Acetaminophen ToxicityNCT06549062
Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol in Morbidly Obese and Non- Obese Patients.
An observational study of Acetaminophen Toxicity and Obesity, Morbid, run by University Hospital, Ghent at 1 site in Belgium.
Trial summary
Obese patients may need higher doses of acetaminophen (APAP) for adequate analgesia, due to increased total clearance and distribution volume. APAP-induced hepatotoxicity is mainly caused through CYP2E1 pathway. Its activity is induced by obesity, potentially endangering the safety profile of APAP. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Acetaminophen Toxicity, Obesity, Morbid
- Type of treatment
- Injection or infusion
- How many people
- 70 participants
- Where
- 1 siteBelgium
- Study dates
- 11 Sep 2020to 1 Jan 2025
- 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 18 to 70 years
- All sexes
- Adult, Older adult
Study population: control group is the cohort of patients with a BMI between 18,5 and 30 kg/m2. study group is the cohort of patients with a BMI over 35 kg/m2. All patients undergo laparscopic surgery because laparoscopy can affect liver function. since there are gender differences in acetaminophen metabolism, both cohorts were stratified into equal amounts of men and women.
Who may be able to join
- Adult ≥ 18 < 70 years old (obese patients) Adult ≥ 18 years old (non-obese patients)
- Able to comprehend, sign, and date the written informed consent document to participate in the clinical trial
- Obese scheduled for laparoscopic bariatric surgery Non obese scheduled for laparoscopic surgery
- Control group BMI ≥18.5 en <30 kg.m-2 or Obese group BMI > 35kg.m-2
- ASA Class I, II or III as assigned by the anaesthesiologist
Who cannot join
- Allergy or inability to tolerate "paracetamol"
- Documented Liver disease or liver enzymes > 3X normal value
- Kidney disease (eGFR < 30ml.min-1)
- Participation in a clinical trial within the past 30 days
- Chronic alcohol abuse or alcohol intake <72hrs
- Gilbert-Meulengracht-syndroom
Show all 9Show fewer
- Chronic malnutrition
- Intake of medication with influence on CYP2E1 or UDP-glucuronosyltransferase
- Pregnancy
Trial locations and contacts
1 site in 1 country.
Belgium1 site, 1 recruiting
- Recruiting
University Hospital
Ghent, Oost-Vlaanderen, 9000
Luc De Baerdemaeker, Md,PhD, 093323281, luc.debaerdemaeker@ugent.be
Ann De Bruyne, 093325933, ann.debruyne@ugent.be
About this study
Official title: Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol/Acetaminophen in Morbidly Obese and Non- Obese Patients.
Obese patients may need higher doses of acetaminophen (APAP) for adequate analgesia, due to increased total clearance and distribution volume. APAP-induced hepatotoxicity is mainly caused through CYP2E1 pathway. Its activity is induced by obesity, potentially endangering the safety profile of APAP. Metabolic-dysfunction associated liver disease (MASLD) is an important associated risk factor for APAP induced-hepatotoxicity.
The primary endpoint of this study is to validate Van Rongen's prediction model on plasma concentration of paracetamol and its metabolites and extend it to the steady state phase over a period of 30 hours by measuring plasma concentrations of paracetamol and its metabolites and comparing them with the plasma concentrations predicted by the model by Van Rongen et al.
Read more
In addition, results obtained from venous blood will be compared with results obtained via VAMS after finger stick. If VAMS correlates well with plasma concentrations of paracetamol and its NAPQI adducts, future interventional studies may utilize the patient-friendly VAMS technology in an effort to further investigate the safety and efficacy of higher doses of paracetamol in obese patients and possibly other patient groups.
The secondary endpoints of this study are liver function tests before and after 30hrs of paracetamol administration, the VAS pain scores, the surgical pleth index (SPI) and the consumption of piritramide as recorded by a PCIA pump.
Read the detailed description
- Pharmacokinetics and pharmacodynamics of Intravenous Paracetamol in morbidly obese and non- obese patients.
Study design: interventional, stratified, controlled, prospective cohort trial
- Hypothesis morbidly obese patients have increased CYP2E1-mediated oxidation of paracetamol, requiring higher dosage to achieve therapeutic concentrations. Higher CYP2E1 activity will produce more of the toxic NAPQI. The concentration of NAPQI adducts are a biomarker of potential liver toxicity. We expect to find ineffective plasma paracetamol concentrations + higher NAPQI adducts in the venous blood samples of obese patients compared to the non-obese patients, as confirmed by Volumetric absorptive microsampling (VAMS) from capillary blood. Based on our results, future studies can explore higher paracetamol dosage in obese using capillary sampling methods.
