effect of propofol and oxygen administration on the...

Document: Master Thesis ‘Effect of propofol and oxygen administration on the reliability of noninvasive hemoglobin

measurements in patients under general anesthesia.’

Author: W.S. de Boer ([email protected]) Institution: University Medical Center Groningen (UMCG), department of anesthesiology.

UNIVERSITAIR MEDISCH CENTRUM GRONINGEN

Effect of propofol and oxygen administration on the reliability of noninvasive hemoglobin measurements

in patients under general anesthesia.

Department of Anesthesiology

Boer, W.S. de

S2208040

8-9-2015

Supervisors

Dr. J.J. Vos

Prof. dr. T.W.L. Scheeren

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Table of contents

Summary………………………………………………………….. p. 03

Introduction……………………………………………………….. p. 04

Hypothesis and research question………………………………… p. 09

Materials and methods………………...………………………….. p. 10

Results………………...……………………………………….….. p. 13

Discussion and conclusion……..……...………………………….. p. 21

References………………...……………………………...……….. p. 24

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Summary

Introduction

The measurement of hemoglobin (Hb) concentration in blood plays a central role in

evaluating blood loss and in the decision whether or not to transfuse red blood cell

concentrates (RBC) in the perioperative setting. Recently, Hb concentration can be measured

in a noninvasive and continuous manner, using a fingerclip. The agreement of noninvasive

assessment of blood hemoglobin via CO-oximetry (SpHb) with conventional, invasive

measurements of Hb (gold standard) is still under investigation. It is suggested that this

agreement can be influenced by certain factors, e.g. drug administration. We hypothesized

that both propofol – the most frequently intravenously administered general anesthetic – and

changes in the inspiratory fraction of oxygen (FiO2), alters SpHb reliability. Therefore, we

investigated in patients under general anesthesia, the influence of these factors, on the

reliability of continuous SpHb measurements.

Method

This study is a retrospective analysis of data, obtained during an earlier conducted prospective

randomized controlled trial. In the original study – which was approved by the local medical

ethical committee (METC) – a total of 30 patients (American Society of Anesthesiologists

Physical Status 1-3) were included. The recorded SpHb data was analyzed for relevant

timeframes (i.e. the period of induction of general anesthesia by propofol and an increase or

decreases in FiO2,). Reliability was tested by comparing SpHb values directly before injection

of propofol, FiO2 increase or FiO2 decrease with 3 and 5 minutes thereafter. Reliability was

defined as a stable Hb concentration over time, not affected by a change in FiO2 or injection

of propofol. Mean Absolute Deviation (MAD) and Median Absolute Deviation (MDAD) of

SpHb were calculated, to evaluate deviation of trend in SpHb readings after alteration of FiO2

or intravenous injection of propofol.

Results

No difference in SpHb values was found between baseline vs. 3 min and baseline vs. 5 min

after injection with propofol (n=9), FiO2 decrease (n=12) or FiO2 increase (n=10). In contrast,

Absolute deviation of SpHb did increase between baseline and 5 min after induction with

propofol (P=0.008). Absolute deviation of SpHb did not significantly alter between baseline

vs. 3 min and baseline vs. 5 min after FiO2 decrease or FiO2 increase.

Discussion

In patients under general anesthesia, the absolute deviation of SpHb measurements increase

after intravenous injection of propofol. Although suggested during previous studies, no

influence of FiO2 alteration on SpHb readings was found. Further technical improvements of

the sensor and software are necessary to improve the accuracy of SpHb spectrophotometry in

order to be less influenced by intravenous injection of propofol. The SpHb device might

become a useful tool to evaluate the extent of blood loss and Hb concentration during surgery.

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Introduction

The measurement of hemoglobin (Hb) concentration in blood plays a central role in the

detection, evaluation, and management of chronic and acute anemia. In patients undergoing

surgery, Hb measurement is used to evaluate the extent of blood loss and to decide whether

transfusion of red blood cell concentrate (RBC) is necessary.

In the University Medical Center Groningen (UMCG), a transfusion protocol is applied

known as the ‘4-5-6 flexinorm’.1 In this protocol, which is based on patient characteristics

such as age and co-morbidities, RBC transfusion is only performed if one of the three

thresholds (of note: in mmol/L) applies. The purpose of this protocol is to minimize the risk of

unnecessary transfusions and, on the other hand, to prevent unnecessarily withholding a

patient RBC transfusion. RBC transfusion bears risks to patients: it is associated with the

development of pulmonary and hemolytic complications. In contrast, unnecessary

withholding RBC’s to the patients also leads to certain risks: e.g., peri-operative anemia can

lead to serious morbidity and possibly even mortality.2,3

Oxygen delivery and consumption

The most important reason to assure whether the level of Hb concentration is sufficient, is

providing or retaining adequate oxygen delivery to the tissue, which should ideally be

adjusted to the needs of the tissues. Effectively, oxygen delivery needs to exceed the tissue’s

need for oxygen.

