Metabolic AcidosisNCT04975906
The Threshold of Serum Anion Gap as a Screening Tool for Organic Acidosis
An observational study of Metabolic Acidosis and Critical Illness, run by Changi General Hospital at 1 site in Singapore.
Trial summary
Background: The serum anion gap (AG) is commonly used as a screening tool for acid-base disorders. With modern laboratory techniques using ion-selective electrodes to measure the main electrolyte components of the AG, our definition high AG (HAGMA) should be reviewed. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Metabolic Acidosis, Critical Illness, Anion Gap Acidosis
- How many people
- 16,475 participants
- Where
- 1 siteSingapore
- Study dates
- 1 Jul 2017to 6 Jun 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Inpatients in acute care hospital admitted from 01 July 2017 to 31 December 2019 who were being assessed for organic acidosis
Who may be able to join
- Admitted from 01 July 2017 to 31 December 2019
- Patients who have had blood lactate, blood ketones and serum salicylates performed during this time period
- Patient who also had urea / creatinine and a comprehensive panel of electrolytes performed up to +/-12h of blood lactate, blood ketones and serum salicylates being performed
Who cannot join
- Patient who did not have blood lactate, blood ketones and serum salicylates performed during this time period
- Patient who did not have urea / creatinine and a comprehensive panel of electrolytes performed up to +/-12h of blood lactate, blood ketones and serum salicylates being performed
Trial locations and contacts
1 site in 1 country.
About this study
Background: The serum anion gap (AG) is commonly used as a screening tool for acid-base disorders. With modern laboratory techniques using ion-selective electrodes to measure the main electrolyte components of the AG, our definition high AG (HAGMA) should be reviewed.
Aim: This study aims to assess the diagnostic value of AG and to determine a diagnostic threshold for HAGMA in a high-prevalence clinical setting.
Method: Computerized extraction of anonymised data from electronic medical records was performed. A pre-defined criteria included all inpatients of an acute-care hospital who had measurements for organic acids (lactate, ketone or salicylate) paired with a serum urea, electrolyte and creatinine panel.
Read the detailed description
BACKGROUND: The urea \& electrolyte (U\&E) panel is a common blood test that is often performed for any ill patients in a hospital. Evaluation of this panel can reveal serious underlying acid-base disturbances, often a harbinger of further haemodynamic compromise. The detection of a gap acidosis often is the first indicator of a serious underlying condition.
The AG is a reflection of the unmeasured anions. The anion gap (AG) is derived from the U\&E panel by subtracting measured anions from measured cations:
AG = [Sodium] + [Potassium] - [Chloride] - [Bicarbonate] The serum potassium can be included in the calculation, but due to low variability of serum potassium, most clinicians omit serum potassium in the calculation of AG.
Accumulation of organic acids (e.g. lactic acid, ketones, uremic toxins) results in a high AG metabolic acidosis (HAGMA) and such patients have a significant risk of further clinical deterioration. It has however been challenging to assess for gap acidosis as the range for normal AG can vary greatly due to historical differences in the laboratory techniques used to measure the constituents of AG as well as a component of interindividual variability. In the past, AG were reported (in milliequivalents per liter, mEq/L) in the range of 9-17 milliequivalents/L or 8-16 milliequivalents/L with older laboratory techniques such as flame photometry, colorimetric method. In more recent years with the advent of use of ion-selective electrodes (ISE), published literature suggests that the AG range may be lower as the ISE may give higher readings of serum chloride. Some clinical texts and laboratories have listed the reference range of AG as 3-11 milliequivalents/L or 5-12 milliequivalents/L.
Despite so, the reference range for serum sodium, potassium and chloride themselves have remained the same over the years despite changes in laboratory techniques. With such conflicting information, it is important to re-evaluate the screening or diagnostic threshold of the AG based on modern laboratory techniques.
OBJECTIVES: To assess the diagnostic threshold of AG to detect gap acidosis due to organic acidosis.
METHODS: Study protocol was reviewed and approved by the institutional ethics committee (SingHealth centralised institutional review board: 2019/2463). A waiver of consent was obtained as data was anonymised.