- Background:
Paracetamol still is the cornerstone of non-opioid analgesia in the obese patient. Current dosing recommendations for acetaminophen limit the adult dose to 4g / day regardless of an obese body constitution.
Recent publications have shown that a higher dose of paracetamol may be required to achieve adequate concentrations in morbidly obese patients due to increased CYP2E1-mediated oxidation of paracetamol (Van Rongen et al. Clin Pharmacokinet. 2016).
In contrast, the increased CYP2E1 activity will also lead to production of the toxic paracetamol metabolite N-Acetyl-p-benzoquinone imine (NAPQI). NAPQI forms compounds or adducts with specific liver proteins. The concentration of NAPQI adducts correlates with the degree of liver damage and can be considered as a biomarker of potential liver toxicity.
Blood sampling is needed to assess plasma concentrations of paracetamol and the NAPQI adducts. Recently, the Volumetric Absorptive MicroSampling (VAMS) method has become available as a minimally invasive sampling strategy, requiring only 10 µl of capillary blood and has been validated for quantitative analysis of paracetamol and the NAPQI adducts in blood and CSF. (Delahaye, Dhont et al. 2019)
Specific objectives:
The primary endpoint of this study is to validate Van Rongen's prediction model on plasma concentration of paracetamol and its metabolites and extend it to the steady state phase over a period of 30 hours by measuring plasma concentrations of paracetamol and its metabolites and comparing them with the plasma concentrations predicted by the model by Van Rongen et al.
In addition, results obtained from venous blood will be compared with results obtained via VAMS after finger stick. If VAMS correlates well with plasma concentrations of paracetamol and its NAPQI adducts, future interventional studies may utilize the patient-friendly VAMS technology in an effort to further investigate the safety and efficacy of higher doses of paracetamol in obese patients and possibly other patient groups.
The secondary endpoints of this study are liver function tests before and after 30hrs of paracetamol administration, the VAS pain scores, the surgical pleth index (SPI) and the consumption of piritramide as recorded by a PCIA pump.
Methods:
The obese cohort group will consist of 40 obese patients undergoing elective laparoscopic bariatric surgery. The control group will consist of non-obese patients undergoing laparoscopic GI surgery because laparoscopic surgery can alter the metabolism of paracetamol. both study groups will be stratified to achieve an equal gender composition due to gender differences in paracetamol metabolism.
Sample size:
70 patients in total (15 male control patients, 15 female control patients, 20 morbidly obese men and 20 morbidly obese women).
Inclusion criteria for obese patients:
- BMI> 35 kg.m-2 undergoing laparoscopic surgery.
- Patients >18 years old
- ASA physical classification II to III
Inclusion criteria for control patients:
- Patients 18.5 ≤ BMI ≤ 30 kg.m-2 undergoing elective laparoscopic surgery (Nissen procedure, inguinal hernia repair, laparoscopic bowel surgery and cholecystectomy).
- ASA physical classification I to III
- Patients > 18 yrs
Exclusion criteria for obese and non-obese patients:
Renal impairment eGFR <30ml / min, Liver disease liver enzymes> 3X normal values or documented liver pathology in the medical record, Patients with Gilbert-Meulengracht syndrome, pregnancy, Chronic alcohol intake or alcohol use within the last 72 hours, Patients treated with drugs known to affect CYP2E1 and UGT (UDP-glucuronosyltransferase), Chronic malnutrition, Paracetamol allergy, Clinical study last 30 days.
Procedures:
After induction, a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm of the first intravenous line and kept patent with a positive pressure needles connector
The paracetamol dose administered is part of the "standard of care" and is not a study specific intervention. All paracetamol will be administered over 15 minutes with a volumetric pump.
T0: administration of standard paracetamol (2g) dose after induction of anesthesia, followed by IV 1g / 6hrs postoperatively up to 30 h after first administration.
In addition to paracetamol, the patients receive a IV- dose of ibuprofen (600mg every 8h) and a patient controlled intravenous analgesia pump with piritramide (1mg/ml).
Routine monitoring:
Non-invasive blood pressure (NIBP), electrocardiography (ECG), pulse oximetry (SpO2) with a Surgical Pleth Index (SPI) module (GE-Health care). The SPI index is a measure of the balance between nociception/antinociception.
