master thesis: accuracy, trend analysis of and influence...

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Document: Master Thesis: “Accuracy, trend analysis of and influence on continuous noninvasive hemoglobin monitoring of

the Masimo Radical-7 Pulse-CO-Oximeter”

Author: R. J. A. van Bommel (S1982109)

E-mail: [email protected]

Master Thesis:

“Accuracy, trend analysis of and influence on continuous noninvasive

hemoglobin monitoring of the Masimo Radical-7 Pulse-CO-

Oximeter”

Author:

R. J. A. van Bommel

S1982109

Supervisors:

J.P. van den Berg, MD

Prof. T.W.L. Scheeren, MD, PhD

University Medical Center Groningen (UMCG), The Netherlands

Department of Anaesthesiology

July 2014

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ABSTRACT (English) Study type Post-hoc analysis of data obtained from a prospective randomized controlled pilot study.

Introduction Peri-operative blood can lead to anemia (shortage of hemoglobin, or Hb) and hypoxia

(lack of adequate oxygen supply in the tissue)endangering patient outcome. To protect and improve

patient outcome Hb is measured during surgery using a satellite laboratory analyzer (Hbsatlab

method).This method requires invasive blood sampling and must be repeated to detect any alteration

in Hb concentration. The Masimo Rainbow Radical-7 Pulse-CO-oximeter is a measuring device

capable of continuous noninvasive hemoglobin monitoring (SpHb method). The aim of this thesis was

to assess whether the SpHb device is suitable to be used as a stand-alone monitor and/or base for

clinical decisions in patients at risk of undetected blood loss during surgery. To achieve this thesis

goal the agreement between the SpHb method and the clinical standard Hbsatlab method, as well as the

trending ability of the SpHb device were assessed.

Methods For the randomized controlled pilot study 30 patients undergoing elective surgery at risk of

undetected blood loss were included and randomized into two groups: a Hbsatlab-group with only the

Hbsatlab values available for the attending anesthesiologist, and a SpHb-group with only the SpHb

values available. Agreement between Hbsatlab and SpHb methods was analyzed using Bland-Altman

analysis for repeated measurements. Trending ability for the two methods was analyzed using polar

plots for changes in sequential paired simultaneous measurements.

Results Mean difference between Hbsatlab and SpHb was -0,32 (0,82) mmol/l. Bland-Altman analysis

showed 95% limits of agreement of -1,92 and 1,29 mmol/l. Correlation between Hbsatlab and SpHb was

0,71 (p<0,001). Analysis of the polar plot showed 59% of the data within the 30° ‘zone of desired

concurrence’.

Conclusion The Masimo Radical-7 Pulse-CO-oximeter did not seem reliable enough to be used as a

stand-alone monitor or the sole basis of clinical decisions in patients at risk of undetected blood loss

during surgery.

ABSTRACT (Nederlands) Type studie Post-hoc analyse van data uit een prospectieve gerandomiseerde pilot studie.

Introductie Perioperatief bloedverlies kan leiden tot anemie (tekort aan hemoglobine, of Hb) en

hypoxie (tekort aan adequate zuurstofvoorziening in de weefsels) wat het welzijn van de patiënt in

gevaar brengt. Om het welzijn van de patiënt te waarborgen en te bevorderen wordt het Hb gedurende

een operatie gemeten met een satelliet laboratorium analyse-apparaat (Hbsatlab methode). Deze methode

vereist invasieve bloedafname en moet herhaald worden om een verandering in de Hb concentratie te

detecteren. De Masimo Rainbow Radical-7Pulse-CO-oximeter is een meetapparaat waarmee

gecontinueerd non-invasief het hemoglobine gemonitord kan worden (SpHb methode). Het doel van

deze scriptie was te beoordelen of dit SpHb meetapparaat geschikt was als alleen staande monitor

en/of als basis voor klinische beslissingen bij patiënten met het risico op onopgemerkt bloedverlies

tijdens een operatie. Om dit doel te behalen werd de overeenkomstigheid van de SpHb methode en de

Hbsatlab methode, evenals de capaciteit van beide methodes om trends te volgen geanalyseerd.

Materiaal & Methode Voor de gerandomiseerde pilot studie werden 30 patiënten, gepland voor

electieve chirurgie met het risico onopgemerkt bloedverlies geïncludeerd en gerandomiseerd in twee

groepen: een Hbsatlab-groep, waarbij alleen de Hbsatlab waarde beschikbaar was voor de anesthesioloog

en een SpHb-groep, waarbij alleen de SpHb waarde beschikbaar was.

Om de overeenkomstigheid van de Hbsatlab en SpHb methodes te analyseren werd gebruik gemaakt van

een Bland-Altman analyse voor herhaalde metingen. De capaciteit van beide methodes om trends te

volgen werd geanalyseerd met behulp van een ‘polar plot’ voor veranderingen in opeenvolgende

gepaarde en gelijktijdige metingen.

Resultaten Het gemiddelde verschil tussen Hbsatlab en SpHb was -0,32 (0,82) mmol/l. Bland-Altman

analyse toonde 95% ‘limits of agreement’ tussen -1,92 en 1,29 mmol/l. Correlatie tussen Hbsatlab en

SpHb was 0,71 (p<0,001). Analyse van de polar plot toonde 59% van de data binnen de 30° ‘zone van

gewenste overeenkomst’.

Conclusie De Masimo Radical-7 Pulse-CO-oximeter leek niet betrouwbaar genoeg om geschikt te zijn

als alleen staande monitor of als basis voor klinische beslissingen in patiënten met het risico op

onopgemerkt bloedverlies tijdens chirurgie.

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CONTENTS

TITLE PAGE ................................................................................................................................ 1

ABSTRACT (English & Nederlands) ........................................................................................ 2

CONTENTS .................................................................................................................................. 3

BACKGROUND AND INTRODUCTION ............................................................................ 4-8

Literature review for the clinical relevance of anemia .......................................................... 4

Physiology of oxygen delivery and the role of hemoglobin .................................................. 5

Oxygenation .......................................................................................................................... 5

Oxygen Delivery.................................................................................................................... 6

Oxygen Consumption ............................................................................................................ 6

Current invasive hemoglobin measurement .......................................................................... 7

Non-invasive hemoglobin measurement and possible influences ......................................... 7

Perfusion Index (PI)............................................................................................................... 7

Pleth Variability Index (PVI) ................................................................................................ 8

Fraction of oxygen in the air (FiO2), norepinephrine and colloid solutions ......................... 8

THESIS GOAL AND HYPOTHESES ...................................................................................... 9

The primary objectives of this thesis will be the assessment of ............................................ 9

Additionally the following hypotheses were defined ............................................................ 9

MATERIALS AND METHODS ......................................................................................... 10-12

Design and objectives ..................................................................................................... 10

Study population ............................................................................................................. 10

Inclusion criteria ............................................................................................................. 10

Exclusion criteria ............................................................................................................ 10

Randomization ................................................................................................................ 10

Anesthesiological Care and Study procedure ................................................................. 10

Data recording and analysis ............................................................................................ 11

Statistical analysis .......................................................................................................... 11

Bland-Altman plot .......................................................................................................... 11

Four-quadrant plots & polar plots .................................................................................. 12

RESULTS .............................................................................................................................. 14-23 Demographic characteristics ................................................................................................ 14

Agreement between HbSatlab and SpHb ................................................................................ 15

Agreement between Hbsatlab and SpHb for Hb values lower than 6,0 mmol/l ..................... 16

Agreement between Hbsatlab and SpHb for Hb values greater than 6,0 mmol/l ................... 16

Perfusion Index (PI) and the difference in measured hemoglobin ...................................... 17

Pleth Variability Index (PVI) and the difference in measured hemoglobin ........................ 17

Fraction of inspired oxygen (FiO2) and the difference in measured hemoglobin ............... 18

Assessment chart for the alteration in FiO2 and its effect on SpHb measurement .............. 18

Norepinephrine and the difference in measured hemoglobin .............................................. 19

Influence of the colloid solution Voluven® on SpHb ......................................................... 19

Deviation between Hbsatlab and SpHb during time ............................................................ 20

Individual deviations per measuring moment ...................................................................... 20

Four Quadrant plot............................................................................................................... 22

Trending analysis of changes in Hb measured by Hbsatlab and SpHb methods .................... 23

DISCUSSION ....................................................................................................................... 24-30 Agreement between Hbsatlab and SpHb ............................................................................. 24

Trend analysis of Hbsatlab and SpHb ................................................................................. 26

Discussion Hypothesis 1 ...................................................................................................... 27

Discussion Hypothesis 2 & 3 ............................................................................................... 28

Discussion Hypothesis 4 & 5 ............................................................................................... 29

THESIS CONCLUSION, THESIS LIMITATIONS& ACKNOWLEDGMENT .................... 30

REFERENCES ..................................................................................................................... 31-34

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BACKGROUND AND INTRODUCTION

Peri-operative blood loss leads to a decrease in hemoglobin (Hb) levels in the blood.

