Anaesthesia 2015, 70, 803–809
doi:10.1111/anae.13028
Original Article Continuous monitoring of haemoglobin concentration after in-vivo adjustment in patients undergoing surgery with blood loss* D. Frasca,1 H. Mounios,2 B. Giraud,2 M. Boisson,2 B. Debaene3 and O. Mimoz4 1 Assistant Professor, 2 Senior Anaesthetist, 3 Professor and Head of Department, 4 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 (HemoCueâ) measurements from an arterial blood sample at the first SpHb measurement (HCueART) would increase the accuracy of the monitor. The study included 41 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 0.4 (1.4), 0.3 (1.1), 0.3 (1.1), 0.6 (0.7), 0.0 (0.4) and 0.5 (1.2) g.dl1, 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 Email: [email protected] *Presented in part to the Societe Francßaise d’Anesthesie et de Reanimation, September 2013, Paris, France. Accepted: 6 January 2015
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, © 2015 The Association of Anaesthetists of Great Britain and Ireland
and do not provide a real-time assessment of change during the acute phase of blood loss. A non-invasive haemoglobin device (SpHb monitor; MasimoTM, 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 [1–10]. Thus, the utility of SpHb for transfusion decision-making remains unproven. Improved 803
Anaesthesia 2015, 70, 803–809 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, 12]. 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 (HemoCueâ; Hb201, 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 30–60 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 2.5 mg.kg1 and sufentanil 0.3 mg.kg1. Tracheal intubation was facilitated with rocuronium 0.6 mg.kg1 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 65 mmHg. Subjects were ventilated using volume-controlled mechanical ventilation (tidal volume: 6–8 ml.kg1) with a mixture of oxygen and air (inspired oxygen fraction = 0.50). Respiratory rate was adjusted to maintain normocapnia. No patient received epidural or regional anaesthesia. Patients wore rainbow adult ReSposable sensors (R2–25, Revision G) connected to a Radical-7â Pulse 804
co-oximeter, software version 7.8.0.1 (Masimo), for continuous and non-invasive measurement of total haemoglobin concentration (SpHb), SpO2, 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 SysmexTM XT-2100i automated haematology analyser (RocheTM Diagnostics, Paris, France). The confidence limits provided by the manufacturer for the Sysmex analyser are 0.2 g.dl1. The same samples were also analysed with a satellite co-oximeter (SiemensTMRapidPoint 405, 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 RapidPoint 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 (firstSpHb) measurement was recorded after the device had been reporting SpHb © 2015 The Association of Anaesthetists of Great Britain and Ireland
Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 2015, 70, 803–809
values for at least 15 min. Concomitantly, a reference HbLAB value (firstHbLAB) and the mean of three HCueART (firstHCueART) were obtained from an arterial blood sample. In-vivo SpHb adjustment (IVadjustedSpHb) was automatically done by the Radical-7 interface and the displayed SpHb value was obtained using the following formula: IVadjusted SpHb
¼ unadjusted SpHb ðfirst SpHb first HCueARTÞ
where unadjustedSpHb 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 (RadjustedSpHb) using the following formula: Radjusted SpHb
¼ unadjusted SpHb ðfirst SpHb first HbLABÞ
Then, simultaneous recording of unadjustedSpHb, IVadjustedSpHb, HbLAB, HbSAT, HCueART and HCueCAP 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 150 measurements (40 patients each with 3–4 measurements) according to Bland and Altman [13–15] recommendations for a precision of 0.3 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. © 2015 The Association of Anaesthetists of Great Britain and Ireland
Therefore, Bland and Altman analysis for repeated measures per subject as reported earlier [14, 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 2 g.dl1. The differences in outliers were analysed by the chi-squared test. Statistical analysis was performed with R 3.0.0 (R Foundation, Vienna, Austria) with a significance level for two-tailed tests at p < 0.05.
Results The study enrolled 42 patients, of whom one was excluded owing to the inability to obtain a SpHb signal with a PI ≥ 1%. The characteristics of the 41 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) HbLAB, HbSAT, HCueART and unadjustedSpHb, HCueCAP values were 12.7 (0.9), 12.4 (0.6), 12.4 (0.7), 12.4 (0.5) and 12.9 (1.0) g.dl1, respectively. Mean (SD) difference between firstHCueART and firstHbLAB was 0.0 (0.1) g.dl1. A median (IQR [range]) of 3 (2–4 Table 1 Characteristics of the 41 patients. Values are median (IQR [range]) or number (proportion).