The first group consists of 40 obese patients undergoing elective laparoscopic surgery. The control group consists of non-obese patients undergoing laparoscopic GI surgery because laparoscopy can alter paracetamol metabolism. Both groups will be stratified to an equal gender composition due to gender differences in paracetamol metabolism. all patients receive the same dose of paracetamol. a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm.
Liver function (AST, ALT, prothrombin time [PT], c-glutamyl transpeptidase [c-GT] and bilirubin) will be assessed before and after 30 h of paracetamol administration (T <0 and T = 30 h).
Venous blood samples are collected at the following times:
T = 0min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 24 hours, 24 hours 15min, 25 hours 30min, 27 hours and 30 hours.
VAMS VAMS samples are generated from the collected venous blood sample and from capillary blood obtained by a fingerstick. Only at T = 0 no VAMS are produced from capillary blood.
T = 30 min, 60 min, 120 min, 180 min, 360 min, 24h 15 min and 30 hours. (7 finger pricks)
In addition, the VAS pain score and Surgical Pleth index will also be monitored, as well as the consumption of piritramide via a patient-controlled intravenous analgesia pump (PCIA pump), to objectively evaluate pain relief in the current dosing regimen.
Visual Analog Scale and Surgical Pleth Index:
VAS pain scores are measured at rest and after movement (coughing) simultaneously with the SPI.
VAS T = 180min, 240min, 300min, 360min, 24h, 24h15, 25h30min, 27h and 30h SPI T = 180min, 240min, 300min, 360min, 24h, 24h15, 25h30min, 27h and 30h
Patients who are discharged within 24hrs and cannot complete the full measurement cycle are not considered dropouts.
statistical analysis
Fisher exact test for Categorical data. For continuous data with normal distribution: unpaired student t-test or rMANOVA for repeated measures. Mann-Whitney test as non-parametric test and to test the AUC 0-8hr for paracetamol + metabolites. The Wilcoxon rank test to test liver function samples. Acetaminophen and metabolite data are analyzed using non-linear mixed effects modelling NONMEM version 7.2. Bland- Altman and Passing \& Bablok regression analysis for agreement between techniques.
- significance
If this study reveals that 4g/day of paracetamol is insufficient to reach therapeutic plasma levels of paracetamol, then higher doses of paracetomol might be needed. If the results of the VAMS method are comparable to the venous blood samples, than future studies can use capillary samples to explore the concentrations of paracetamol and its toxic metabolites when higher doses of paracetamol are administered.
- Flowchart
Inclusion criteria for obese patients:
- BMI> 35 kg.m-2 undergoing laparoscopic bariatric surgery.
- Patients >18 years old
- ASA physical classification II to III
Inclusion criteria for control patients:
- Patients 18.5 ≤ BMI ≤ 30 kg.m-2 undergoing elective laparoscopic surgery (Nissen procedure, inguinal hernia repair, laparoscopic bowel surgery and cholecystectomy).
- ASA physical classification I to III
- Patients > 18 yrs
- Conditions
- Acetaminophen Toxicity, Obesity, Morbid
- Keywords
- acetaminophen pharmacokinetics, obesity, NAPQI protein adducts, CYP 2E1
- Medical subject headings
- Obesity, Morbid, Obesity
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 |
|---|---|---|
| obese patients WHO class > 2 | patients with a BMI > 35 undergoing laparoscopic surgery. venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions. | |
| non obese and overweight patients | patients with a BMI between 18,5 - 30 undergoing laparoscopic surgery. Venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions. |
What is being measured
The primary outcome is the main question the study is designed to answer.