Hemoglobin is a crucial oxygen transporting protein in the human body and part of the

erythrocytes (red blood cells). Decreased Hb levels are associated with enhanced risks of

prolonged hospitalization, morbidity and mortality post-operatively especially in the more

vulnerable patients like the elderly patient (1-4). Hb is responsible for oxygen delivery to

body tissues, insufficient hemoglobin levels can results in hypoxia (lack of adequate oxygen

supply in the tissue) and death. As one of the key targets in anesthesia is to prevent hypoxia or

to intervene early in patients suffering from hypoxia, hemoglobin levels are measured on a

regularly basis to detect any perioperative anemia (i.e. shortage of qualitative erythrocytes and

functioning hemoglobin).

However, in cases where no significant blood loss is expected or no clinical signs of blood

loss are present, Hb measurement is not always preformed on a regularly base, or not taken at

all. Therefore, in certain cases anemia usually keeps unnoticed, leading to unknown persistent

anemia, increasing postoperative morbidity and mortality risks. Recently a new measurement

device has become commercially available: the Masimo Radical-7 Pulse CO-Oximeter. This

device provides a continuous non-invasive hemoglobin measurement, meaning the

anesthesiologist does not have to perform an invasive Hb measurement on a regular basis,

possibly leading to a better chance to detect the “silent” anemia. Continuous non-invasive

hemoglobin measurement thus attributes in improving patient outcome.

In the first part of this thesis a brief literature review will be given to provide the reader with

some background information about the incidence, risks and patient outcome of anemia.

Following on this brief literature review an introduction to the physiology of hemoglobin in

oxygen transport and the clinical relevance of hemoglobin will be provided as well as a

description of the current used methods and the new alternative measuring method for

hemoglobin using spectrometry. At the end of the introduction part of this thesis the thesis

goal and hypotheses addressed in this thesis will be stated.

Literature review for the clinical relevance of anemia

Anemia leads to decreased oxygen (O2) transport, resulting from the shortage of qualitative

erythrocytes and functioning hemoglobin as mentioned before. Normal hemoglobin

concentrations lie in the range of 8,7 – 10,6 mmol/l for men and 7,5 – 9,9 mmol/l for women.

Anemia in patients scheduled for surgery is not uncommon, with one in three non-cardiac

surgery patients and almost half the cardiac surgery patients presenting a preoperative anemia

(4,5). Under normal conditions the body can compensate for anemia with four mechanisms;

increased cardiac output, selective shunting of blood, increasing the oxygen extraction from

the hemoglobin and stimulating the bone marrow to increase en accelerate new erythrocyte

and hemoglobin production (6,7).

During general anesthesia, since normal physiology has been partly altered by the hypnotic,

vasoactive and analgesic medication, the human body itself can only compensate partially for

anemia by enhancing the cardiac output.

Pre-operative and peri-operative anemia are strongly associated with increased risks of 30-day

morbidity and mortality post-operatively (1-4).Treatment of perioperative anemia is often

managed using blood transfusion based on a predetermined threshold. Some studies proved

the possibility of survival with Hb levels under 3,0 mmol/l to even extreme conditions with

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Hb concentration as low as 0,8 mmol/ during general anesthesia (8,9). To enable the survival

of these low Hb concentrations extreme measures such as hypothermia or deep stages of

anesthesia were necessary. These conditions are not without consequences; hence one would

rather prevent hypoxia instead of using these extreme measures to lower oxygen demand. To

prevent hypoxia as well as the need for extreme measures, a hemoglobin concentration

threshold for blood transfusion is maintained in most hospitals in Western Europe. The

University Medical Center Groningen (UMCG) uses a transfusion protocol based on the

patient’s individual situation. This protocol is known as the “4-5-6 flexi norm” (10). This

protocol was introduced, because blood transfusion is not without risk. Blood transfusions

should therefore be restricted and needs to be administered with the right timing. Unnecessary

blood transfusion increases risks of pulmonary or hemolytic complications whereas

unnecessary delay of transfusion increases the risk of cardiac ischemia (11-13).

When Hb can be measured repeatedly and reliably the oxygen delivery can be monitored

consequently, possibly preventing hypoxia and its consequences.

Physiology of oxygen delivery and the role of hemoglobin

The process for oxygen uptake and transport can be separated into three components:

oxygenation, oxygen delivery and oxygen consumption. All three components rely on

sufficient hemoglobin concentrations. In the following part the calculation, clinical relevance

of each three components will be further explained. The roll of hemoglobin in these

components will be further explained as well.

Oxygen (O2) is diffused from air through the alveolar-capillary membrane of the lung into the

bloodstream and subsequently into the erythrocyte. The protein hemoglobin inside the

erythrocyte is capable of reversibly binding to O2 and carbon dioxide (CO2). Hemoglobin,

saturated with oxygen, is transported to the capillaries to release its oxygen to enable aerobe

metabolism in the tissue (14), depending on partial gas pressures.

In the lung, a higher partial O2-pressure (PO2) prevails over the partial O2-pressure in the

bloodstream. Due to this positive pressure difference O2 diffuses from the alveoli into

erythrocytes of the bloodstream where it binds to hemoglobin. This hemoglobin, already

containing the CO2 formed during metabolism in tissues, releases its CO2 as it binds O2. The

exchange of CO2 for O2 is also known as the Haldane-effect (14).

The oxygenated Hb is transported to tissues via the bloodstream, where hemoglobin under

influence of the partial O2- and CO2-pressures releases its O2 and binds the present CO2: the

Bohr-effect(14). The deoxygenated hemoglobin flows back towards the lung where it can

release its CO2 to bind new O2 after which the loop starts again.

Oxygenation

In clinical settings the anesthesiologist wants to assess how much oxygen the patient has

absorbed from the lungs into the arterial bloodstream, to assess if the oxygenation is sufficient

or if the amount of provided oxygen must be altered. The absorbed oxygen in the arterial

blood is mostly chemically bound with hemoglobin, only a small amount of absorbed oxygen

is physically dissolved in the arterial blood. The total amount of arterial oxygen (bound and

physically dissolved) is called the arterial oxygen content (CaO2) and can be calculated using

the following formula:

CaO2 (ml O2/dL) = (1,34 x hemoglobin concentration x SaO2) + (0,0031 x PaO2)

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In this formula 1,34 stands for the amount of ml O2 that can be bound per gram hemoglobin

(15). The SaO2 states the arterial oxyhemoglobin saturation (the percentage of O2 bound to

hemoglobin) whereas PaO2 is the arterial oxygen tension.

The oxygenated hemoglobin flows along the arterial bloodstream into the microcirculation

(capillaries) to enable aerobe metabolism. The microcirculation ends up to the efferent vein

which merges with other veins into the caval vein where the oxygen content is expressed as

the central venous blood oxygen content (CvO2). Due to oxygen consumption the CvO2 is

lower than its arterial counterpart. In order to calculate the CvO2 the hemoglobin

concentration is multiplied by the oxygen saturation in the venous blood. The amount of

dissolved oxygen in the venous blood is added:

CvO2 (mL O2/dL) = (1,34 x hemoglobin concentration x SvO2) + (0,0031 x PvO2)

Knowing the CaO2 and CvO2, the extent of oxygen consumption can be calculated (CaO2 -

CvO2). This difference is known as the arteriovenous (AV) oxygen difference and can be

further used to calculate the cardiac output (the amount of blood the heart pumps out every

minute) or Q, using the Fick equation:

Q (L/min) = Oxygen consumption / (10 x atriovenous oxygen difference)

Q (L/min) = Oxygen consumption / ( 10 x (CaO2 - CvO2))

Q (L/min) = Oxygen consumption / ( 10 x ((1,34 x hemoglobin concentration x SaO2) +

(0,0031 x PaO2))- ( (1,34 x hemoglobin concentration x SvO2) + (0,0031 x PvO2))

As demonstrated by writing out the equations, the hemoglobin concentration must be known

to calculate the uptake of oxygen, extent of metabolism and cardiac output in order to monitor

the patient’s oxygen state. It is therefore of great relevance in oxygen consumption and

delivery.

To prevent a mathematical coupling error the oxygen consumption in the Fick equation must

be measured by respirometry or estimated using a nomogram.

