The importance of POCT in diabetes management · Blood S.Ketone2+ Acetoacetate82.9µmol/L(

CHA의과학대학교 분당차병원

김 수 경

25th Spring Congress of the Korean Diabetes Association

The importance of POCT in

diabetes management

Introduction

Point of care test (POCT)

현장검사 vs. 간이검사

Any test that is performed near the patients with the intent to

assist caregivers in the quick formulation of diagnosis

and/or clinical interventions by providing immediate results

Error prevention to avoid inappropriate care; primary requirement

in the POCT context

Matteucci E. & Giampietro O. Mini Rev Med Chem 2011;11:178

Surveillance of quality testing

Centers for Medicare & Medicaid Services (CMS) through Clinical

Laboratory Improvement Amendments (CLIA)

Three categories of test method

1) High complexity

2) Moderate complexity

3) Waived complexity

⋅ Simple

⋅ Accurate

⋅ Usable at home with no requirement for trained analysts, internal or

external QC assessment


CLIA list of waived test


Aerobic/anaerobic organisms-vaginal

Albumin

Alanine aminotransferase

Alkaline phosphatase

Amylase

Aspartate aminotransferase

B-type natriuretic peptide

Bilirubin, total

Bladder tumor associated antigen

BUN

Calcium

Calcium-ionized

Carbon dioxide

Chloride

Catalase

Cholesterol

Creatinine

Drugs of abuse

ESR

Esterone-3-glucuronide

Fern test

FSH

Fructosamine

γ-glutamyl transferase

Glucose

Glycosylated hemoglobin

HDL-cholesterol

Helicobacter pylori

Hematocrit

Hemoglobin

HIV

Influenza

Ketones (blood)

Lactic acid

LDL-cholesterol

Lead

Lipid profile

Lithium

LH

Microalbumin

Nicotine

Occult blood

Ovulation test

pH

Platelet aggregation

Potassium

Pregnancy test (urine)

Protime

Protein, total

Respiratory Syncytial virus

Semen

Sodium

Streptococcal antigen test

Trichomonas

Triglyceride

TSH

Uric acid

Urinalysis

Usefulness of POCTin general practice setting


Not consistently confirm (qualities, benefit, cost effectiveness)

However, some evidence supports its role in improving glycemic control, lipid levels,

& oral anti-coagulant therapy safety

- Screening for diabetes risk

- Screening or monitoring treatment of dyslipidemia

- Prevention, detection, & treatment of diabetes-related complications through

monitoring several tests

CLIA list of waived test


Aerobic/anaerobic organisms-vaginal

Albumin

Alanine aminotransferase

Alkaline phosphatase

Amylase

Aspartate aminotransferase

B-type natriuretic peptide

Bilirubin, total

Bladder tumor associated antigen

BUN

Calcium

Calcium-ionized

Carbon dioxide

Chloride

Catalase

Cholesterol

Creatinine

Drugs of abuse

ESR

Esterone-3-glucuronide

Fern test

FSH

Fructosamine

γ-glutamyl transferase

Glucose

Glycosylated hemoglobin

HDL-cholesterol

Helicobacter pylori

Hematocrit

Hemoglobin

HIV

Influenza

Ketones (blood)

Lactic acid

LDL-cholesterol

Lead

Lipid profile

Lithium

LH

Microalbumin

Nicotine

Occult blood

Ovulation test

pH

Platelet aggregation

Potassium

Pregnancy test (urine)

Protime

Protein, total

Respiratory Syncytial virus

Semen

Sodium

Streptococcal antigen test

Trichomonas

Triglyceride

TSH

Uric acid

Urinalysis

Glucose meters

Glucose meter

1980s; portable glucometer have become widely accepted clinical devices

Transformed diabetes care by enabling the identification of hyperglycemia

Made possible the use of intensive glucose control

Self monitoring of blood glucose (SMBG)

Walsh J, et al. J Diabetes Sci Technol 2012;6:466

Glycemic recommendations for manynon-pregnant adults with diabetes

ADA. Diabetes Care 2012;35:S11

Meta-analysis of benefit of SMBG on glycemic control in T2DM

Poolsup N, et al. Diabetes Technol Ther 2009;11:775

SMBG & long-term outcomes

Martin S, et al. Diabetologia 2006;49:271

Without SMBG (n=1789) vs. With SMBG (n=1479)

Mean F/U period; 6.5 years

SMBG cohort

Non-SMBG cohort

Clar C, et al. Health Technol Assess 2010;14:1

SMBG in ADA (2012)

SMBG should be carried out three or more times daily for patients using

multiple injection or insulin pump. (B)

For patients using less-frequent insulin injections, non-insulin therapies, or

MNT alone, SMBG may be useful as a guide to management. (E)

To achieve postprandial glucose targets, postprandial SMBG may be

appropriate. (E)