acetaminophen
plasma concentrations and capillary blood concentrations
Measured: first six hours after IV administration of the loading dose of 2g
acetaminophen
plasma concentrations and capillary blood concentrations
Measured: the six hours after IV administration of the fifth dose of 1g acetaminophen
acetaminophen-glucuronide metabolite
plasma concentrations and capillary blood concentrations
Measured: the first six hours after IV administration of a loading dose of 2g acetaminophen
acetaminophen-glucuronide metabolite
plasma concentrations and capillary blood concentrations
Measured: the first six hours after IV administration of fifth dose of 1 g acetaminophen
acetaminophen-sulphate metabolite
plasma concentrations and capillary blood concentrations
Measured: the first six hours after IV administration of 2g IV acetaminophen
acetaminophen-sulphate metabolite
plasma concentrations and capillary blood concentrations
Measured: the six hours after IV administration of fifth dose of 1g IV acetaminophen
acetaminophen- Cysteine protein adduct
plasma concentrations and capillary blood concentrations
Measured: the first six hours after IV administration of 2 g loading dose of acetaminophen
acetaminophen- Cysteine protein adduct
plasma concentrations and capillary blood concentrations
Measured: the six hours after IV administration of the fifth dose of 1g acetaminophen
acetaminophen- mercapturate protein adduct
plasma concentrations and capillary blood concentrations
Measured: the first six hours after IV administration loading dose 2g acetaminophen
acetaminophen- mercapturate protein adduct
plasma concentrations and capillary blood concentrations
Measured: the six hours after IV administration of the fifth dose of 1g acetaminophen
Secondary outcomes (5)
pain score using Visual analog scale at rest
patient indicates the pain score on a visual analog scale ranging from 0-100mm
Measured: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
pain score using Visual analog scale after movement
patient indicates the pain score on a visual analog scale ranging from 0-100mm
Measured: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
surgical pleth index (SPI) at rest
non invasive measurement of the balance between nociception and antinociception ranging from 0-100.
Measured: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
surgical pleth index (SPI) after movement
non invasive measurement of the balance between nociception and antinociception ranging from 0-100.
Measured: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
patient controlled intravenous analgesia: piritramide consumption
piritramide consumption as a measure of the quality of pain relief with acetaminophen and ibuprofen.
Measured: first 30 hours after starting acetaminophen or until discharge from the hospital
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Aug 2024
- Study start11 Sep 2020
- Primary completion1 Jan 2025 (estimated)
- Study completion1 Jan 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acetaminophen ToxicityStudies of the same condition, open and under way.
- More trials run by University Hospital, GhentThe sponsor's other registered studies.
- 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
- Prospective
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Ghent
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Patrick F Wouters, MD PhD, University Hospital, Ghent
- Investigators
- Luc De Baerdemaeker, Md,PhD, Principal investigator, University Hospital, Ghent
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06549062
- Sponsor's protocol ID
- BC-07469
- Status last verified
- Aug 2024
- First submitted
- 8 Aug 2024
- Last updated
- 12 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
van Rongen A, Valitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, van Dongen EPA, van den Anker JN, Knibbe CAJ. Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen. Clin Pharmacokinet. 2016 Jul;55(7):833-847. doi: 10.1007/s40262-015-0357-0.
PubMed 26818482
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics and Pharmacodynamics of Intravenous Paracetamol/Acetaminophen in Morbidly Obese and Non- Obese Patients.
- ClinicalTrials.gov ID
- NCT06549062
- Acronym / sponsor ID
- BC-07469
- Conditions
- Acetaminophen Toxicity, Obesity, Morbid
- Keywords
- acetaminophen pharmacokinetics, obesity, NAPQI protein adducts, CYP 2E1
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- University Hospital, GhentUniversity, hospital or other
- Study start
- 11 Sep 2020 (actual)
- Primary completion
- 1 Jan 2025 (estimated)
- Study completion
- 1 Jan 2025 (estimated)
- First posted
- 12 Aug 2024 (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.
Obese patients may need higher doses of acetaminophen (APAP) for adequate analgesia, due to increased total clearance and distribution volume. APAP-induced hepatotoxicity is mainly caused through CYP2E1 pathway. Its activity is induced by obesity, potentially endangering the safety profile of APAP. Metabolic-dysfunction associated liver disease (MASLD) is an important associated risk factor for APAP induced-hepatotoxicity.
The primary endpoint of this study is to validate Van Rongen's prediction model on plasma concentration of paracetamol and its metabolites and extend it to the steady state phase over a period of 30 hours by measuring plasma concentrations of paracetamol and its metabolites and comparing them with the plasma concentrations predicted by the model by Van Rongen et al.
In addition, results obtained from venous blood will be compared with results obtained via VAMS after finger stick. If VAMS correlates well with plasma concentrations of paracetamol and its NAPQI adducts, future interventional studies may utilize the patient-friendly VAMS technology in an effort to further investigate the safety and efficacy of higher doses of paracetamol in obese patients and possibly other patient groups.
The secondary endpoints of this study are liver function tests before and after 30hrs of paracetamol administration, the VAS pain scores, the surgical pleth index (SPI) and the consumption of piritramide as recorded by a PCIA pump.