Oxygen Delivery

The oxygen delivery (DO2) shows the amount of oxygen delivered from the lung to the tissue

and can be calculated using the following formula:

DO2 (mL/min) = Q x CaO2

DO2 (mL/min) = Oxygen consumption / (10 x (CaO2 - CvO2)) x CaO2

DO2 (mL/min) = Oxygen consumption / (10 x (CaO2 - CvO2)) x (1,34 x hemoglobin

concentration x SaO2) + (0,0031 x PaO2)

Oxygen Consumption

The oxygen uptake and transport as well as the role of hemoglobin during these stages have

been illustrated. The amount of oxygen extracted from the bloodstream for aerobe metabolism

is known as the oxygen consumption (VO2). The amount of extracted oxygen and the slope

between oxygen delivery (DO2) and oxygen consumption (VO2) has clinical significance

since it can be used to differentiate between multiple causes of oxygen/perfusion mismatches.

The amount of oxygen, which is required for maintaining aerobic cellular metabolism for

example can be increased in critically ill patients (e.g. acute respiratory distress syndrome,

sepsis or septic shock) (16-19).

VO2 (mL/min) = Q x (CaO2 - CvO2)

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Current invasive hemoglobin measurement

The current clinical standard for perioperative hemoglobin measurement is by use of a point-

of-care satellite laboratory blood gas analyzer (Hbsatlabmethod). For measurement with this

device patient blood must be actively collected from the patient. In general, the invasive

measurement is often only preformed when a hemoglobin drop is expected. When no distinct

blood loss, blood dilution or signs of oxygen distress are evident, the hemoglobin

measurement is often omitted. Without (scheduled) hemoglobin measurements, perioperative

anemia could go unnoticed, possibly leading hypoxia and suboptimal timing of transfusion,

and thus increasing the risk for patient morbidity (11-13).

Non-invasive hemoglobin measurement and possible influences

The FDA approved and CE marked Radical-7 Pulse CO-Oximeter (Masimo Corp., Irvine,

California, USA) is a device capable of continuously delivering a non-invasively measured

total hemoglobin value (SpHb), Perfusion Index (PI) and a Pleth Variability Index (PVI). The

technology of the Radical-7 is based on pulse oximetry measurements, using multiple

wavelengths of light and adaptive filters to isolate the signals of the arterial pulsations trough

the finger in order to calculate total hemoglobin concentration.

Where conventional invasive measurement methods only provides a “snap shot” impression

of the hemoglobin concentration and require multiple blood samples to monitor changes in

Hb over time, the Radical-7 could monitor changes non-invasively and continuously.

Figure 1 The Masimo Radical-7 Pulse CO-Oximeter (left) showing a SpHb (red) and PVI (white) value. The

SpHb sensor (right) is adjusted to a patients ring finger, the light diode and light sensor are placed on opposite

sides.

Perfusion Index (PI)

The Perfusion Index is the ratio of pulsating blood flow versus non-pulsating blood in

peripheral tissue and therefore gives an indication of the peripheral tissue perfusion. The PI is

expressed as the percentage of the total amount of infrared light reflected by the pulsating

blood in respect of the amount of infrared light reflected by the non-pulsating blood.

Alteration in the PI seems to influence the SpHb measurement (20).

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Pleth Variability Index (PVI)

The PVI is a measure for the dynamic changes in PI, which occur during respiratory

variations. During spontaneous inspiration the pressure inside the airway and thorax changes

negatively, causing an increased venous return of blood to the heart, stretching the right

ventricle and enhancing the contractility of the ventricle, therefore increase the cardiac output.

Increased negative intrathoracal pressure thus increases cardiac output. During exhalation the

pressures reverses because increased positive intrathoracal pressure decreases cardiac output.

When patients are mechanically ventilated, the patients is 'forced' to inhale using positive air

pressure, decreasing the cardiac output during inhalation and increasing cardiac output during

exhalation, in contrary to normal physiology. These alterations in cardiac output influence the

amount of pulsating versus non-pulsating peripheral blood, especially in mechanically

ventilated patients and patients with volume depletion (21). Alterations in PVI might, just like

alterations in PI influence the SpHb measurement.

Figure 2 Variation in Perfusion Index, enabling the calculation of the Pleth Variability Index using the equation:

PVI= (PImax – PImin) / PImax *100. Each peak represents a volume of blood pumped through the capillary.

Fraction of oxygen in the air (FiO2), norepinephrine and colloid solutions

The fraction of oxygen in air administered to the patient is expressed as the ‘fraction of

inspired air’ (FiO2). Natural air contains about 21% oxygen, corresponding with a FiO2 of

0,21. During anesthesia the FiO2 can be altered to improve oxygen supply as demonstrated

earlier in this thesis. Too long exposure to high FiO2 values can be harmful and is therefore

discouraged (22).

A pilot study in 2011 showed that the FiO2 could influence the SpHb measurement, with the

SpHb increasing when FiO2 increased (23). Later on, more clinicians came to the same

conclusion (24). The administering of the catecholamine hormone norepinephrine or colloid

solutions also seemed to influence the SpHb value (25,26).

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THESIS GOAL AND HYPOTHESES

The Radical-7 is FDA approved, CE marked and has shown accuracy compared with

laboratory CO-Oximeter measurement in (healthy) volunteers undergoing hemodilution (27).

The peri-operative accuracy of the Radical-7 was also extensively surveyed in other studies

(20,25,28-35) and even meta-analyzed (36). However, none of these studies investigated the

SpHb measurement specifically in patients at risk of undetected bleeding.

This thesis will focus on the latter patient group. In this thesis the agreement between

hemoglobin measurement using the (clinical standard) satellite-laboratory analysis (Hbsatlab)

and the non-invasive Masimo Rainbow Radical-7 monitor (SpHb) will be analyzed. The

trending ability of the SpHb device and the deviation in accuracy will be addressed, as well as

the influence of the FiO2, Perfusion Index (PI), Pleth Variability Index (PVI), administering

of colloid solution and norepinephrine on SpHb measurement.

For this thesis, data from the pilot study “Monitoring of intraoperative blood loss: benefit of

continuous noninvasive hemoglobin monitoring?” were used. The pilot study hypothesized

that continuous real-time hemoglobin monitoring could help identifying the right moment for

transfusion in patients at risk of undetected bleeding.

The primary objectives of this thesis will be the assessment of:

The agreement between Hbsatlab and SpHb

The trending ability of Hbsatlab and SpHb to detect changes in Hb concentration

Additionally the following hypotheses were defined:

1. There will be no deviation between Hbsatlab and SpHb after in vivo-calibration in the

course of time.

2. Alteration of FiO2 will alter SpHb value as previously shown (23).

3. Alteration of PI and PVI will decrease the reliability of SpHb measurements.

4. Administering colloid solutions will decrease the reliability of SpHb measurement as

is described in previous research (25).

5. Administering norepinephrine will decrease the reliability of SpHb measurements.

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MATERIALS AND METHODS

Design and objectives

Data were used from a prospective randomized controlled pilot study investigating the impact

of continuous Hb monitoring on the time period of Hb being below the individual transfusion

trigger. This study has been approved by the local medical ethics committee (METC) and was

performed in patients at risk for “silent” occult blood loss. This study aimed to investigate the

agreement between noninvasively measured Hb (SpHb) and invasively measured Hb by using

the clinical standard, satellite-lab Hb analysis (Hbsatlab).

Study population

30 patients, age 23-84 years, scheduled to undergo elective surgery at risk of undetected intra-

operative blood loss were included and randomized into two groups, with either the Radical-7

monitor available for the attending anesthesiologist or the conventional monitoring by blood

gas analysis. Randomization took place following the design of the original study.

Inclusion criteria

Inclusion criteria were defined as follows:

Patients at the age of 18 years or older, planned for elective surgery at-risk for

undetected blood loss.

American Society of Anesthesiologists (ASA) Physical Status Classification 1-4

Exclusion criteria

Patients who refused to participate and/or were scheduled for emergency surgery were being

excluded.

Randomization

The randomization took place conform the design of the original study and is of no further

relevance in this thesis.

Anesthesiological Care and Study procedure

After the patient arrived in the operating room, he/she was connected to standard monitoring

equipment (Philips Intellivue, Eindhoven, the Netherlands) including pulse-oximetry, non-

invasive blood pressure measurement (NIBP) and electrocardiography (ECG).

The SpHb sensor (Rev K, version R125) connected to the Radical-7 (Masimo Corp., Irvine,

California, USA) was placed on either the second or third finger of the hand that was most

suitable for measurements. The sensor was shielded to prevent ambient light from influencing

the measurements.