This is a retrospective study. Data will be extracted from electronic medical and laboratory records from all inpatient admissions to an acute hospital. Data extracted will be anonymized.
The search criteria will include the following parameters:
- all inpatient admissions 2017 - 2020 and
- patients with serum lactate, ketones and salicylates performed, and
- patients with urea, electrolytes and creatinine at the same time.
Data to be extracted include baseline demographic data, admission date, and laboratory results including urea / electrolytes / creatinine, albumin, glucose, calcium, phosphate, magnesium, albumin, liver function test, arterial blood test and hemoglobin.
If patients had multiple blood samples taken, only laboratory results from a single sample will be included. This will be selected by an automated algorithm which selects the sample with the most complete information.
Statistical Analysis Plan: The patients will be divided into 2 groups - with / without organic acidosis (elevated serum lactate, ketones and/or salicylates). An area under the curve (AUC) of receiver operating characteristics (ROC) analysis of AG for the detection of organic acidosis will be performed. The optimal cut-off threshold will be explored using the Youden index. Analysis of the diagnostic threshold of AG at different cut-off levels will be performed and the performance of the AG as a screening test at different cut-off thresholds will be assessed by reviewing the sensitivity, specificity, positive/negative predictive values and related indicators. A recommended cut-off value will be determined based on a test sensitivity adjudicated to be acceptable.
- Conditions
- Metabolic Acidosis, Critical Illness, Anion Gap Acidosis, Lactic Acidosis, Keto Acidosis, Acid Base Disorder
- Keywords
- Anion Gap, Metabolic Acidosis, Lactic Acidosis, Ketoacidosis, Screening Test
- Medical subject headings
- Acidosis, Critical Illness, Acidosis, Lactic, Ketosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Participants | All inpatient admissions with serum lactate, ketones and/or salicylates performed, and with urea, electrolytes and creatinine at the same time. The patients will be grouped into patients with organic (gap) acidosis (elevated serum lactate, ketones and/or salicylates) and patients with no organic acidosis. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Curve of Receiver Operating Characteristics
An area under the curve (AUC) of receiver operating characteristics (ROC) of Anion Gap for the presence of organic acidosis will be calculated.
An AUC >0.8 suggests that Anion Gap performs well as a test for the presence of organic acidosis.
Measured: End of study period, estimated 3 years
An optimal cut-off threshold of Anion Gap
The optimal cut-off threshold will be determined. At each cut-off level. the sensitivity and specificity will be calculated. One recommended cut-off value for Anion Gap with a sensitivity >95% will be accepted.
Measured: End of study period, estimated 3 years
Secondary outcomes (1)
Subgroup Analysis for Performance of Anion Gap as a screening test for Organic Acidosis
The AUC-ROC for Anion Gap will be calculated for each patient subgroup: serum urea (≤7.7 mmol/L or >7.7 mmol/L), age (below or above median age), sex, race and concomitant respiratory acid-base disorders (present or absent)
Measured: End of study period, estimated 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2021
- Study start1 Jul 2017
- Primary completion31 Dec 2021
- Study completion6 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Metabolic AcidosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 16,475 participants (actual)
Sponsor and investigators
- Lead sponsor
- Changi General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Chionh Chang Yin, Changi General Hospital
- Investigators
- Chang Y Chionh, Principal investigator, Changi General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04975906
- Sponsor's protocol ID
- SingHealth CIRB: 2019/2463
- Status last verified
- Jun 2023
- First submitted
- 28 May 2021
- Last updated
- 15 Jun 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Winter SD, Pearson JR, Gabow PA, Schultz AL, Lepoff RB. The fall of the serum anion gap. Arch Intern Med. 1990 Feb;150(2):311-3.
PubMed 2302006Sadjadi SA, Manalo R, Jaipaul N, McMillan J. Ion-selective electrode and anion gap range: What should the anion gap be? Int J Nephrol Renovasc Dis. 2013 Jun 7;6:101-5. doi: 10.2147/IJNRD.S44689. Print 2013.
PubMed 23776389Lolekha PH, Vanavanan S, Lolekha S. Update on value of the anion gap in clinical diagnosis and laboratory evaluation. Clin Chim Acta. 2001 May;307(1-2):33-6. doi: 10.1016/s0009-8981(01)00459-4.