The total amount of oxygen offered to the tissue (DO2; mL/min) is calculated by the following

formula:

DO2 = Cardiac Output * arterial oxygen content

Cardiac Output (CO; L/min) is the product of stroke volume (SV; mL/beat) and heart rate

(HR; beats per minute).

The arterial oxygen content (CaO2; mL/dL) consists of two parts: oxygen bound to

hemoglobin and oxygen dissolved in plasma. The latter accounts only for a small quantity of

CaO2 and is often omitted. The formula for CaO2 is shown below. The first part accounting

for the oxygen bound to hemoglobin, and the second part accounting for the oxygen dissolved

in the plasma. The sum of these formulas is the CaO2.

2.16 x [Hb; mmol/L] x oxygen saturation (SaO2; %)

0.0031 x partial pressure of oxygen (PaO2; mmHg)

Oxygen consumption (VO2; mL/min) is calculated using the following formula:

VO2 = DO2 – venous oxygen content (CvO2; mL/L)

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Under physiologic conditions, when blood hemoglobin levels decrease, CaO2 decreases but

DO2 remains stable due to an increase in cardiac output. The limit of this compensation is

reached when hemoglobin is about 5 mmol/L. For lower levels of hemoglobin, DO2 will

decrease and oxygen extraction will increase. Under physiologic conditions, DO2 is three to

four times above VO2. Therefore, a decrease in DO2 will not immediately compromise tissue

oxygen needs. Even so, tissue hypoxia will ensue after hemoglobin levels decrease enough to

affect VO2.4

This situation should be prevented, since it is associated with organ failure and

death during the intraoperative and early post-operative period.5 In addition, many in-hospital

patients are anemic, and furthermore, a substantial number of critically ill patients may have

increased VO2 (e.g. due to sepsis or septic shock).6,7

The quantity of oxygen delivered to the tissue, as is shown in the formulas above, is

determined by: SaO2, CO and Hb. As is apparent, oxygen delivery substantially depends on

the content of Hb. Therefore, an accurate measurement of Hb is one of the most important

means in monitoring components of oxygen delivery and in preventing both (global) tissue

hypoxia and unnecessary blood transfusions.

Hb measurement

There are multiple techniques and devices for the measurement of Hb concentration, each of

which has its own intrinsic measurement-variability.8 Furthermore, physiological influences,

for example sitting vs. standing position, also influence Hb concentration and can add extra

variability to its measurement.9,10

The gold standard for laboratory determination of Hb is hemoglobin cyanide (HiCN).11

HiCN

testing is not routinely used in hospitals due to its complexity, so cyanide free central

laboratory hematology analyzers have become the clinical standard.12

On the operating rooms

in our hospital as well as in many other Western European hospitals, invasive determination

of Hb concentration by point-of-care satellite laboratory blood gas analysis (Hbsatlat) is

considered the clinical (gold) standard. The satellite lab point-of-care device being used in our

institution is the ABL 800, Radiometer GmbH, Copenhagen. Although this device is not

completely interchangeable with central laboratory hematology analyzers, it is well correlated

to central laboratory Hb analysis with a repeatability error <2% over a test Hb range of 1.6-

14.3 mmol/L.13,14

Disadvantages using this method are blood sampling, intermittent results,

and a delay between the result and the actual Hb concentration.15,16

Recently, Hb concentration can be measured noninvasively and continuously using a

fingerclip. The monitor, the Masimo Radical-7®

(Masimo Corp, Irvine, California, USA),

uses multi-wavelength analysis of hemoglobin absorption spectra to calculate total

hemoglobin concentration (SpHb). The agreement of SpHb with conventional invasive

measurements of Hb, is currently still under investigation: hitherto, existing studies reveal

somewhat conflicting results concerning agreement with invasive Hb measurement.13-22

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Assessment of noninvasive hemoglobin measurement

An earlier study about the assessment of the accuracy of SpHb monitoring stated that,

clinically, SpHb monitoring should be highly accurate at Hb concentrations between 3.7 and

6.2 mmol/L.25

It is in this particular range that, patients may receive RBC transfusion,

depending on the choice of the physician and the locally applied relevant protocol regulations.

In the referred study, the Hb error grid (Fig. 1) for the assessment of the accuracy of SpHb

monitoring was introduced. An accuracy of ±10% for the assessment of SpHb monitoring in

their defined anemic range (Hb level from 3.7 to 6.2 mmol/L) was used. In zone A of the Hb

error grid, the high accuracy of 10% error is required in a range of Hb level from 3.7 to 6.2

mmol/L so that the zone becomes narrow. Below 3.7 mmol/L patients will likely receive RBC

transfusion. In addition, high accuracy is not required in a range above 6.2 mmol/L as

transfusion will likely not occur.26

Zone C represents the area for critical errors of

unnecessary transfusion and avoidance of necessary transfusion.