During surgery, patients received standard care; balanced anesthesia using hypnotics titrated

to a bispectral index (BIS) between 40 and 60. Opioids (fentanyl, sufentanil or remifentanil)

were administered by continuous infusion as required. If necessary to maintain sufficient

vascular tone vasopressor agents (phenylephrine, norepinephrine or ephedrine) were

administered at the attention of the anesthesiologists. In addition, if clinically required a

thoracic or lumbar epidural catheter was placed. After induction of anesthesia, a radial artery

canula was inserted for continuous monitoring of arterial blood pressure. Fluid management

was left to the discretion of the attending anesthesiologist.

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For determining the transfusion threshold the locally used transfusion protocol was applied

during the time the patient was in the operating room.

In half the patient population (n=15) Hbsatlab blood samples were taken with an interval of 30

minutes, in the other half Hbsatlab samples were taken only on indication of the attending

anesthesiologist.

Hbsatlab samples were drawn from the radial arterial catheter. Before taking each blood

sample, sufficient blood volume was being removed from the arterial catheter. Blood was

drawn into standard blood collection tubes appropriate for the method of analysis. The filled

blood tubes were mixed by gently rotating the tube 10 times. After mixing each blood sample

was analyzed by the same laboratory analyzer (ABL 800 Flex; Radiometer GmbH,

Copenhagen, Denmark) to avoid variation induced by using multiple laboratory devices.

This satellite laboratory device was comparable with a central laboratory analyzer, with a bias

of -0,008 mmol/l (37). The first Hbsatlab value was used for in-vivo calibration of the SpHb

device according to manual instructions.

Data recording and analysis

Data was collected by using Rugloop® software (DeMed, Temse, Belgium) recording all

continuous data every second from the Intellivue and Radial-7 monitors. A case report file

(CRF) was used to register individual patient characteristic, medical history, type of surgery,

fluid balance and blood test results. Relevant patient data (such as age, sex, height) were

recorded from the appropriate digital hospital information system.

All data was merged in to a Microsoft Excel 2010spread sheet for further analysis. Data was

analyzed using SPSS® version 20 (IBM Statistics, New York, USA). Polar plots were created

using and Sigmaplot® 10.0 (Systat Software Inc., San Jose, California, USA).

Statistical analysis

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

confirmed using the Kolmogorov-Smirnov and Shapiro-Wilk tests.

If normally distributed, quantitative data are listed as mean (standard deviation, SD). If the

quantitative data are not normally distributed the data are written down as median values with

the upper and lower ranges. Categorical data are expressed as number and percentage.

Correlation was tested using the Pearson correlation test.

In statistical tests a P-value of < 0,05 was defined as statistically significant.

Bland-Altman plot

To assess the agreement between the simultaneously measured SpHb and Hbsatlab, a Bland-

Altman plot was performed (38). The Bland-Altman plot was adjusted for repeated measures

in multiple subjects (39).

Bland-Altman plots are helpful to assess the agreement between two measuring methods,

when neither of the two is regarded as the ‘golden standard’.

By plotting the mean values of both measuring methods (x-axis) against the difference in

value between the two measuring methods (y-axis) at the same moment (simultaneous

measurements) the Bland-Altman plots can show if the two measuring methods principally

differ from each other.

The Bland-Altman plot also shows the limits of agreement (mean ± 1,96 times the standard

deviation), providing insight in which the degree random variation may influence the ratings.

95% of the data lie between the upper and lower limits of agreement.

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If the test shows narrow limits of agreement a good interchangeability between the two

measuring methods is suggested, whereas wide limits of agreement are suggestive for a poor

interchangeability.

Four quadrant plots & polar plots

Bland-Altman plots are popular as an analytical method to evaluate the agreement between a

new measuring device (in this thesis the SpHb monitor) and a reference device (in this thesis

the satellite laboratory analyzer, or Hbsatlab method). It does not show any insight into the

capability of the new device to detect changes or trends. To assess changes and trends four

quadrant plots and polar plots are more useful.

Four-quadrant plots can be used to visually assess the magnitude and degree of agreement

between two measuring methods in order to determine the trending ability of the two

measuring methods. The plot is divided in four equal quadrants. In case of a trending ability

most data points lie in the upper right and lower left quadrant. When upon inspection most

data points lie in these two quadrants along a 45° line, also known as ‘the line of identity’ (x =

y) there is a good trending ability between the test devices. Small deviations between two

measurements devices result in data points close to the center of the plot. These small

deviations tend to be randomly distributed, making assessment more difficult.

For more information about the four-quadrant plot, see also figure 3.

Just as small deviations, large changes in hemoglobin concentration can bias a four-quadrant

plot, for large alterations in one device will nearly always be in agreement with the other

device. Therefore it is advised to convert the x-y values to polar coordinates, thus creating a

polar plot (40). Polar plots are mostly used to assess the trending abilities of cardiac output

measuring devices, but can also be used to assess the trending ability of the Hb monitors in

this study.

The angle made by the vector with the line of identity (y = x) shows the agreement. The

length of the vector (calculated by using the Pythagoras theorem; square root of Δx +Δy =

length vector) corresponds with the magnitude of change. When 95% of the data points are

within the “zone of desired concurrence” as described in earlier research (41) the trending

ability can be defined as a good concurrence. This zone of desired concurrence is the zone

ranging from -30° until +30° and from 150° until 210°. For more information about the polar

plot, see also figure 3.

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Figure 3 The principle of the four-quadrant plot and the polar plot. A (four-quadrant plot): changing value

measured by the new method (SpHb) is plotted against the changing values measured by the conventional

method (Hbsatlab). The dotted line represents the line of identity (45° line), indicating the line on which all data

points should lie if both measuring methods concur exact. The vector of the two example points, not lying on the

line of identity, represents the change in measurements taken by both methods. The angle 01 shows that there is a

positive deviation from the line of identity. This deviation is the result of over-reading the positive change by the

new method. Angle 02 indicates another positive deviation (relative to x-axis), resulting from the over-estimating

of the negative change by the new method.

B (polar plot): The x-y values from the quadrant plot are converted to polar coordinates and plotted is the angle

from the line of identity with the length of the vector (obtained from the square root of Δx + Δy as described

before). When 95% of the points lie within an absolute deviation of ±30° from the polar axis (between the blue

dotted lines) concurrence can be declared “Good”. It is customary to exclude small changes in values, identified

as those lying within the circular zone of exclusion (the blue marked center). The cutoff point for these small

changes in this theses was set on a Δ Hb equal to or between -0,2 and 0,2 mmol/l.

[Figure used by permission from the master thesis of JP van den Berg. “Near-Infrared spectroscopy measured

cerebral tissue and thenar muscle oxygen saturation poorly correlate with central venous oxygen saturation

during heart surgery. University of Groningen 2013]

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RESULTS

For this thesis data from a pilot study to investigate if the continuous noninvasive hemoglobin

monitoring (SpHb) could reduce the total time a patient’s Hb is below a predetermined

transfusion threshold was used. For that pilot study a total of 41 patients were assessed for

eligibility. 11 patients were excluded for not meeting the inclusion criteria (n=2), declination

to participate from the patient (n=2), declination to participate from the operation team (n=4),

and technical reasons (n=3).

The remaining 30 patients were analyzed according to protocol. Demographic characteristics

are shown in table 1. In total 228 blood samples were taken simultaneously with the

registration of SpHb. Of these 228 samples, 30 were used to in-vivo calibrate the SpHb at the

start of surgery. The remaining 198 blood samples could be used to assess the agreement

between Hbsatlab and SpHb.

Of the 198 Hbsatlab values 77 were greater than 6,5 mmol/l. The median Hbsatlab>6,5 value was

7,5 mmol/l (6,6 – 8,7). From all corresponding 198 SpHb values, 102 were greater than 6,5

mmol/l. Median SpHb>6,5 was 7,3 (6,6 – 10,5).

37 of the 198 in-vivo calibrated measurements had both Hbsatlab and SpHb values below 6,0

mmol/l, with a mean bias of -0,03 (0,62).

Table 1 Patient demographics. Results are presented as numbers or mean ± Standard Deviation

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Agreement between satellite laboratory blood gas analyzer ABL 800 Flex (HbSatlab) and

Pulse CO-Oximeter (SpHb)

The Bland-Altman plot shows a wide spread scatter plot with 198 measuring moments from

30 patients. On the x-axis the mean measured Hb, ((Hbsatlab + SpHb) / 2) is demonstrated. The

y-axis represents the difference between the invasive measured Hbsatlab and the simultaneously

non-invasive measured SpHb. The mean difference between Hbsatlab and SpHb (also called

bias) was -0,32 mmol/l with a precision (SD) of 0,82 mmol/l. The concomitant 95% limits of

agreement for this mean and SD were 1,29 mmol/l for the upper limit and -1,92 mmol/l for

the lower limit.