When prescribing SMBG, ensure that patients receive initial instruction in,

and routine f/u evaluation of, SMBG technique & their ability to use data

to adjust therapy. (E)


적당한지식과 skill을갖춘환자에서

지속적인당뇨병자가관리교육의일부분으로써

SMBG protocol (intensity & frequency)는개별화하고

환자와충분한동의가이뤄져야하고

Glucose meter의정밀도와정확도를지속적으로모니터해야@

IDF 2009

SMBG in non-insulin treated type 2 diabetes. IDF. 2009

Schnell O, et al. Diabetes Technol Ther 2011;13:959

Basal bolus

4~8/day 주로식전과취침전검사식후검사는 7~10/week

야간검사는 1/week

Basal/premixed insulin

2~4/day 주로식전검사식후검사는 1~2/day

야간검사는 1/1~2 week

D&E only or OHA

6~8/week 식전/식후검사비슷하게

빈번하게측정안하는경우

Couplets

7 point/week or month

European Consensus Statement

당뇨병학회진료지침(2011)

자가혈당측정은최소한공복과식후 2시간혈당(식사개시후 2시

간)을포함하여측정하도록권장한다.

자가혈당 측정의 횟수는 환자의 혈당 조절 정도에 따라 달라지지

만, 임상영양치료, 운동요법, 경구혈당강하제 치료, 2회 이내의 인

슐린 치료를 하는 T2DM환자에서 매일 최소 1회 이상의 자가혈당

측정을 권고하며, 다회 인슐린 치료를필요로 하는 T1DM, T2DM 환

자는매일최소 3회이상의자가혈당측정을고려한다.

Limitation of SMBG

Accuracy (정확도) & Precision (정밀도)

Between lot differences ranging from 0.7% to 18.2%

Many interferences

⇒ Should not use in the screening or diagnosis of diabetes

100 deaths associated with potential glucometers inaccuracies between

1992 & 2009

12,672 serious injuries from 2004 to 2008


Inaccurate SMBG in patients on CAPD with icodextrin

Pavlicek V, et al. Exp Clin Endocrinol Diabetes 2006;114:124

Fasting sample 2h postprandial

sample

4h postprandial

sample

Plasma glucose 7.7±3.3 7.8±2.5 6.4±1.9

Ascensia elite (Glucose oxidase) 8.0±3.4 8.2±2.3 6.5±1.9

Accu-Chek Sensor (GDH) 11.9±2.9* 12.5±2.3* 10.6±1.6*

Glucotrend2 (Glucose-dye-oxyreductase) 11.6±3.0* 11.6±2.0* 9.7±1.6*

Factors to influence the results of SMBG

Hematocrit

Altitude

Environmental temperature & humidity

Hypotension

Hypoxia

Triglyceride concentration

Both extremes of glucose concentration

Interfering substance; ascorbic acid, acetaminophen, uric acid, bilirubin

ADA. Diabetes Care 1994;17:81

Current glucose meter performancerecommendation & standards


Some currently approved glucometers failed to meet FDA or ISO standards in post-

approval testing.

Clinical Accuracy Recommendation % within range

ADA 1987 ±10% 100%

ADA 1994 ±5% 100%

Meter Approval

Standards

Glucose concentration % within range

At < 75 mg/dL At ≥ 75 mg/dL

FDA within ±15 mg/dL within ±20% 95%*

ISO 15187 2003 within ±15 mg/dL within ±20% 95%*

* Both FDA & ISO standards allow 5% of meter values to be outside these limits. There is no limitation on the clinical

severity of these outliers.

New proposal


Meter Approval

Standards

Glucose concentration % within range

At < 75 mg/dL At ≥ 75 mg/dL

ISO 2003 within ±15 mg/dL within ±20% 95%

New proposal within ±10 mg/dL within ±15% 95%

within ±15 mg/dL within ±20% 98%

Kim SK, et al. Unpublished data

Comparison between the reference values & each ofthe three successive SMBG values

Gluco-meter

Blood glucose ≥75 mg/dL

±20 % ±15 % ±10 %

A 95.5% 84.9% 66.3%

B 95.5% 89.7% 76.6%

C 80.8% 61.9% 40.9%

D 99.3% 95.5% 83.5%

E 86.9% 68.4% 48.8%

F 86.3% 75.9% 61.9%

In future

Re-certification for determination of accuracy post approval

Several standard dependent on intended use

Point of care HbA1c test

HbA1c

Index of long-term glycemic status & measure of risk for the development of

diabetes complication

Target; < 6.5 or 7.0%

Frequency; from twice per year to every 2~3 months

2008;11:607

Criteria for the Diagnosis of Diabetes

In the absence of unequivocal hyperglycemia, criteria 1~3 should be confirmed by repeat testing.