Similar to the pulse oximetry for SpO2, SpHb could help to evaluate changes, or absence of

changes, in Hb concentrations. This method may allow an earlier detection of anemia during

an operation with occult blood loss.15,16

Therefore, besides a high accuracy in the range

described above, SpHb measurements need to agree with invasive Hb measurement to

evaluate trending Hb concentrations. Earlier detection of anemia is only possible when Hb

measurements agree with actual Hb concentrations especially in the range where transfusion

decisions are being made.

Figure 1. Hemoglobin error grid, in g/dL.

An accuracy of ±10% is used for the

assessment of noninvasive hemoglobin

monitoring in an anemic range (Hb level

from 6 to 10 g/dL or 3.7 to 6.2 mmol/L).

25

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Possible influences of noninvasive hemoglobin measurement accuracy

As mentioned earlier, results of studies investigating the accuracy of the SpHb device are

somewhat conflicting. These discrepancies could be explained by differences in the clinical

situation in which SpHb monitoring was studied, e.g. non-bleeding versus bleeding patients.

In hemodynamically stable patients scheduled for elective surgery, Hb concentrations are

expected to remain relatively constant before incision. The following factors have been found

to diminish SpHb reliability.

Hb concentration

The bias of SpHb to reference Hb is reported to be inversely correlated with Hb

concentration.17,27,28

In a study conducted during neurosurgery in children, they measured

SpHb and Hbsatlab and found a bias of -0.02 mmol/L when Hb concentration was ≥6.8

mmol/L, which was significantly lower in comparison with biases when Hb concentration was

<5.6 mmol/L (0.77 mmol/L) and when Hb concentration was 5.6 - 6.8 mmol/L (0.73

mmol/L).17

As such, in case Hbsatlab appears low, SpHb seems to overestimate true Hb

concentration. This alters the risk of underestimating patients need for transfusion.

Fluid infusion

SpHb monitoring might be influenced by fluid administration. In a healthy volunteer-study, it

was demonstrated that subjects who received crystalloids (Ringers’s acetate, 20 ml kg-1

), a

stronger decrease in SpHb than Hbsatlab (15 vs. 8%; P<0.005; n=10) was found. When colloid

fluid (6% hydroxyethyl starch 130/0.4, 10ml kg-1

solution) was infused, the decrease in

Hbsatlab was more profound compared to the decrease in SpHb (-7 vs. -11%; P<0.02; n=20).29

An other study from our department found a decreased correlation of SpHb with Hbsatlab after

colloid infusion during liver surgery (R2=0.25).

14 These results suggest that SpHb reliability

will decrease after fluid administration.

Perfusion

The perfusion index (PI) is the ratio of the pulsatile blood flow to the nonpulsatile or static

blood in peripheral tissue. PI thus represents a noninvasive measure of peripheral perfusion,

expressed as a percentage. Optimal pulse oximetry monitoring accuracy is dependent on the

selection of a monitoring site characterized by good perfusion with oxygenated blood, in most

cases, the finger is selected. The PI provides instant and continuous feedback as to the

perfusion status of the selected monitoring site. In clinical scenarios where peripheral

perfusion may drop below the minimums required for tissue oxygenation and cellular

respiration, the PI alerts the clinician to consider another monitoring site. PI may change

substantially in response to sympathetic changes and pain stimuli. Several studies reported a

significant decrease in SpHb accuracy and precision when PI was low.18-20

Pleth Variability

Index (PVI) is a measure of dynamic change in PI during a complete respiratory cycle and,

like PI, might be related to SpHb accuracy.

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Induction of general anesthesia

Increased perfusion of the finger where the SpHb measurement is taken, as reflected by an

increased PI, improves SpHb agreement with Hbsatlab concentration.30

Intravenous induction

of general anesthesia with propofol, induces peripheral vasodilatation and results to some

extent in changes in peripheral blood flow.31

Therefore, SpHb measurement might be affected

by induction of anesthesia as well.

Fractions of inspired oxygen

The Masimo Radical-7 measures SpHb through spectrometry and 7 different wavelenghts of

light are separately analyzed. Since changes in oxyhemoglobin saturation affect its color,

variations in fraction of inspired oxygen (FiO2) can influence SpHb measurement. For

instance, some studies previously found that an increase in FiO2 under steady state conditions,

i.e. absence of bleeding, caused an apparent increase in SpHb, while under these conditions,

actual Hb concentrations are not expected to change.32,33

An observational report from our

department shows an almost systematically increase in SpHb, after variations in FiO2 (Fig. 2).