The Pearson correlation test showed a correlation of 0,71 (p<0,001).

Figure 4 Bland-Altman plot, adjusted for repeated measurements showing the agreement between Hbsatlab and

SpHb methods. All 198 in-vivo calibrated measuring moments from 30 patients were included for this plot.

Mean Hb bias is represented by the solid line, limits of agreement by the dotted lines.

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Agreement between Hbsatlab and SpHb for Hb values lower than 6,0 mmol/l

In 11 of the 30 patients (37%) 37 of the 198 in-vivo calibrated measuring moments (18%) had

both Hbsatlab and SpHb values below 6,0 mmol/l. Mean bias was -0,03 (0,62) with upper and

limit of agreement on 1,19 and -1,25 mmol/l respectively.

The Pearson correlation test showed a weak correlation between bias in Hb (Hbsatlab-SpHb)

and mean Hb ((Hbsatlab+SpHb)/2) of -0,34 (p=0,039).

Figure 5 (left) Bland-Altman plot adjusted for repeated measurements, showing the agreement for Hbsatlab and

SpHb values lower than 6,0 mmol/l. For this plot 37 in-vivo calibrated measuring moments from 11 patients

were included. Mean Hb bias is represented by the solid line, limits of agreement by the dotted lines. Every

patient is indicated with a different color. Figure 6 (right) Bland-Altman plot adjusted for repeated

measurements, showing the agreement for Hbsatlab and SpHb values greater than 6,0 mmol/l. For this plot 105 in-

vivo calibrated measuring moments from 21 patients were included. Mean Hb bias is represented by the solid

line, limits of agreement by the dotted lines. Every patient is indicated with a different color.

Agreement between Hbsatlab and SpHb for Hb values greater than 6,0 mml/l

In 21 of the 30 patients (70%), during 105 of the 198 in vivo-calibrated measurements (53%)

both Hbsatlab and SpHb value were greater than 6,0 mmol/l. Mean bias was -0,26 (0,57) with

upper and limit of agreement on 0,86 and -1,37 mmol/l respectively.

During these 105 measurements the “mean Hb” ((Hbsatlab + SpHb)/2) shown on the x-axis in

figure 6 had a median value of 7,10 (6,15 – 9,50) mmol/l. The Pearson correlation test

showed a weak correlation between bias in Hb (Hbsatlab-SpHb) and mean Hb

(Hbsatlab+SpHb)/2) of -0,21 (p=0,026).

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Perfusion Index (PI) and the difference in measured hemoglobin

During all 198 measuring moments in 30 patients Perfusion Index was measured. Figure 7

shows a broad scatterplot with a median PI of 3,85 (0,40 – 10) percent. The mean difference

between Hbsatlab and SpHb is -0,32 (0,82) mmol/l. The Pearson correlation test showed no

correlation for PI and difference between Hbsatlab and SpHb with r = -0,55 (p=0,441).

Figure 7 (left) Perfusion Index versus the measured difference between Hbsatlab and SpHb. 198 in vivo calibrated

measuring moments in 30 patients were included for this plot. Every patient is indicated with a different color.

Figure 8 (right) Pleth Variability Index (PVI) and the measured difference between Hbsatlab and SpHb. 198 in-

vivo calibrated measuring moments in 30 patients were included for this plot. Every patient is indicated with a

different color.

Pleth Variability Index (PVI) and the difference in measured hemoglobin During all 198 measuring moments in 30 patients the hemoglobin and PVI was measured. A

median PVI of 13 (3 – 41) percent was found. Mean difference between Hbsatlab and SpHb

was -0,32 (0,82) mmol/l. Figure 8 shows the scatterplot for PVI and difference in Hbsatlab and

SpHb. The Pearson correlation test showed no correlation for PVI and difference between

Hbsatlab and SpHb with r = -0,07 (p=0,346).

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Fraction of inspired oxygen (FiO2) and the difference in measured hemoglobin

FiO2 and Hb values were simultaneously measured during 139 of the 198 in-vivo calibrated

measurement moments (70%) in 21 of the 30 patients (70%). From these measurement

moments a median FiO2 of 0,39 (0,31 – 0,95) was distillated. Mean difference between

hemoglobin measurement via Hbsatlab and SpHb was -0,35 (0,85) mmol/l.

Pearson correlation test showed a correlation for FiO2 and the difference in Hbsatlab and SpHb

of -0,30 (p<0,001).

Figure 9 FiO2 and the measured difference between Hbsatlab and SpHb. For this plot 139 in-vivo calibrated

measuring moments from a total of 21 patients were used. Every patient is indicated with a different color.

In 16 of the 21 patients (76%) FiO2 was altered during our SpHb measurement. In 4 patients

the FiO2 only increased, as a result in 2 patients the SpHb remained stable, in 1 patient SpHb

increased and in 1 patient SpHb decreased. In 4 patients FiO2 only decreased, resulting in 2

decreased and 2 unaltered SpHb values. In 8 patients the FiO2 both increased and decreased

during measurement, resulting in 6 patients with both increased and decreased SpHb values, 1

patient with an increased SpHb value and 1 patient with an unaltered SpHb value.

Figure 10 Assessment chart for the alteration in FiO2 and its effect on SpHb measurement.

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Norepinephrine and the difference in measured hemoglobin

In figure 11 the influence of increasing doses of norepinephrine is plotted against the

measured difference in hemoglobin. During 83 measurements, 22 of the 30 (73%) patients

had registered doses of norepinephrine, allowing the assessment of its influence on the bias in

Hb measurement. The median norepinephrine dose administered was 0,10 (0,02 – 0,85)

µg/kg/minute. The median difference between Hbsatlab and SpHb in patients treated with

norepinephrine was -0,3 (-2,0 – 1,2) mmol/l. Pearson correlation test showed a weak

correlation of 0,34 (p=0,001) for the administering of norepinephrine and difference between

Hbsatlab and SpHb.

Figure 11 Norepinephrine dosage and the difference between Hbsatlab and SpHb. For this plot 83 in-vivo

calibrated measuring moments from 22 patients were used. Every patient is indicated with a different color.

Influence of the colloid solution Voluven® on SpHb

In total 14 of our 30 patients (47%) received the colloid solution Voluven® (6% hydroxyethyl

starch in sodium chloride injection) in addition to the standard crystalloid (0,9% NaClsolution

and/or lactated Ringer's solution). A total of 11500 ml Voluven® were administered in 14

patients, with a median Voluven® volume of 500 (500-2000) ml per patient. In addition to

Voluven® the 14 patients received a total of 63500 ml Ringer lactate solution, with a median

of 3500 (1500-14500) ml per patient and a total of 8600 ml 0,9% NaCl solution, with a

corresponding median of 1000 (100-3500) ml per patient. The (absolute) mean difference

between the Hbsatlab and SpHb was 0,64 (0,40) mmol/l for the Voluven® group (n=14) and

0,41 (0,24) mmol/l for the crystalloid group (n=16).

The 16 patients (53%) in the crystalloid group received a total amount of 56900 ml Ringer

lactate solution, with a median of 4000 (900-6500) ml per patient. In addition they received a

total of 10545 ml 0,9% NaCl solution with a median of 500 (45-5500) ml per patient.

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Deviation between Hbsatlab and SpHb over time

In 15 of the 30 patients (50%) 169 of the 198 measuring moments (85%) were taken with an

interval of 30 minutes and useable for the assessment of the deviation between Hbsatlab and

SpHb over time.

In these patients the deviation between values in Hbsatlab and SpHb was assessed during 12

measuring moments, or 6 hours of continuous SpHb measurement. Before in-vivo calibration

the SpHb underestimated the Hbstalab values with 0,3 mmol/l. For two and a half hours, no

clinical relevant deviation was detected in the assessed patients. From measuring moment 6

until measuring moment 12 (three to six hours) SpHb overestimate Hbsatlab and the difference

between Hbsatlab and SpHb fluctuated from a mild -0,1mmol/l to as far as -0,7 mmol/l.

Figure 12 shows the measured difference between Hbsatlab and SpHb (left y-axis) during

multiple measuring moments (x-axis). The fat red line represents the median deviation of

these 15 patients.

Individual deviations per measuring moment are demonstrated in table 2. Measurement

moment 0 is the measurement moment on which the in-vivo calibration was performed.

Table 2 Alteration in difference between Hbsatlab and SpHb over the course of time for 12 measuring moments.

Between each measuring moment lies an interval of 30 minutes. The red accentuated measuring moment 0 was

used for the in-vivo calibration of the SpHb device. The number of measurements taken per patient varied, the

cumulative amount of taken measurements per measuring moment is stated as “Total amount of measurements /

moment” at the bottom of the table.

