the solid line and 95% limits of agreement by dashed lines. One hundred and seventy-three measurements were obtained. 15 The Association of Anaesthetists of Great Britain and Ireland 87

6 Anaesthesia 15, 7, Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment Table 3 Percentages of outliers defined as difference values between haemoglobin obtained by tested methods and the main laboratory equal to or higher than 1 g.dl 1 or g.dl 1 (n = 173 measurements). g.dl 1 unadjustedsphb 18 IVadjustedSpHb 8* 31* RadjustedSpHb 8* 3* HbSAT 1 HCueART < 1 HCueCAP 1 1 g.dl 1 unadjustedsphb, unadjusted continuous non-invasive haemoglobin measurement; IVadjustedSpHb, SpHb adjusted in vivo; RadjustedSpHb, SpHb adjusted retrospectively; HbSAT, satellite co-oximeter; HCueART, haemoglobinometer (arterial); HCueCAP, haemoglobinometer (capillary). *p =.1 (vs unadjusted SpHb). p =.1 (vs IVadjusted SpHb). only one arterial HemoCue moderately decreased the precision, but the difference was not clinically significant. The use of in-vivo adjustment when SpHb monitoring has the potential to improve patient care. Percentage of outliers between estimated and HbLAB haemoglobin values decreased from % with unadjustedsphb to 31% with IVadjusted SpHb for a difference over 1 g.dl 1, and from 18% to 8% for a difference over g.dl 1. These percentages were lower than those observed with capillary HemoCue, a method which is currently widely used in patients undergoing surgery to help with transfusion decisionmaking. These findings correlated well with the results of previous studies [11, 1] and may have clinical implications for the management of blood transfusion. In neurosurgery with SpHb monitoring [1], clinicians were able to initiate transfusions faster compared with physicians not using the technology, because they did not have to wait for a laboratory haemoglobin value. In-vivo adjusted SpHb may be even more relevant in such clinical settings, although large studies are required to confirm these interesting findings. Unfortunately, the accuracy of the SpHb device, even after in-vivo adjustment, remained lower than those observed with the use of arterial HemoCue or satellite co-oximeter. However, these techniques have their own limitations, including their invasiveness and inherent time delay for results. Moreover, their ability to detect a decrease in haemoglobin concentration earlier is lower than techniques with continuous monitoring of haemoglobin concentration. In our study, differences between in-vivo adjusted SpHb and actual haemoglobin values as high as 3 g.dl 1 were noted, although this observation was uncommon. Manufacturers should be encouraged to continue to improve the SpHb technology to make it even more accurate in the future, as they did with pulse oxygen saturation monitoring [17]. In conclusion, in-vivo adjustment using the mean of three arterial HemoCue measurements improves SpHb accuracy and facilitates faster transfusion decision-making. Prospective randomised trials should be considered to investigate further the clinical potential of in-vivo adjusted SpHb monitoring to reduce blood transfusions during surgery at high risk of bleeding. Competing interests The study was funded by University Hospital of Poitiers. Masimo Corp. supplied the Radical-7 monitors and the sensors used for measurements. The manufacturer had no input into the design or conduct of this study or in the decision to submit the manuscript for publication. DF and OM have received lecture fees and travel expenses from Masimo Corp. References 1. Gayat E, Bodin A, Sportiello C, et al. Performance evaluation of a noninvasive hemoglobin monitoring device. Annals of Emergency Medicine 11; 57: Frasca D, Dahyot-Fizelier C, Catherine K, Levrat Q, Debaene B, Mimoz O. Accuracy of a continuous noninvasive hemoglobin monitor in intensive care unit patients. Critical Care Medicine 11; 39: Mimoz O, Frasca D, Medard A, Soubiron L, Debaene B, Dahyot-Fizelier C. Reliability of the HemoCue â hemoglobinometer in critically ill patients: a prospective observational study. Minerva Anestesiologica 11; 77: Coquin J, Dewitte A, Manach YL, et al. Precision of noninvasive hemoglobin-level measurement by pulse co-oximetry in patients admitted to intensive care units for severe gastrointestinal bleeds. Critical Care Medicine 1; : Causey MW, Miller S, Foster A, Beekley A, Zenger D, Martin M. Validation of noninvasive hemoglobin measurements using the Masimo Radical-7 SpHb Station. American Journal of Surgery 11; 1: Lamhaut L, Apriotesei R, Combes X, Lejay M, Carli P, Vivien B. Comparison of the accuracy of noninvasive hemoglobin monitoring by spectrophotometry (SpHb) and HemoCue â with automated laboratory hemoglobin measurement. Anesthesiology 11; 115: Miller RD, Ward TA, Shiboski SC, Cohen NH. A comparison of three methods of hemoglobin monitoring in patients undergoing spine surgery. Anesthesia and Analgesia 11; 11: The Association of Anaesthetists of Great Britain and Ireland

7 Frasca et al. Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 15, 7, Applegate RL nd, Barr SJ, Collier CE, Rook JL, Mangus DB, Allard MW. Evaluation of pulse cooximetry in patients undergoing abdominal or pelvic surgery. Anesthesiology 1; 11: Giraud B, Frasca D, Debaene B, Mimoz O. Comparison of haemoglobin measurement methods in the operating theatre. British Journal of Anaesthesia 13; 111: Vos JJ, Kalmar AF, Struys MMRF, et al. Accuracy of non-invasive measurement of haemoglobin concentration by pulse cooximetry during steady-state and dynamic conditions in liver surgery. British Journal of Anaesthesia 1; 19: Isosu T, Obara S, Hosono A, et al. Validation of continuous and noninvasive hemoglobin monitoring by pulse CO-oximetry in Japanese surgical patients. Journal of Clinical Monitoring and Computing 13; 7: Miyashita R, Hirata N, Sugino S, Mimura M, Yamakage M. Improved non-invasive total haemoglobin measurements after in-vivo adjustment. Anaesthesia 1; 9: Bland JM, Altman DG. Agreement between methods of measurement with multiple observations per individual. Journal of Biopharmaceutical Statistics 7; 17: Bland JM, Altman DG. Agreed statistics: measurement method comparison. Anesthesiology 1; 11: Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 198; 1: Lindner G, Exadaktylos AK. How noninvasive haemoglobin measurement with pulse co-oximetry can change your practice: an expert review. Emergency Medicine International 13; 13: Levrat Q, Petitpas F, Bouche G, Debaene B, Mimoz O. Usefulness of pulse oximetry using the SET technology in critically ill adult patients. Annales Francßaises d Anesthesie et de Reanimation 9; 8:. 15 The Association of Anaesthetists of Great Britain and Ireland 89