PubMed 11369334Ayala-Lopez N, Harb R. Interpreting Anion Gap Values in Adult and Pediatric Patients: Examining the Reference Interval. J Appl Lab Med. 2020 Jan 1;5(1):126-135. doi: 10.1373/jalm.2019.029496.
PubMed 32445342
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Threshold of Serum Anion Gap as a Screening Tool for Organic Acidosis
- ClinicalTrials.gov ID
- NCT04975906
- Acronym / sponsor ID
- SingHealth CIRB: 2019/2463
- Conditions
- Metabolic Acidosis, Critical Illness, Anion Gap Acidosis, Lactic Acidosis, Keto Acidosis, Acid Base Disorder
- Keywords
- Anion Gap, Metabolic Acidosis, Lactic Acidosis, Ketoacidosis, Screening Test
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 16,475 participants (actual)
- Lead sponsor
- Changi General HospitalUniversity, hospital or other
- Study start
- 1 Jul 2017 (actual)
- Primary completion
- 31 Dec 2021 (actual)
- Study completion
- 6 Jun 2023 (actual)
- First posted
- 26 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: The serum anion gap (AG) is commonly used as a screening tool for acid-base disorders. With modern laboratory techniques using ion-selective electrodes to measure the main electrolyte components of the AG, our definition high AG (HAGMA) should be reviewed.
Aim: This study aims to assess the diagnostic value of AG and to determine a diagnostic threshold for HAGMA in a high-prevalence clinical setting.
Method: Computerized extraction of anonymised data from electronic medical records was performed. A pre-defined criteria included all inpatients of an acute-care hospital who had measurements for organic acids (lactate, ketone or salicylate) paired with a serum urea, electrolyte and creatinine panel.
Detailed description
BACKGROUND: The urea \& electrolyte (U\&E) panel is a common blood test that is often performed for any ill patients in a hospital. Evaluation of this panel can reveal serious underlying acid-base disturbances, often a harbinger of further haemodynamic compromise. The detection of a gap acidosis often is the first indicator of a serious underlying condition.
The AG is a reflection of the unmeasured anions. The anion gap (AG) is derived from the U\&E panel by subtracting measured anions from measured cations:
AG = [Sodium] + [Potassium] - [Chloride] - [Bicarbonate] The serum potassium can be included in the calculation, but due to low variability of serum potassium, most clinicians omit serum potassium in the calculation of AG.
Accumulation of organic acids (e.g. lactic acid, ketones, uremic toxins) results in a high AG metabolic acidosis (HAGMA) and such patients have a significant risk of further clinical deterioration. It has however been challenging to assess for gap acidosis as the range for normal AG can vary greatly due to historical differences in the laboratory techniques used to measure the constituents of AG as well as a component of interindividual variability. In the past, AG were reported (in milliequivalents per liter, mEq/L) in the range of 9-17 milliequivalents/L or 8-16 milliequivalents/L with older laboratory techniques such as flame photometry, colorimetric method. In more recent years with the advent of use of ion-selective electrodes (ISE), published literature suggests that the AG range may be lower as the ISE may give higher readings of serum chloride. Some clinical texts and laboratories have listed the reference range of AG as 3-11 milliequivalents/L or 5-12 milliequivalents/L.
Despite so, the reference range for serum sodium, potassium and chloride themselves have remained the same over the years despite changes in laboratory techniques. With such conflicting information, it is important to re-evaluate the screening or diagnostic threshold of the AG based on modern laboratory techniques.
OBJECTIVES: To assess the diagnostic threshold of AG to detect gap acidosis due to organic acidosis.
METHODS: Study protocol was reviewed and approved by the institutional ethics committee (SingHealth centralised institutional review board: 2019/2463). A waiver of consent was obtained as data was anonymised.
This is a retrospective study. Data will be extracted from electronic medical and laboratory records from all inpatient admissions to an acute hospital. Data extracted will be anonymized.
The search criteria will include the following parameters:
- all inpatient admissions 2017 - 2020 and
- patients with serum lactate, ketones and salicylates performed, and
- patients with urea, electrolytes and creatinine at the same time.