Measuring moment 0 1 2 3 4 5 6 7 8 9 10 11 12

Patient 1 -0,7 0,6 0,9 0,4 0,9 0,6 0,6 1,2 0,2 1,2 -0,3 0,2

Patient 2 0 0,1 0,1 0,2 0,4 0,2 0,1 0,9 0,6 0,2 0,2 0,4 0,9

Patient 3 2 0,1 0,3 -0,5 -0,7 -0,4 -0,3

Patient 4 -0,9 0,1 0,4 0,4 -0,2 0,1 0,4 -0,1 -0,4

Patient 5 -0,1 0,1 -0,1 0 -0,1 0,1 0,2

Patient 6 1 0 -0,1 -0,2 -0,3 -0,7 -0,6 -0,6 -1,4 -1,2 -1,2 -1,8 -2,1

Patient 7 0,5 -0,6 -0,5 -0,5 -0,6 -0,5 -0,4 -0,3 -0,2 0

Patient 8 1,2 0,1 0 0,1 0,2 0,3 -0,6 -1,1 -0,6 -0,4

Patient 9 -0,1 -0,4 0 -0,3 0,3 -0,2 -0,1 -1,2 -0,6 -0,9 -0,9

Patient 10 0,4 0,6 0 0,6 0,9 0,8 0,9 0,6 0,2 0,5 0,4 0,4 -0,4

Patient 11 0,3 -1,2 -0,5 -0,7 -0,6 -0,6 -0,4 -1,1 -0,9 -1,2 -1 -1 -0,9

Patient 12 0,4 -0,3 -0,3 -0,4 -0,3 -0,1 -0,1 -0,5 -0,7 -0,9 -1,4 -2,7 -1,7

Patient 13 -0,2 -0,3 0,3 -0,1 -0,1 0,3 0 -0,3 -0,1 -0,1 -0,5 0,1 0

Patient 14 0,2 0,3 0,4 0,6 0,9 0,8 0,3 0,6 -0,7

Patient 15 0,7 0 0,2 0,1 -0,3 -0,5 -0,3 -0,4 -0,1 -0,1

Median difference

Hbsatlab – SpHb (mmol/l) 0,3 0,1 0 0 -0,1 0,1 -0,1 -0,3 -0,4 -0,1 -0,7 0,1 -0,7

Lower range -0,9 -1,2 -0,5 -0,7 -0,7 -0,7 -0,6 -1,2 -1,4 -1,2 -1,4 -2,7 -2,1

Upper range 2 0,6 0,9 0,6 0,9 0,8 0,9 1,2 0,6 1,2 0,4 0,4 0,9

Total amount of

measurements / moment

15 15 15 15 15 15 15 13 13 11 8 7 6

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Figure 12 Deviation between Hbsatlab and SpHb over time. The left y-axis represents the difference in Hb

measured using the Hbsatlab method and the SpHb method. The right y-axis represents number of measurements

in total, expressed as the green area in the background of the figure. On the x-axis the measuring moments are

shown. Between each moment lies an interval of 30 minutes. Each colored line represents an individual patient.

The fat red line represents the median difference between Hbsatlab and SpHb of the 15 individual lines. The

number of measuring moments per patients varies, as can be seen by difference in length per line.

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Four-quadrant plot

To assess the trending ability of the Hbsatlab and the SpHb 154 of the 198 (78%) in vivo-

calibrated measuring moments were included from 15 out of 30 (50%) patients. In these 15

patients the 154 measuring moments for Hbsatlab and the corresponding SpHb values had an

interval of 30 minutes between each measuring moment. All measuring moments expect for

the last measuring moment from each patient were useable to calculate the alteration in Hb

between two measuring moments for both measuring methods. After this selection 139 Δ

SpHb and 139 Δ Hbsatlab values remained. Δ SpHb and Δ Hbsatlab were normally distributed

based on their histograms (not shown). Mean Δ SpHb was -0,01 (0,45) mmol/l and mean Δ

Hbsatlab was -0,05 (0,48) mmol/l. The ranges for Δ SpHb and Δ Hbsatlab were (-1,6 / 2,0) and (-

1,6 / 3,0) mmol/l respectively.

16 of the 139 (12%) calculated Δ SpHb (absolute) values and 14 of the 139 (10%) calculated

Δ Hbsatlab (absolute) values were greater than 0,6 mmol/l.

Of the 14 Δ Hbsatlab values with a greater absolute value than 0,6 mmol/l, only 4 (29%) were

accompanied by an absolute Δ SpHb value greater than 0,6 mmol/l.

Pearson Correlation test showed a correlation of 0,39 (p<0,001) between all measured Δ

SpHb and Δ Hbsatlab.

Figure 13 shows the four-quadrant plot with the alterations between two measuring moments

for both measuring methods. The x-axis represents the Δ SpHb between two following

measurement moments; the y-axis represents the Δ Hbsatlab between two following

measurement moments.

Figure 13 Four-quadrant plot showing the alteration in hemoglobin concentration measured every 30 minutes

using the ABL 800 Flex and the Masimo Radical-7. The dotted line represents the “Line of Identity” (y=x) at an

angle of 45° measured form the axis. In case of a perfect agreement between both measuring methods all data

points will lay on this “Line of Identity”. Every patient is indicated with a different color.

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Trending analysis of changes in Hb measured by Hbsatlab and SpHb methods For the polar plot the 139 Δ SpHb and Δ Hbsatlab values used for the four-quadrant plots were

assessed. Values with both Δ Hbsatlab and Δ SpHb equal to or between -0,2 and 0,2 mmol/l

were excluded for these alterations have little clinical significance and could distort the

trending assessment for the investigated devices. This exclusion zone is marked with a blue

circle in figure 14. After exclusion 85 measurements from 15 patients remained for

assessment. Of these 85 vector points 35 (59%) lied within the 30° ‘zone of desired

concurrence’ (between the blue lines).

Figure 14 Polar plot demonstrating the trending ability between Hbsatlab and SpHb. The distance from the center

of the plot represents the mean change in hemoglobin concentration. The area between the blue lines is known as

the ‘zone of desired concurrence’, where 95% of the data should lie in case of a good trending ability of the

devices. Within the circular zone of exclusion (the blue marked center) Δ Hbsatlab and Δ SpHb equal to or

between -0,2 and 0,2 mmol/l were excluded, to maintain a well-ordered plot.

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DISCUSSION

Agreement between satellite laboratory blood gas analyzer ABL 800 Flex (HbSatlab) and Pulse

CO-Oximeter (SpHb)

In this thesis a mean difference between Hbsatlab and SpHb was found with a large standard

deviation (precision) and wide 95% limits of agreement.

Recent meta-analysis (36) assessed 32 studies, including 12 studies performed in the

operating room, among these 12 studies were relevant studies mentioned earlier in this thesis

(25,28-30,32-34). The meta-analysis found a mean difference between Hb measurement using

the laboratory analyzer and SpHb method of 0,24 mmol/l with a SD of 0,82. Their limits of

agreement were -1,37 to 1,85 mmol/l.

Presuming that the Hbsatlab value is the ‘true Hb’ value, a found mean difference between

Hbsatlab and SpHb applies as the level of accuracy of the SpHb device.

In this thesis the SpHb value overestimated the Hbsatlab or ‘true Hb’ by 0,32 mmol/l. The meta-

analysis, however, found an underestimation of the ‘true Hb’ by the SpHb device of 0,24

mmol/l. The precisions (SD) found in this thesis and the meta-analysis were identical with

0,82 mmol/l. Limits of agreement in both studies varied between 0,55 and 0,56 respectively

for the upper and lower 95% limits of agreement. This discrepancy might be due to the fact

that 24 different laboratory analyzers were included by the meta-analysis versus one

laboratory analyzer used in this thesis.

Earlier research claimed that SpHb accuracy seems to increase when decreases (25), which is

in agreement with the findings of this thesis.

Various studies evaluated SpHb measurement in the OR, including hepatic (25), spine (28-

30), abdominal and pelvic surgery (32), caesarean section (33) and pediatric neurosurgery

(34). These specific studies will now be elaborated on individually.

In hepatic surgery (n=30) SpHb accuracy varied, depending on the phase of the surgery (25).

A mean difference between Hbsatlab and SpHb of -0,17 (0,66) mmol/l for the steady-state and -

0,01 (0,66) mmol/l for the dynamic phases of hepatic surgery was found. These results differ

from the results in this thesis. This discrepancy might be due to the more controlled study

circumstances in one specific patient group for the hepatic study, versus varies surgeries and

circumstances in this thesis.