SpHb values often increased by as much as 40%, even in ASA physical status I and II patients

scheduled for elective surgery.32

Figure 2. Change of SpHb during induction of general anesthesia in a typical patient. TCI =

target-controlled infusion; FiO2 = fractions of inspired oxygen.32

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Hypothesis and research question

During the randomized controlled trial ‘intraoperative monitoring of blood loss’, which was

performed in our institution. SpHb was measured in adult patients scheduled for elective

surgery who were at risk for development of undetected, i.e., difficult to monitor

intraoperative blood loss. In this study, SpHb was measured from induction of anesthesia until

the end of surgery. In the time period before surgical incision blood loss is not expected to

occur. Therefore, Hb concentration is subsequently expected to remain stable and hence, we

hypothesized that SpHb measurements also remained stable.

Therefore, the goal of this retrospective study was at first, to determine whether there was a

deviation in trend (i.e. a reduced stability) of SpHb after intravenous injection of propofol

during the time period between induction of anesthesia and surgical incision. At second, we

investigated whether changes in FiO2 might also be responsible for a decreased reliability of

SpHb measurements during the aforementioned time period. We formulated the following

research question; Does the injection of propofol or do changes in the FiO2, influence SpHb

readings in patients under general anesthesia?

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Materials and Methods

Study design

Retrospective analysis of data, obtained during an earlier conducted prospective randomized

controlled trial ‘intraoperative monitoring of blood loss’. The original study was approved by

the local medical ethical committee (METC) and registered in a clinical trial registry

(NCT01864980). This study aimed to investigate whether continuous SpHb monitoring

improved the detection of perioperative anemia, in comparison with intermittent measurement

of Hb concentration.

Population

The original study comprised of thirty patients with physical status 1-3 as defined by the

American Society of Anesthesiologists (“ASA classification”). Patients were >18 years,

scheduled for elective surgery and were assumed to be at risk for development of undetected,

i.e., difficult to monitor intraoperative blood loss. Exclusion criteria were patient refusal or

emergency surgery.

For the current study, analysis was based on the existing data, which could only be used when

there was sufficient documentation and all technical data recordings were adequate without

artifacts. Also, data on the time of injection with propofol, changes in FiO2 and SpHb, were

required to be recorded.

Sample size calculation

Sample size calculation was not possible, since this was a retrospective study and there is no

sufficient data available on SpHb variability. Future prospective studies can be based on an a

priori power analysis based on the data obtained in this retrospective study.

Main Study parameter/endpoints

It was assessed whether SpHb changed over time after intravenous injection of propofol

during the time period between induction of anesthesia and surgical incision, which would

confirm trend deviation of SpHb measurement.

Secondary study parameters/endpoints

It was assessed whether SpHb changed over time after moments of increases and decreases in

FiO2 during the time period between induction of anesthesia and surgical incision, which

would confirm trend deviation of SpHb measurement. A decrease or increase in FiO2 was

defined as an instantaneous change in FiO2 > 20%.

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Other study parameters

Baseline data include general information on:

- Date of birth - Sex

- Height - Weight

- Hbsatlab concentration - ASA classification

- Type of surgery

Randomization

In the original study, patients were randomized using envelopes. The exact timing for

randomization was immediately before patient arrival in the operating room, prior to

induction of anesthesia. Patients in both groups were matched with respect to the type of

surgery in order to assure homogeneity of both groups. Randomization was necessary to

decide whether blood transfusion would be based on SpHb measurements or on standard

Hbsatlab values. This had no influence on the retrospective data analysis, since induction of

anesthesia and further anesthetic management was equal in both groups.

Study procedures

Patients received a standardized, balanced anesthesia (standard of care) using target-

controlled infusion with propofol as hypnotic titrated to either a bispectral index (BIS)

between 40 and 60 or a SedLine value between 25 and 50. Opioids (fentanyl, sufentanil or

remifentanil) were administered by continuous infusion as required (standard of care). If

clinically required, a thoracic or lumbar epidural catheter was placed before induction of

anesthesia.

Monitoring began preoperatively at patient arrival at the operating room, when the Masimo®

SpHb sensor was attached to the patient. The SpHb sensor was applied, following

manufacturer’s Directions for Use (DFUs), to the 2nd

or 3rd

finger of the patient, where the

blood pressure was not measured. The sensor was not applied on any finger with obvious

deformities that may interfere with proper reading, and was applied with emitter and detector

directly opposite to each other, with no gap between sensor and fingertip, then covered with

an optical shield, since ambient light may influence the reliability of measurements.

Data recording started when all hemodynamic variables, requested for the original study, were

simultaneously available and minimally 5 minutes after the first values appeared on the

Masimo SpHb monitor screen. Fluid and vasoactive drug medication was recorded from the

moment the patient arrived in the operating room till end of surgery.