Age; years Male Surgery Total hip or knee replacement (redux) Hepatectomy Spinal surgery Aortic aneurysm repair Nephrectomy Prostatectomy Meningioma Blood loss; ml Red cell transfusion Fluid expansion; ml.h1 Use of vasopressor during procedure
65 (56–72 [34–83]) 29 (70%) 16 (40%) 9 5 5 3 2 1 500 16 950 10
(22%) (12%) (12%) (7%) (5%) (2%) (300–1200 [100–2300]) (39%) (750–1250 [500–1750]) (24%)
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Anaesthesia 2015, 70, 803–809 Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment
[2–8]) measurements was carried out per patient, leading to a total of 173 haemoglobin measurements. During the surgical procedure, HbLAB values dropped below 10 g.dl1 in 22% of measurements and below 8 g.dl1 in < 1% of measurements. Of the 41 patients, 10 (24%) received vasopressors during surgery for a total of 43 measurements (25% 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 2 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 (0.4 g.dl1 vs 0.3 g.dl1) and precision (1.2 g.dl1 vs 1.1 g.dl1) of the device. In multivariate analysis, there was no influence of tested covariates (including perfusion index and use of vasopressors) on unadjustedSpHb and IVadjustedSpHb bias. Percentages of outliers are indicated in Table 3.
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 20 surgical patients requiring 92 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 0.2 (1.5) g.dl1 before and 0.7 (1.0) g.dl1 after retrospective adjustment [11]. In a second study including 19 adult surgical patients requiring 73 measurements, both the bias (0.68 g.dl1 vs 0.16 g.dl1) and precision (1.02 g.dl1 vs 0.77 g.dl1) improved after in-vivo adjustment [12]. 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 0.86 to 0.95) was not statistically tested. In this study, in-vivo adjustment improved SpHb precision to 0.3 g.dl1 without significant impact on SpHb bias, which remained close to 0 g.dl1. 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 < 2 min. The use of
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.
Table 2 Bias, precision and 95% limits of agreement for tested methods compared to reference method (based on 173 measurements). Values are number (95% CI).
unadjustedSpHb IVadjustedSpHb RadjustedSpHb HbSAT HCueART HCueCAP
Bias; g.dl1
Precision; g.dl1
0.4 0.3 0.3 0.6 0.0 0.5
1.4 1.1 1.1 0.7 0.4 1.2
(0.5 to 0.3) (0.3 to 0.3) (0.3 to 0.3) (0.6 to 0.6) (0.0 – 0.0) (0.6 to 0.4)
(1.2 (0.9 (0.9 (0.6 (0.3 (1.0
1.5) 1.2) 1.2) 0.8) 0.4) 1.5)
95% limits of agreement*; g.dl1 3.2 2.4 2.4 2.0 0.8 2.9
(3.4 (2.5 (2.5 (2.0 (0.8 (3.0
to to to to to to
3.0) 2.4) 2.4) 2.0) 0.8) 2.8)
to to to to to to
2.4 1.8 1.8 0.7 0.8 1.9
(2.2 (1.7 (1.7 (0.7 (0.8 (1.8
2.5) 1.8) 1.8) 0.7) 0.8) 2.1)
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. 806
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 2015, 70, 803–809 (b) 6
6
4
4
2
2.4
0 –0.4 –2
HbLAB -IVadjusted SpHb (g.dl–1)
HbLAB -unadjusted SpHb (g.dl–1)
(a)
–3.2
–4
0 –0.3 –2 –2.4
–6 4
6
8 10 12 14 Mean of HbLAB and unadjusted SpHb (g.dl–1)
4
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8 10 12 14 Mean of HbLAB and IVadjusted SpHb (g.dl–1)
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(d) 6
6
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2 1.8 0 –0.3 –2 –2.4
HbLAB - HbSAT (g.dl–1)
HbLAB -Radjusted SpHb (g.dl–1)
1.8
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2 0.7
0
–0.6 –2
–2.0
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8 10 12 14 Mean of HbLAB and Radjusted SpHb (g.dl–1)
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2 0.8
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HbLAB - HCueART (g.dl–1)
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2 1.9 0 –0.5 –2 –2.9 –4
–4
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6
8 10 12 Mean of HbLAB and HCueART (g.dl–1)
14
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8 10 12 Mean of HbLAB and HCueCAP (g.dl–1)
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Figure 1 Bland and Altman plot for (a) unadjusted continuous non-invasive haemoglobin measurement (unadjustedSpHb), (b) SpHb adjusted in vivo (IVadjustedSpH) or (c) retrospectively (RadjustedSpHb), (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.