ADA. Clinical Recommendation. 2012

1. HbA1c ≥ 6.5% (method that is NGSP certified & standardized to the DCCT assay)

OR

2. FPG ≥ 126 mg/dL (Fasting; no caloric intake for at least 8 h)

OR

3. 2-h plasma glucose ≥ 200 mg/dL during an 75-g OGTT

OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic

crisis, a random plasma glucose ≥ 200 mg/dL

POCT HbA1c

Cagliero E, et al. Diabetes Care 1999;22:1785

Miller CD, et al. 2003;26;1158

Nichols JH, et al. Clinica Chimca Acta 2007;379;14

There are some evidence to show that POCT HbA1c testing will lead to an economic

benefit. But the data are limited.

6.8

7

7.2

7.4

7.6

7.8

8

8.2

Jun-Nov2001

Dec2001-May

2002

Jun-Nov2002

Dec2002-May

2003

Jun-Nov2003

Dec2003-May

2004

Jun-Nov2004

Dec2004-May

2005

Jun-Nov2005

FM Clinic Diabetes Clinic

Effect of POCT on maintenance of glycemic controlas measured by A1c

Petersen JR, et al. Diabetes Care 2007;30:713

Main pathology lab.

Main pathology lab.

POC A1c

Main pathology lab.

HbA

1c (%)

** * *

Meta-analysis of results from trials in which change in the mean HbA1c was reported

Al-Ansary L, et al. Clin Chem 2011;57:568

Only two instruments met the acceptance criteria of having a total CV < 3%

in the clinically relevant range

In ADA, point-of-care HbA1c assay

Not sufficiently accurate to use for diagnostic purposes

Provide the opportunity for more timely treatment changes

ADA. Clinical Recommendation. 2012

Ketone bodies determination

Ketones measured in urine/blood

Used in the management of diabetic patients as adjuncts for both diagnosis

& ongoing monitoring of diabetic ketoacidosis (DKA)

Performed, both in an office/hospital setting & by patients at home

ADA recommends that ketosis-prone patients with diabetes check urine or

blood ketones in situations characterized by deterioration in glycemic

control in order to detect & preempt the development of DKA.

Sacks DB, et al. Clin Chem 2011;57;e1

KETONE BODY

Acetoacetate

Acetone3-hydroxy

butyrate

Acetoacetate

3-hydroxybutyrate

1

1

1

3

In normal In DKA

Ketones

U. Ketone 3+U/AS. Ketone 2+Blood

Acetoacetate 82.9 µmol/L (< 70)

β-hydroxbutyrate 215.0 µmol/L (<90)

Total ketone 297.9 µmol/L (< 160)

Ketone B.

Colorimetric reaction that occurs between acetoacetate & nitroprusside

⇒ available in the form of dipsticks & tablets in both the urine & blood

Method to measure ketones

Enzymatic methods for the quantification of β-hydroxybutyrate

False (+) in highly colored urine (sulfhydryl-containing drug)

False (-) in air exposure, highly acid urine (ascobic acid, bacteria)

Clinical use

Urine ketone measurement

- Should not be used to diagnosis or monitor the course of DKA

- Positive urine ketone reading are found up to 30% of 1st morning urine

samples from pregnant women, during starvation, & after hypoglycemia

(GPP)

Blood ketone determinations

- Method using nitroprusside reaction should be used only as an adjunct

to diagnose DKA & should not used to monitor DKA treatment (B)

- Specific measurement of β-hydroxybutyrate in blood can be used for

diagnosis & monitoring of DKA (B)


Ketone measurement using handheld meters

FDA cleared for both laboratory use & home use by patients (2009)

Use dry-chemistry test strips


Diagnostic accuracy of POCT for DKA

DKA criteria; serum glucose ≥ 250 mg/dL; anion gap > 10 mmol/L; carbon

dioxide ≤ 18 mmol/L; pH ≤ 7.30

Arora S, et al. Diabetes Care 2011;34:852

Sensitivity Specificity Positive

predictive value

Negative

predictive value

Urine dipstick 98.1 35.1 15.0 99.4

Capillary β-OHB

(> 1.5 mmol/L)

98.1 78.6 34.9 99.7

Correlation of β-hydroxybutyrate measurementby Abbott & reference methods

Yu HY, et al. Pediatr Diabetes 2011;12:649

Blue dots indicate measurements within total

allowable error of 0.3 mmol/L or 15%. Red

dots that were encircled indicate

measurements with % difference of 25–43%.

Conclusion

POCT technology offers convenient aspects; immediate results, decision-

making without the need for repeated visits, use of finger-stick blood

sample.

Easily accessible POCT could help screening, diagnosis, & monitoring

efforts in several clinical setting.

However, POCT devices did not achieve optimum performance.

(Need effective strategies for error prevention)

Thank you!

The importance of POCT in diabetes management · Blood S.Ketone2+ Acetoacetate82.9µmol/L(

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