In spine surgery (28-30) means for differences in Hbsatlab and SpHb (0,16 / -0,01 / -0,06

mmol/l respectively) were found in all three studies. However these studies had few patients

with Hb levels as low as reported in this thesis, for it was protocol to maintain Hb level above

6,0 mmol/l during these spine surgeries.

In the study to abdominal and pelvic surgery patients (32) a mean difference in Hbsatlab and

SpHb of 0,31 (0,89) mmol/l was reported, a similar result to the mean difference in Hbsatlab

and SpHb found in this thesis. The types of surgeries investigated (32) were similar to those

assessed in this thesis, possibly explaining the similarities in results.

A different study (33) measured SpHb values prior to, and immediately post caesarean

section. In the absence of significant hemorrhage the difference between Hbsatlab and SpHb

dropped 0,67 mmol/l within the two measuring moments. This alteration in accuracy implies

that the SpHb measurement can be influenced by more than just blood loss alone. Sudden

hemodynamic alterations, venous instead of arterial blood sampling, and the use of neuraxial

instead of general anesthesia might explain the alteration. Although study setting and results

were not similar to this thesis, it showed that SpHb measurement could be influenced by

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exterior variations. The extent to which SpHb measurement can be influenced will be further

discussed later on.

A study in pediatric neurosurgery patients (34) published a mean accuracy (Hbsatlab – SpHb)

of 0,56 (0,84) mmol/l. This study found a precision of the SpHb device similar to the

precision found in this thesis. The pediatric study defined their accuracy as SpHb – Hbsatlab,

which is in contrast to the definition used in this thesis, meaning that 0,56 mmol/l in the

pediatric neurosurgery study correspond with -0,56 mmol/l according to the definition of

accuracy maintained in this thesis (Hbsatlab – SpHb). The results from the study (34) and this

thesis showed that SpHb accuracy could be similar in both pediatric and adult patients.

The Radical-7 was also investigated outside the operating room. Two studies (31,35)

investigated the Radical-7 in the intensive care unit (ICU). A mean difference in Hb of 0,0

(0,6) mmol/l was found in one study (35), but half of these patients were not fully sedated, in

contradiction to patients in this thesis and most other SpHb studies. In the cardiac ICU study

(31) two different SpHb sensor versions were uses, resulting in two different mean bias

(difference Hbsatlab and SpHb) values: -0,81 versus 1,06 mmol/l. Difference between the two

values might be due to an unequal amount of patients (14 versus 27) or a sensor update.

Either way, the described results in cardiac ICU patients do not match the results in this

thesis, possibly due to the different study setting (ICU versus OR with active surgery).

A different study (42) looked for SpHb potentials in the emergency department, to find that

SpHb results were too unreliable to guide transfusion decisions. These findings matched the

results and conclusion (presented later on in this discussion) of this thesis.

In a hepatic surgery study (25) the influence of gender on discrepancy between Hbsatlab and

SpHb was assessed.

The study population in this thesis existed out of 11 female and 19 male patients. Similar to

the findings of the hepatic surgery study, there was no significant difference (p=0,28) in

baseline Hb level for the female or male patients, with a mean and SD of 7,9 (1,2) mmol/l

versus 7,5 (1,1) mmol/l respectively. One could have expected higher baseline Hb values in

the male patients, for under normal conditions men tend to have higher hemoglobin

concentrations than females. This thesis found no evident explanation for this lack of

significant difference.

The (absolute) mean difference between Hbsatlab and SpHb was also not significantly different

(p=0,55) between genders with 0,1 (0,1) mmol/l.

The discrepancy between Hbsatlab and SpHb therefor does not seem to be gender determined in

this thesis.

The SpHb device measures hemoglobin concentrations in the fingertip, using both

macrocirculatory hemoglobin of the arteries, arterioles, venules and veins bloodstream and

the microcirculatory hemoglobin of the capillary blood. This microcirculation has a reduced

hematocrit compared to the macrocirculatory hematocrit (43). In case of (rapid) blood loss the

macrociculatory Hb concentration drops while the microcirculatory Hb does not alter

substantially (44). The microcirculatory Hb relatively increases when the macrocirculatory

Hb drops, meaning the SpHb is based on a (relatively) bigger proportion of microcirculatory

Hb than before the hemorrhage, possibly explaining discrepancy between SpHb and Hbsatlab

during active bleeding.

The discrepancy between Hbsatlab and SpHb might also be caused by specific types of surgery.

Some operations are known for fast and massive blood loss, for instance some orthopedic or

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trauma surgery. The SpHb device might need some time to detect the alteration in the

macrocirculatory hemoglobin during these surgeries.

The type of surgery also affects the fluid management, with hepatic surgery for example

having a less flexible fluid administering than other surgeries.

These examples describe that although specific conditions as volume of blood loss, surgery

time or fluid management can be similar among different studies, patients in the OR are

subject to many variables capable of influencing SpHb measurement. Therefore it is hard to

distillate a true overall agreement between ‘true Hb’ / Hbsatlab and SpHb applicable to every

patient or surgery type.

The SpHb tended to underestimate Hbsatlab in this thesis and accuracy of the SpHb device

differed substantially to the accuracy found in the meta-analysis (36) and individual studies

(25,28-31,33,35). In surgical patients, especially in whom anemia is already present, this lack

of consistent accuracy might result in false clinical decisions, for instance denying blood

transfusion or even to start blood transfusion without actual need can cause serious health

risks (11-13).

If metaphorically the SpHb device would be a marksman, the marksman often seems to miss

the center of its target (the bull’s-eye), due to bad accuracy. The precision of the marksman is

consistent, often hitting the target on the same spot (but not on the wanted spot). Due to

consistent limits of agreement the misfires are consistently varied to all sides around the

bull’s-eye.

Although precise, due to the lack of accuracy and wide limits of agreement, the SpHb device

does not seem fitted to use as a stand-alone monitor or as base for clinical decisions in

patients at risk of undetected blood loss during surgery.

Trending analysis of changes in Hb measured by Hbsatlab and SpHb methods

Most studies regarding SpHb measurement tested the accuracy of the device or the external

influences on the device (for example perfusion index), few studies investigated purely the

trending ability of changes in Hb measured by the Radical-7. Hoping to contribute in filling

this hiatus, this thesis assessed the trending ability of changes in Hb measured by Hbsatlab and

SpHb methods.

Based on the mean Δ Hbsatlab and Δ SpHb found in this thesis one could conclude that

between two measuring moments the mean Δ Hb values did not decrease in a way that would

be considered clinically relevant. This lack of clinical relevant alterations might be due to the

interval time, since 30 minutes between two measurements might be too short to reveal

drastic Hb alterations in the absence of evident blood loss.

Standard deviations for Δ SpHb and Δ Hbsatlab are clinically more relevant and possibly

indicate that although mean Δ SpHb and Δ Hbsatlab were near zero on a population level, the

deviation in measured hemoglobin could be extensive per individual patient in time.

According to an earlier study which assessed deviations in measurements (40), large changes

in Δ values measured with one device (for example Hbsatlab) will nearly always be in

agreement with the corresponding Δ values measured with the other device (SpHb). In this

thesis absolute changes of more than 0,6 mmol/l were deemed as large.

In 14 Δ Hbsatlab-values (10% of the total Δ Hbsatlab values) absolute alteration greater than 0,6

mmol/l were not accompanied by an equal absolute alteration in Δ SpHb except in 4 cases.

This lack of trend following is disappointing in view of the fact that the manufacturer of the

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SpHb device claims that 80% of the Hbsatlab values below 0,6 mmol/l will be followed by a

corresponding SpHb value. In order to make a non-invasive hemoglobin measurement device

clinically safe and useful alterations in Hbsatlab as large as 0,6 mmol/l need to be detected and

followed by a similar trend.

Beside these Δ SpHb and Δ Hbsatlab values from the four-quadrant plot, assessment of the

polar plot also showed poor trending ability with only 59% of data points within the 30° ‘zone

of desired concurrence’. This is in contrast to a recent study in which the trending ability of

the SpHb device was tested in 12 patients on the intensive care unit (45). This study found

95% of their data between 24.4° and -16.2° in the polar plot. Their study used a different

population and reference device (Crit-Line® instead of the ABL800 Flex®), possibly

explaining the difference. A different study among 20 spine surgery patients showed 90% of

the 29 data points within the 30° ‘zone of desired concurrence’(46). This study however

offers little insight in patient and surgery details, making analysis for the deviation in results

difficult.

Based on the results in this thesis does the trending ability between SpHb and Hbsatlab not

seem to be reliable enough to be the sole basis of clinical decisions in patients at risk of

undetected blood loss during surgery.