Before drawing the blood sample for Hbsatlab measurements, adequate dead space of the aterial

line was removed and the sample tube was adequately mixed. All blood samples were read by

the same laboratory analyzer (ABL 800 Flex; Radiometer GmbH, Copenhagen, Denmark) to

avoid variation due to inter-device variability. This satellite laboratory device was comparable

with a central laboratory analyzer, with a bias of -0.008 mmol/L.

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Data recording

All continuously monitored data was collected at 1Hz in a time-synchronized way using

RUGLOOP II®

software (Demed, Temse, Belgium). Therefore all monitors were connected to

the medical grade computer using shielded cables via a RS-232 serial interface. Real time

comments were added to the data streams if required.

Noninvasive hemoglobin measurement was done with the Masimo Radical 7® monitor

(Masimo Corp, Irvince, California, USA). The sensor being used was the Rev K, version 125.

As mentioned earlier, this monitor uses spectrometry with seven wavelengths of light and as

such, is able to calculate “total hemoglobin concentration”, SpHb. In addition, the device

measures the perfusion Index (PI; explained previously) and the variation in PI, pleth

variability index (PVI).

All data were imported to Microsoft® Office Excel 2010 and were subsequently analyzed

using SPSS® version 20 (IBM Statistics, New York, USA).

Data analysis

The first Hbsatlab value was used for in-vivo calibration of the SpHb device according to

manufacturer’s instructions. This calibration is a linear offset to aid the physician in

interpreting measurements and is not available in every country; therefore this calibration was

removed from the data before further analysis.

Normal distribution of continuous data was assessed using histograms and if necessary

confirmed using the Shapiro-Wilks test. For continuous data median and range were provided

and for dichotomous and categorical data, frequency and percentage were calculated.

Depending on normal distribution of data, a paired t-test or Wilcoxon signed rank test was

applied. P-values were 2-tailed and a value of P <0.05 was considered statistically significant.

The main study variable was the SpHb signal after intravenous injection of propofol. To

investigate SpHb stability and to gain information about trend deviation of SpHb, for each

patient SpHb (y-axis) was plotted against time (x-axis).

All artefacts from the data were removed after visual inspection. To exclude remaining

artefacts, a running median was calculated for all relevant data with a timeframe of 30

seconds. For the purpose of this study, moments of propofol injection were identified and

corresponding timeframes and associated SpHb values were collected to test for reduced

stability. Stability was tested by comparing SpHb values directly before (baseline) injection of

propofol until 3 and 5 minutes thereafter. Mean Absolute Deviation (MAD) and Median

Absolute Deviation (MDAD) of SpHb were calculated in order to evaluate whether or not

SpHb measurements are deviating over time, while the median SpHb measurement may still

appear to remain constant after injection of propofol. Data were further analyzed to identify

moments of increases or decreases in FiO2, which were also tested for reduced SpHb stability

and increased MAD or MDAD of SpHb. Depending on normal distribution of data, a paired t-

test or Wilcoxon signed rank test was applied.

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Results

Propofol

Retrospective data analysis revealed that in 9 patients, sufficient data were available at the

moment of induction of anesthesia using propofol. During these moments, there was no

change in the level of FiO2; only in 1 patient, FiO2 was decreased 3 minutes after injection of

propofol. See table 6 for descriptive statistics.

Group Characteristics Injection of Propofol

Number of Patients 9

Gender (male/female) 5/4

Age (years) 62 ± 9

Length (cm) 173 ± 9

Weight (kg) 78 ± 15

BMI (kg/m2) 26 ± 4

ASA class (n) I=3, II=5, III=1

Baseline SpHb (mmol/L) 6.9 ± 0.6

SpHb (mmol/L) 6.7 ± 0.7

Hbsatlab (mmol/L) 6.4 ± 0.8

Surgery time (minutes) 534 ± 200

Type of surgery (n)

Urology

Surgical Oncology

ENT

1

7

1

Table 1. Group characteristics for injection of propofol. Continuous variables are expressed

as mean ± standard deviation.

The median SpHb measurements during injection with propofol are shown in figure 3.

Median SpHb directly before intravenous injection of propofol (baseline) was 6.8 (5.9-7.8)

mmol/L. After 3 and 5 minutes, median SpHb were 6.8 (6.0-7.8) mmol/L and 6.6 (5.9-7.3)

mmol/L, respectively (table 2). The difference in SpHb between baseline and 3 min after

injection of propofol showed no statistical difference (P=0.738), which was also true for the

difference in SpHb between baseline and 5 min after injection of propofol (P=0.141).

Time since propofol injection N Median Mean SD Min. Max Normality*

SpHb (mmol/L) Baseline 9 6.8 6.9 0.6 5.9 7.8 Yes (P=0.975)

+3 min 9 6.8 6.8 0.5 6.0 7.8 Yes (P=0.831)

+5 min 9 6.6 6.7 0.4 5.9 7.3 Yes (P=0.923)

Table 2. Median, mean, SD, minimum and maximum SpHb measurements (mmol/L) after

injection of propofol.