Data to be extracted include baseline demographic data, admission date, and laboratory results including urea / electrolytes / creatinine, albumin, glucose, calcium, phosphate, magnesium, albumin, liver function test, arterial blood test and hemoglobin.
If patients had multiple blood samples taken, only laboratory results from a single sample will be included. This will be selected by an automated algorithm which selects the sample with the most complete information.
Statistical Analysis Plan: The patients will be divided into 2 groups - with / without organic acidosis (elevated serum lactate, ketones and/or salicylates). An area under the curve (AUC) of receiver operating characteristics (ROC) analysis of AG for the detection of organic acidosis will be performed. The optimal cut-off threshold will be explored using the Youden index. Analysis of the diagnostic threshold of AG at different cut-off levels will be performed and the performance of the AG as a screening test at different cut-off thresholds will be assessed by reviewing the sensitivity, specificity, positive/negative predictive values and related indicators. A recommended cut-off value will be determined based on a test sensitivity adjudicated to be acceptable.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Participants | – | –All inpatient admissions with serum lactate, ketones and/or salicylates performed, and with urea, electrolytes and creatinine at the same time. The patients will be grouped into patients with organic (gap) acidosis (elevated serum lactate, ketones and/or salicylates) and patients with no organic acidosis. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Inpatients in acute care hospital admitted from 01 July 2017 to 31 December 2019 who were being assessed for organic acidosis
Key inclusion criteria (3 listed)
- Admitted from 01 July 2017 to 31 December 2019
- Patients who have had blood lactate, blood ketones and serum salicylates performed during this time period
- Patient who also had urea / creatinine and a comprehensive panel of electrolytes performed up to +/-12h of blood lactate, blood ketones and serum salicylates being performed
Key exclusion criteria (2 listed)
- Patient who did not have blood lactate, blood ketones and serum salicylates performed during this time period
- Patient who did not have urea / creatinine and a comprehensive panel of electrolytes performed up to +/-12h of blood lactate, blood ketones and serum salicylates being performed
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Area Under the Curve of Receiver Operating Characteristics
Time frame: End of study period, estimated 3 years
An area under the curve (AUC) of receiver operating characteristics (ROC) of Anion Gap for the presence of organic acidosis will be calculated. An AUC >0.8 suggests that Anion Gap performs well as a test for the presence of organic acidosis.
An optimal cut-off threshold of Anion Gap
Time frame: End of study period, estimated 3 years
The optimal cut-off threshold will be determined. At each cut-off level. the sensitivity and specificity will be calculated. One recommended cut-off value for Anion Gap with a sensitivity >95% will be accepted.
1 secondary outcome
Subgroup Analysis for Performance of Anion Gap as a screening test for Organic Acidosis
Time frame: End of study period, estimated 3 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2023.
- Background: PubMed 2302006Winter SD, Pearson JR, Gabow PA, Schultz AL, Lepoff RB. The fall of the serum anion gap. Arch Intern Med. 1990 Feb;150(2):311-3.
- Background: PubMed 23776389Sadjadi SA, Manalo R, Jaipaul N, McMillan J. Ion-selective electrode and anion gap range: What should the anion gap be? Int J Nephrol Renovasc Dis. 2013 Jun 7;6:101-5. doi: 10.2147/IJNRD.S44689. Print 2013.
- Background: PubMed 11369334Lolekha PH, Vanavanan S, Lolekha S. Update on value of the anion gap in clinical diagnosis and laboratory evaluation. Clin Chim Acta. 2001 May;307(1-2):33-6. doi: 10.1016/s0009-8981(01)00459-4.
- Background: PubMed 32445342Ayala-Lopez N, Harb R. Interpreting Anion Gap Values in Adult and Pediatric Patients: Examining the Reference Interval. J Appl Lab Med. 2020 Jan 1;5(1):126-135. doi: 10.1373/jalm.2019.029496.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chang Y Chionh principal investigator
Changi General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Metabolic Acidosis and Critical Illness, run by Changi General Hospital at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area Under the Curve of Receiver Operating Characteristics (time frame: End of study period, estimated 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04975906, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2023.