Hypothesis 1: There will be no deviation between Hbsatlab and SpHb after in vivo-calibration

in the course of time

After this moment Hbsatlab and SpHb values should not have deviated substantially from each

other. According to the manufacturer, the SpHb device should have had a consistent accuracy

of 1,0 g/dl (= 0,6 mmol/l). This thesis found that before in-vivo calibration SpHb tended to

underestimate Hbsatlab. After in-vivo calibration hemoglobin measurement by both Hbsatlab and

SpHb methods showed no clinical relevant deviation until three hours after in-vivo

calibration, when SpHb started to overestimate Hbsatlab values with a overestimation ranging

from 0,1 up to 0,7 mmol/l. A deviation of a scale as large as found in this thesis could result

in drastic clinical decisions based on false hemoglobin values, endangering patients. Based on

the results of this thesis it is recommendable to repeat in-vivo calibration during long lasting

operations.

Hypothesis 1 is rejected, since this thesis found a deviation between Hbsatlab and SpHb in the

course of time .

Hypothesis 2: Alteration of FiO2 will alter the SpHb value as previously proven (23)

A pilot study in 2011 showed FiO2 could influence the SpHb measurement (23). During that

pilot study eight patients had their FiO2 increased during general anesthesia. Mean SpHb

value decreased in two patients, remained stable in two and increased in four patients. In this

thesis 21 patients were assessed for the influence of FiO2 on the SpHb measurement. Only one

patient had an increased FiO2 followed by an increased SpHb. Most patients in this thesis had

both a decreased and increased FiO2, after which six patients had an altered SpHb following

in the same direction.

Due to the limited scale on which FiO2 data was registered and the variability to which

alterations in FiO2 altered SpHb values it is hard to draw conclusions on whether or not FiO2

was the sole reason for a following alteration in SpHb.

A letter to the editor of an earlier study to the influence of FiO2 (47) explained that SpHb

might be influence not only by the FiO2 but also by the Fähreus effect (hematocrit tends to

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decrease in smaller vessels/capillaries), the transcapillary fluid filtration absorption ratio,

vasomotor tone, and ambience temperature. This might explain the absence of a clear relation

between altered FiO2 altered SpHb. Although this thesis cannot provide a hard overall

conclusion, alteration in FiO2 did alter SpHb values in some cases, as described earlier

(23,24).

Therefore, hypothesis 2 is retained.

Hypothesis 3: Alteration of PI and PVI will decrease the reliability of SpHb measurement

In this thesis patients had a median Perfusion Index of 3,85 (0,40 – 10) percent and a median

PVI of 13 (3 – 41) percent during Hb measuring moments. According to the manufacturer, the

PI may range from 0,02% up to 20%, with low values indicating lower perfusion.

Hypovolemia and vascular diseases also tend to influence the perfusion index beside

vasopressors. Other studies proved that manipulating the regional blood flow in the finger

either by using a digital nerve block (48) or changing the skin temperature (49) did seem to

influence the perfusion index, thereby altering the SpHb measurement.

The low perfusion index in patients assessed in this thesis might explain why SpHb values

sometimes could not be obtained properly.

Based on the finding in this thesis PI and PVI did not seem to influence the discrepancy

between Hbsatlab and SpHb.

This thesis was not the only study to find low perfusion index in during SpHb measurement.

A study in volunteers found an average perfusion index level of 4,1% (2,0%), with range

0,9% to 9,9% and also no correlation between PI and difference in SpHb and true Hb value

(27). During a study in intensive care patients the perfusion index did not seem to influence

the accuracy of SpHb measurement either(35).

Some studies did find that perfusion index could alter Hb accuracy. When perfusion

diminished, SpHb underestimated true Hb during spine surgery (28). For this study no

insights were given into the amount of administered vasopressors or patient temperature,

therefore making it difficult to explain their deviant results.

In cardiac surgery patients admitted to the intensive care unit, difference between true Hb and

SpHb became greater when perfusion index was low (31). Their study environment however

had no active surgery and the surrounding temperature was properly higher than most

operating rooms, possibly explaining the deviant results.

Although previous studies described negative relations between PI, PVI and reliability of

SpHb measurement (in terms of difference between Hbsatlab and SpHb) for surgical patients,

this seemed not the case in this thesis.

Hence, hypothesis 3 is rejected.

Hypothesis 4: Administering colloid solutions will decrease the reliability of SpHb

measurement as is described in previous research (25)

Earlier research (25) found that the administering of colloid solutions decreased the accuracy

of the SpHb measurement in 15 patients during liver surgery (25). During fluid administering

the difference between Hbsatlab and SpHb changed from -0,17 (0,66) to -0,01 (0,66) mmol/l.

Although the difference between Hbsatlab and SpHb decreases, the alteration indicates that the

reliability of the SpHb device is subject to external influences.

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In a pediatric study (34) the administering of colloid solution also decreased the accuracy of

the SpHb measurement, with an alteration of 0,20 mmol/l.

In this thesis 14 patients received the colloid solution Voluven® (6% hydroxyethyl starch in

sodium chloride injection) in addition to the standard crystalloid fluid (0,9% NaClsolution

and/or lactated Ringer's solution). A significant difference in Hb accuracy (Hbsatlab – SpHb) of

0,18mmol/l (p=0,03) between both groups was found, indicating that the admission of colloid

solution decreases the reliability of the SpHb device in these 14 patients, matching previously

finding (25,34).

Although one could doubt the clinical significance of this relatively small difference between

groups, hypothesis 4 is retained.

Hypothesis 5: Administering Norepinephrine will decrease the reliability of SpHb

measurement

Norepinephrine alters the degree of vasoconstriction, leading to an alteration in PI and PVI, in

turn leading to a decreased reliability of non-invasive Hb measurement. This concept is

widely accepted among anesthesiologists, even though a study found that norepinephrine had

no influence on SpHb accuracy on their ICU patients (35). In the discussion of hypothesis 3

the alteration in PI and PVI was found of no influence on SpHb.

When norepinephrine leads to decreased SpHb reliability via altered PI and PVI, the rejection

of hypothesis 3 suggest that norepinephrine alone does not lead to a decreased SpHb

reliability.

In this thesis 22 ‘norepinephrine-treated patients’ had a median norepinephrine dose of 0,10

(0,02 – 0,85) µg/kg/minute. The median difference in Hb of these patients did not differ

significantly from the rest not receiving norepinephrine. The correlation between

norepinephrine and the difference between Hbsatlab and SpHb was 0,34 (p=0,001). Since these

‘norepinephrine-treated patients’ underwent more alteration during surgery than just receiving

norepinephrine, the median difference in Hb and correlation of 0,34 is not deemed strong

enough to retain this hypothesis.

Hypothesis 5 is therefore rejected.

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Thesis limitations

This thesis used data from a pilot study intended to investigate the effect of a non-invasive

continuous hemoglobin-measuring device on the timing of blood transfusion. The primary

objectives of this thesis and the used pilot study did not fully concur with each other. Data

administration was performed with the study objectives of the pilot study in mind. Therefore

some data, assessed in this thesis, was not registered to the full extent. The author of this

thesis was not always present on the OR during data collection for the original pilot study,

making interpretation of certain data artifacts difficult in some cases.

Due to the limited scale of the study population used for this thesis no general

epidemiological conclusions can be drawn. Study protocol of the pilot study used for this

thesis stated that according to local transfusion protocol patients with hemoglobin

concentrations of 4,0 mmol/l or less had to receive concentrated red blood cells in order to

assure patient safety. No results could therefore be provided for patients with hemoglobin

values below 4,0 mmol/l as was provided by others (8).

Thesis conclusion

This thesis showed an agreement between Hbsatlab and SpHb of -0,32 (0,82) mmol/l, and a

poor trending ability of the SpHb device with only 59% within the ‘zone of concurrence’.

SpHb tended to increasingly overestimate Hbsatlab over time. Alteration of FiO2, PI, PVI and

norepinephrine did not decrease reliability of SpHb measurement as expected, colloid

solutions however did.

Based on the results of this thesis the Masimo Radical-7 Pulse-CO-oximeter does not seem

reliable enough to be the sole basis of clinical decisions in patients at risk of undetected blood

loss during surgery.

Acknowledgment

In addition to my direct supervisors, J.P. van den Berg MD and prof. T.W.L. Scheeren, MD

PhD, I would like to thank J.J. Vos MD for his support throughout the stages of this research,

for without his support I would not have been able to learn so much from this research.

Furthermore I would also like to thank the physicians' assistants I shared an office with for the

shared laughs and mental support during my research clerkship. Finally, I would like to thank

my fellow research students, especially Pieter Buisman, for helping each other during any

obstacles that stood in our way.

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master thesis: accuracy, trend analysis of and influence...

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