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Figure 3. SpHb measurements before and after intravenous injection of propofol. The thick

red line is median deviation of SpHb, the other lines represent 9 individual patients.

Figure 4 shows the Mean Absolute Deviation (MAD) and Median Absolute Deviation

(MDAD) after injection of propofol. The MDAD 3 minutes after injection of propofol was

0.20 mmol/L and 0.30 mmol/L 5 minutes after injection of propofol (table 3).

The Wilcoxon signed-rank test showed no significant increase for MDAD baseline versus 3

minutes after injection of propofol (P=0.188). A difference was found for baseline versus 5

minutes (P=0.008).

Time since propofol injection N MDAD MAD SD Min. Max.

SpHb (mmol/L) Baseline 9 0.00 0.09 0.12 0.00 0.30

+3 minutes 9 0.20 0.18 0.15 0.00 0.50

+5 minutes 9 0.30 0.38 0.29 0.10 0.90

Table 3. MDAD, MAD, SD and minimum and maximum absolute deviation of SpHb

(mmol/L), after injection of propofol.

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Figure 4. SpHb measurements after injection of propofol. This figure shows the absolute

deviation from SpHb of 9 individual patients. The thick red line represents the Median

Absolute Deviation and the thick green line is the Mean Absolute Deviation of SpHb.

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Fraction of Inspired Oxygen

For this study, SpHb reliability was also assessed in case FiO2 was either decreased or

increased by more than 20%. A total of 10 moments of an increase in FiO2 and 12 moments of

a decrease in FiO2 were included. In one patient, FiO2 was decreased twice (table 4).

Patient Characteristics Increase in FiO2 Decrease in FiO2

Number (n) 10 12

Gender (male/female) 3/7 6/6

Age (years) 64 ± 10 62 ± 8

Length (cm) 168 ± 3 172 ± 8

Weight (kg) 86 ± 24 80 ± 13

BMI (kg/m2) 31 ± 9 27 ± 5

ASA class (n) I=1, II=2, III=7 I=3, II=5, III=4

Baseline SpHb (mmol/L) 6.4 ± 0.7 6.7 ± 0.8

SpHb (mmol/L) 6.4 ± 0.5 6.6 ± 0.8

Hbsatlab (mmol/L) 6.3 ± 0.9 6.1 ± 0.9

Surgery time (minutes) 458 ± 201 508 ± 197

Type of surgery (n)

Urology

Gynecology

Neurosurgery

Hepatobiliairy

Surgical Oncology

ENT

1

2

1

5

2

1

2

1

5

1

Table 4. Patient characteristics for FiO2 increase and decrease. Continuous variables are

expressed as mean ± standard deviation.

Figure 5 shows the median FiO2 and median SpHb measurement from 10 min before, till 10

min after the FiO2 increase. SpHb is expressed as deviation in mmol/L from -10 min. Before

the increase in FiO2, median SpHb was 6.1 (5.7-7.7) mmol/L. 3 minutes and 5 minutes after

FiO2 increase, median SpHb were 6.1 (5.8-7.7) mmol/L and 6.2 (5.8-7.6) mmol/L,

respectively (table 5). SpHb at baseline was not statistical different from SpHb 3 min after

FiO2 increase (P=0.240), which was also true for SpHb between baseline and 5 min

(P=0.109).

Time since FiO2 increase N Median Mean SD Min. Max. Normality*

SpHb

(mmol/L)

Baseline 10 6.1 6.4 0.68 5.7 7.7 Yes (P=0.131)

+3 minutes 10 6.1 6.5 0.76 5.8 7.7 No (P=0.006)

+5 minutes 10 6.2 6.5 0.70 5.8 7.6 No (P=0.013)

*Shapiro Wilk-test

Table 5. Median, mean, SD, minimum and maximum SpHb measurements (mmol/L) after

increase in FiO2.

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Figure 5. Effects of increases in FiO2 on SpHb measurements. Data are deviation of SpHb -

10 individual patients and the median of these patients. The thick black line is median FiO2,

the thick red line is median deviation of SpHb.

Median FiO2 and median SpHb are shown in figure 6 from 10 min before, till 10 min after the

start of the FiO2 decrease. SpHb is expressed as the deviation in mmol/L starting from 10

minutes before FiO2 decrease. Median SpHb at baseline was (5.1-7.7) mmol/L. 3 minutes and

5 minutes after FiO2 increase, SpHb were 6.6 (5.2-7.8) mmol/L and 6.5 (5.2-7.8) mmol/L,

respectively (table 6). No statistical difference was found for SpHb between baseline and 3

min (P=0.732) or between baseline and 5 min (P=0.240).