© 2015 The Association of Anaesthetists of Great Britain and Ireland
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Anaesthesia 2015, 70, 803–809 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.dl1 or 2 g.dl1 (n = 173 measurements). ≥ 2 g.dl1 unadjustedSpHb IVadjustedSpHb RadjustedSpHb HbSAT HCueART HCueCAP
18 8* 8* 2
doi:10.1111/anae.13028
Original Article Continuous monitoring of haemoglobin concentration after in-vivo adjustment in patients undergoing surgery with blood loss* D. Frasca,1 H. Mounios,2 B. Giraud,2 M. Boisson,2 B. Debaene3 and O. Mimoz4 1 Assistant Professor, 2 Senior Anaesthetist, 3 Professor and Head of Department, 4 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 (HemoCueâ) measurements from an arterial blood sample at the first SpHb measurement (HCueART) would increase the accuracy of the monitor. The study included 41 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 0.4 (1.4), 0.3 (1.1), 0.3 (1.1), 0.6 (0.7), 0.0 (0.4) and 0.5 (1.2) g.dl1, 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 Email: [email protected] *Presented in part to the Societe Francßaise d’Anesthesie et de Reanimation, September 2013, Paris, France. Accepted: 6 January 2015
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, © 2015 The Association of Anaesthetists of Great Britain and Ireland
and do not provide a real-time assessment of change during the acute phase of blood loss. A non-invasive haemoglobin device (SpHb monitor; MasimoTM, 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 [1–10]. Thus, the utility of SpHb for transfusion decision-making remains unproven. Improved 803
Anaesthesia 2015, 70, 803–809 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, 12]. 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 (HemoCueâ; Hb201, 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 30–60 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 2.5 mg.kg1 and sufentanil 0.3 mg.kg1. Tracheal intubation was facilitated with rocuronium 0.6 mg.kg1 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 65 mmHg. Subjects were ventilated using volume-controlled mechanical ventilation (tidal volume: 6–8 ml.kg1) with a mixture of oxygen and air (inspired oxygen fraction = 0.50). Respiratory rate was adjusted to maintain normocapnia. No patient received epidural or regional anaesthesia. Patients wore rainbow adult ReSposable sensors (R2–25, Revision G) connected to a Radical-7â Pulse 804
co-oximeter, software version 7.8.0.1 (Masimo), for continuous and non-invasive measurement of total haemoglobin concentration (SpHb), SpO2, 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 SysmexTM XT-2100i automated haematology analyser (RocheTM Diagnostics, Paris, France). The confidence limits provided by the manufacturer for the Sysmex analyser are 0.2 g.dl1. The same samples were also analysed with a satellite co-oximeter (SiemensTMRapidPoint 405, 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 RapidPoint 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 (firstSpHb) measurement was recorded after the device had been reporting SpHb © 2015 The Association of Anaesthetists of Great Britain and Ireland
Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 2015, 70, 803–809
values for at least 15 min. Concomitantly, a reference HbLAB value (firstHbLAB) and the mean of three HCueART (firstHCueART) were obtained from an arterial blood sample. In-vivo SpHb adjustment (IVadjustedSpHb) was automatically done by the Radical-7 interface and the displayed SpHb value was obtained using the following formula: IVadjusted SpHb
¼ unadjusted SpHb ðfirst SpHb first HCueARTÞ
where unadjustedSpHb 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 (RadjustedSpHb) using the following formula: Radjusted SpHb
¼ unadjusted SpHb ðfirst SpHb first HbLABÞ
Then, simultaneous recording of unadjustedSpHb, IVadjustedSpHb, HbLAB, HbSAT, HCueART and HCueCAP 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 150 measurements (40 patients each with 3–4 measurements) according to Bland and Altman [13–15] recommendations for a precision of 0.3 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. © 2015 The Association of Anaesthetists of Great Britain and Ireland
Therefore, Bland and Altman analysis for repeated measures per subject as reported earlier [14, 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 2 g.dl1. The differences in outliers were analysed by the chi-squared test. Statistical analysis was performed with R 3.0.0 (R Foundation, Vienna, Austria) with a significance level for two-tailed tests at p < 0.05.
Results The study enrolled 42 patients, of whom one was excluded owing to the inability to obtain a SpHb signal with a PI ≥ 1%. The characteristics of the 41 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) HbLAB, HbSAT, HCueART and unadjustedSpHb, HCueCAP values were 12.7 (0.9), 12.4 (0.6), 12.4 (0.7), 12.4 (0.5) and 12.9 (1.0) g.dl1, respectively. Mean (SD) difference between firstHCueART and firstHbLAB was 0.0 (0.1) g.dl1. A median (IQR [range]) of 3 (2–4 Table 1 Characteristics of the 41 patients. Values are median (IQR [range]) or number (proportion).