Time since FiO2 decrease N Median Mean SD Min. Max. Normality*

SpHb

(mmol/L)

Baseline 12 6.7 6.7 0.81 5.1 7.7 Yes (P=0.335)

+3 minutes 12 6.6 6.7 0.89 5.2 7.8 No (P=0.260)

+5 minutes 12 6.5 6.6 0.93 5.2 7.8 Yes (P=0.249)

*Shapiro Wilk-test

Table 6. Median, mean, SD, minimum and maximum SpHb measurements (mmol/L) before

and after decrease in FiO2.

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Figure 6. Effects of decreases in FiO2 on SpHb measurements. Data are median deviation of

SpHb and SpHb deviation of 12 individual patients. The thick black line is median FiO2, the

thick red line is median deviation of SpHb.

The median SpHb does not significantly differ after a change in FiO2, as described above. To

gain more insight in the deviation of trend in SpHb before and after a change in FiO2, the

MDAD and MAD of SpHb is calculated and plotted with the corresponding FiO2 against

time. Figure 7 shows the MAD and MDAD of SpHb during FiO2 increase. Figure 8 shows the

MAD and MDAD of SpHb during FiO2 decrease.

Time since FiO2 increase N MDAD MAD SD Min. Max.

SpHb

(mmol/L)

Baseline 10 0.10 0.16 0.08 0.10 0.30

+3 minutes 10 0.10 0.21 0.33 0.00 1.10

+5 minutes 10 0.15 0.20 0.19 0.00 0.70


(mmol/L), before and after FiO2 increase.

Time since FiO2 Decrease N MDAD MAD SD Min. Max.

SpHb

(mmol/L)

Baseline 12 0.20 0.29 0.27 0.00 0.80

+3 minutes 12 0.15 0.31 0.37 0.00 1.10

+5 minutes 12 0.25 0.42 0.38 0.10 1.20


(mmol/L), before and after FiO2 decrease.

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Comparing the absolute deviation of SpHb at baseline with 3 minutes after FiO2 increase,

revealed no difference (P=0.999). When comparing the absolute deviation of SpHb, between

baseline and 5 min after FiO2 increase, no difference was found either (P=0.766). Similar

results were found for the absolute deviation of SpHb between baseline and 3 min (P=0.863)

and between baseline and 5 min after FiO2 decrease (P=0.111). Descriptive statistics for

MAD and MDAD after FiO2 alteration can be found in tables 7 and 8. Above testing was

done using the Wilcoxon signed-rank test.

Figure 7. Effects of increases in FiO2 on SpHb measurements. The black line represents the

median FiO2, the red line is the Median Absolute Deviation and the thick blue line is the

Mean Absolute Deviation of SpHb.

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Figure 8. Effects of decreases in FiO2 on SpHb measurements. The black line represents the

median FiO2, the red line is the Median Absolute Deviation and the thick blue line is the Mean

Absolute Deviation of SpHb.

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Discussion

In the present study, we investigated whether noninvasive, transcutaneous measurement of

Hemoglobin concentration (SpHb) by the Masimo Radical 7 monitor is influenced by

intravenous injection of propofol in patients under general anesthesia. At second, we

investigated whether a change in administration of oxygen, influenced SpHb readings.

After injection of propofol, while the patient was not bleeding, we observed a deviation of

trend in SpHb readings. In contrast, a change in FiO2 did not induce trend alterations in SpHb

readings. These findings suggest that the injection of propofol – and not applying changes in

the level of oxygen administration – influence the stability of SpHb readings.

In patients undergoing (major) surgery, it is of importance to assure whether Hb concentration

is sufficient to meet oxygen demands, since the content of Hb is a major determinant of tissue

oxygen supply. Obviously, performing surgery can lead to blood loss, which can compromise

tissue oxygenation if Hb concentration falls below a certain threshold. Also, many in-hospital

patients scheduled to undergo surgery, are anemic already preoperatively and as such, little

blood loss can sometimes be “sufficient” to substantially decrease tissue oxygenation.7 Also,

the surgical stress response increase tissue oxygen demands, necessitating sufficient Hb

available to tissues.6,34

Hence, an accurate measurement of Hb is required to decide whether

RBC transfusion is indicated: on one hand to prevent (global) tissue hypoxia (in case of

anemia) and on the other hand to prevent unnecessary RBC transfusion (in case Hb is above

the individual transfusion threshold). The latter is highly important as – as mentioned earlier –

RBC transfusion bears risks to patients: it is associated with the development of pulmonary

and hemolytic complications and induces life-long immunological upregulation. In contrast,

unnecessary withholding RBC’s to the patients also leads to certain risks, which are all related

to tissue hypoxia (e.g. myocardial infarction, cerebral ischemia, acute kidney failure). As

such, peri-operative anemia can lead to serious morbidity and possibly even mortality.2,3

SpHb

could help to evaluate changes, or absence of changes, in Hb concentrations, since it measures

Hb concentration continuously instead of intermittently. This method may allow an earlier

detection of anemia during surgery in which occult blood loss can occur as blood loss is not

always directly visible to the clinican.15,16

Earlier detection of anemia is only possible when

Hb measurements agree with actual Hb concentrations especially in the range where

transfusion decisions are being made.