Age; years Male Surgery Total hip or knee replacement (redux) Hepatectomy Spinal surgery Aortic aneurysm repair Nephrectomy Prostatectomy Meningioma Blood loss; ml Red cell transfusion Fluid expansion; ml.h1 Use of vasopressor during procedure
65 (56–72 [34–83]) 29 (70%) 16 (40%) 9 5 5 3 2 1 500 16 950 10
(22%) (12%) (12%) (7%) (5%) (2%) (300–1200 [100–2300]) (39%) (750–1250 [500–1750]) (24%)
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Anaesthesia 2015, 70, 803–809 Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment
[2–8]) measurements was carried out per patient, leading to a total of 173 haemoglobin measurements. During the surgical procedure, HbLAB values dropped below 10 g.dl1 in 22% of measurements and below 8 g.dl1 in < 1% of measurements. Of the 41 patients, 10 (24%) received vasopressors during surgery for a total of 43 measurements (25% 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 2 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 (0.4 g.dl1 vs 0.3 g.dl1) and precision (1.2 g.dl1 vs 1.1 g.dl1) of the device. In multivariate analysis, there was no influence of tested covariates (including perfusion index and use of vasopressors) on unadjustedSpHb and IVadjustedSpHb bias. Percentages of outliers are indicated in Table 3.
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 20 surgical patients requiring 92 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 0.2 (1.5) g.dl1 before and 0.7 (1.0) g.dl1 after retrospective adjustment [11]. In a second study including 19 adult surgical patients requiring 73 measurements, both the bias (0.68 g.dl1 vs 0.16 g.dl1) and precision (1.02 g.dl1 vs 0.77 g.dl1) improved after in-vivo adjustment [12]. 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 0.86 to 0.95) was not statistically tested. In this study, in-vivo adjustment improved SpHb precision to 0.3 g.dl1 without significant impact on SpHb bias, which remained close to 0 g.dl1. 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 < 2 min. The use of
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.
Table 2 Bias, precision and 95% limits of agreement for tested methods compared to reference method (based on 173 measurements). Values are number (95% CI).
unadjustedSpHb IVadjustedSpHb RadjustedSpHb HbSAT HCueART HCueCAP
Bias; g.dl1
Precision; g.dl1
0.4 0.3 0.3 0.6 0.0 0.5
1.4 1.1 1.1 0.7 0.4 1.2
(0.5 to 0.3) (0.3 to 0.3) (0.3 to 0.3) (0.6 to 0.6) (0.0 – 0.0) (0.6 to 0.4)
(1.2 (0.9 (0.9 (0.6 (0.3 (1.0
1.5) 1.2) 1.2) 0.8) 0.4) 1.5)
95% limits of agreement*; g.dl1 3.2 2.4 2.4 2.0 0.8 2.9
(3.4 (2.5 (2.5 (2.0 (0.8 (3.0
to to to to to to
3.0) 2.4) 2.4) 2.0) 0.8) 2.8)
to to to to to to
2.4 1.8 1.8 0.7 0.8 1.9
(2.2 (1.7 (1.7 (0.7 (0.8 (1.8
2.5) 1.8) 1.8) 0.7) 0.8) 2.1)
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. 806
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Frasca et al. | Continuous monitoring of haemoglobin concentration using in-vivo adjustment Anaesthesia 2015, 70, 803–809 (b) 6
6
4
4
2
2.4
0 –0.4 –2
HbLAB -IVadjusted SpHb (g.dl–1)
HbLAB -unadjusted SpHb (g.dl–1)
(a)
–3.2
–4
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–6 4
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8 10 12 14 Mean of HbLAB and unadjusted SpHb (g.dl–1)
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8 10 12 14 Mean of HbLAB and IVadjusted SpHb (g.dl–1)
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2 1.8 0 –0.3 –2 –2.4
HbLAB - HbSAT (g.dl–1)
HbLAB -Radjusted SpHb (g.dl–1)
1.8
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0
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8 10 12 14 Mean of HbLAB and Radjusted SpHb (g.dl–1)
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HbLAB - HCueCAP (g.dl–1)
HbLAB - HCueART (g.dl–1)
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8 10 12 Mean of HbLAB and HCueART (g.dl–1)
14
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8 10 12 Mean of HbLAB and HCueCAP (g.dl–1)
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Figure 1 Bland and Altman plot for (a) unadjusted continuous non-invasive haemoglobin measurement (unadjustedSpHb), (b) SpHb adjusted in vivo (IVadjustedSpH) or (c) retrospectively (RadjustedSpHb), (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.
© 2015 The Association of Anaesthetists of Great Britain and Ireland
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Anaesthesia 2015, 70, 803–809 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.dl1 or 2 g.dl1 (n = 173 measurements). ≥ 2 g.dl1 unadjustedSpHb IVadjustedSpHb RadjustedSpHb HbSAT HCueART HCueCAP
18 8* 8* 2