Results of studies investigating the accuracy of the SpHb device are somewhat conflicting.13-

22 Many factors have been proven to influence SpHb agreement with reference Hb values. In

case Hbsatlab appears low, SpHb readings seem to overestimate true Hb concentration. 17,27,28

Also, infusion of colloid solution was shown to induce a more profound decrease in

correlation with Hbsatlab than crystalloid solution.14,29

Multiple studies reported a significant

decrease in SpHb accuracy and precision when peripheral tissue perfusion (PI, as explained

before) was low.18-20

In contrast – an increased perfusion of the finger where the SpHb

measurement is taken, after a digital nerve block, as reflected by an increased PI, improves

SpHb agreement with Hbsatlab concentration.30

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In our institution, general anesthesia is often induced and/or maintained with propofol as

hypnotic component. This study showed a deviation of trend of SpHb readings, secondary to

intravenous injection of propofol. During this time period, patients were not actively bleeding

as the surgical incision had not yet been made. Also, patients were receiving maintenance

fluid therapy with crystalloids only, at an estimated rate of 1-3ml/kg/hr of crystalloid solution,

according to institutional practice. As described above, infusion with colloid fluid has proven

to influence SpHb readings, but no colloids were used for maintenance fluid therapy. In the

presence of normal or near-normal kidney function, maintenance fluid therapy is usually

undertaken when the patient is not expected to be able to eat or drink normally for a

prolonged period of time (e.g., perioperatively). The goal of maintenance fluid therapy is to

preserve water and electrolyte balance and to provide nutrition, therefore, hemodilution is

unlikely. Under these conditions, the observed deviation of trend of SpHb readings after

intravenous injection of propofol, was not expected.

The effect of propofol injection on SpHb measurement could be explained by the drug itself,

since its color, white, could affect the absorption spectra of the device. Another explanation

for the effect of propofol injection on SpHb readings are the vasoactive effects of propofol.

Intravenous induction of general anesthesia, induces peripheral vasodilatation and results to

some extent in changes in peripheral blood flow.31

Increased perfusion of the finger where the

SpHb measurement is taken, as reflected by an increased PI, improves SpHb agreement with

Hbsatlab concentration.30

Lastly, these results could be due to more complex blood flow

changes secondary to intravenous injection of propofol. The exact algorithm and absorption

spectra used by the Masimo Radical 7 to calculate SpHb are currently still unrevealed.

Therefore, these explanations remain purely hypothetical.

The effect of injection of propofol on SpHb readings was “only” 0.30 mmol/L. This deviation

of trend in SpHb is statistically significant, but the difference might not be clinically relevant,

as it is unlikely to influence the decision on whether to transfuse RBC to an individual patient

or not. On the other hand these results reveal another factor which affects SpHb readings and

decreasing SpHb reliability.

Alteration of FiO2 did not affect SpHb stability, which contrasts previous studies.32,33

In both

studies that suggested an effect of FiO2 alteration on SpHb stability, a different and earlier

version of the SpHb sensor (Ref E) was used.32,33

The new sensor type (Ref K) used in the

present study could explain why SpHb values remained stable after changes in FiO2. Which

specific modifications have been made to the current sensor version are not published by the

manufacturer. Another explanation might be a lack of statistical power, as described below.

The current study has several limitations.

At first, we did not perform an a priori power analysis for this retrospective study. Therefore,

we cannot exclude that there might be an effect of oxygen on SpHb measurement (type II

error). Nevertheless, the current data can be used for sample size calculations in a prospective

study in order to elucidate this issue more clearly.

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At second, not in all patients SpHb was already recorded during induction, since the original

study was focused on intraoperative SpHb measurement. Hence, only a limited number of

patients were included, reducing the robustness of the observed results.

At third, multiple changes occur during induction of anesthesia, which is already partly

mentioned previously. Besides the injection of propofol, other drugs are administered during

this time period (e.g., opioids, antibiotics, vasoactive drugs) which might affect SpHb

readings. Effects of these medications – which cannot be excluded based on this study –

might trouble a formal analysis of the current results. Also, induction of anesthesia is

associated with a loss of autonomic regulation of body temperature and therefore, temperature

of extremities in general decreases. This might also influence SpHb readings secondary to a

decrease in temperature which induces peripheral venoconstriction – causing complex

(micro)vascular flow changes together with general anesthesia-related peripheral vasodilation.

Conclusion

In conclusion, in patients under general anesthesia SpHb measurement by the Masimo Radical

7 pulse co-oximeter is affected by intravenous injection of propofol during induction of

anesthesia. Future prospective studies are necessary to elucidate these effects more clearly.

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