Detailed description
- Pharmacokinetics and pharmacodynamics of Intravenous Paracetamol in morbidly obese and non- obese patients.
Study design: interventional, stratified, controlled, prospective cohort trial
- Hypothesis morbidly obese patients have increased CYP2E1-mediated oxidation of paracetamol, requiring higher dosage to achieve therapeutic concentrations. Higher CYP2E1 activity will produce more of the toxic NAPQI. The concentration of NAPQI adducts are a biomarker of potential liver toxicity. We expect to find ineffective plasma paracetamol concentrations + higher NAPQI adducts in the venous blood samples of obese patients compared to the non-obese patients, as confirmed by Volumetric absorptive microsampling (VAMS) from capillary blood. Based on our results, future studies can explore higher paracetamol dosage in obese using capillary sampling methods.
- Background:
Paracetamol still is the cornerstone of non-opioid analgesia in the obese patient. Current dosing recommendations for acetaminophen limit the adult dose to 4g / day regardless of an obese body constitution.
Recent publications have shown that a higher dose of paracetamol may be required to achieve adequate concentrations in morbidly obese patients due to increased CYP2E1-mediated oxidation of paracetamol (Van Rongen et al. Clin Pharmacokinet. 2016).
In contrast, the increased CYP2E1 activity will also lead to production of the toxic paracetamol metabolite N-Acetyl-p-benzoquinone imine (NAPQI). NAPQI forms compounds or adducts with specific liver proteins. The concentration of NAPQI adducts correlates with the degree of liver damage and can be considered as a biomarker of potential liver toxicity.
Blood sampling is needed to assess plasma concentrations of paracetamol and the NAPQI adducts. Recently, the Volumetric Absorptive MicroSampling (VAMS) method has become available as a minimally invasive sampling strategy, requiring only 10 µl of capillary blood and has been validated for quantitative analysis of paracetamol and the NAPQI adducts in blood and CSF. (Delahaye, Dhont et al. 2019)
Specific objectives:
The primary endpoint of this study is to validate Van Rongen's prediction model on plasma concentration of paracetamol and its metabolites and extend it to the steady state phase over a period of 30 hours by measuring plasma concentrations of paracetamol and its metabolites and comparing them with the plasma concentrations predicted by the model by Van Rongen et al.
In addition, results obtained from venous blood will be compared with results obtained via VAMS after finger stick. If VAMS correlates well with plasma concentrations of paracetamol and its NAPQI adducts, future interventional studies may utilize the patient-friendly VAMS technology in an effort to further investigate the safety and efficacy of higher doses of paracetamol in obese patients and possibly other patient groups.
The secondary endpoints of this study are liver function tests before and after 30hrs of paracetamol administration, the VAS pain scores, the surgical pleth index (SPI) and the consumption of piritramide as recorded by a PCIA pump.
Methods:
The obese cohort group will consist of 40 obese patients undergoing elective laparoscopic bariatric surgery. The control group will consist of non-obese patients undergoing laparoscopic GI surgery because laparoscopic surgery can alter the metabolism of paracetamol. both study groups will be stratified to achieve an equal gender composition due to gender differences in paracetamol metabolism.
Sample size:
70 patients in total (15 male control patients, 15 female control patients, 20 morbidly obese men and 20 morbidly obese women).
Inclusion criteria for obese patients:
- BMI> 35 kg.m-2 undergoing laparoscopic surgery.
- Patients >18 years old
- ASA physical classification II to III
Inclusion criteria for control patients:
- Patients 18.5 ≤ BMI ≤ 30 kg.m-2 undergoing elective laparoscopic surgery (Nissen procedure, inguinal hernia repair, laparoscopic bowel surgery and cholecystectomy).
- ASA physical classification I to III
- Patients > 18 yrs
Exclusion criteria for obese and non-obese patients:
Renal impairment eGFR <30ml / min, Liver disease liver enzymes> 3X normal values or documented liver pathology in the medical record, Patients with Gilbert-Meulengracht syndrome, pregnancy, Chronic alcohol intake or alcohol use within the last 72 hours, Patients treated with drugs known to affect CYP2E1 and UGT (UDP-glucuronosyltransferase), Chronic malnutrition, Paracetamol allergy, Clinical study last 30 days.
Procedures:
After induction, a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm of the first intravenous line and kept patent with a positive pressure needles connector
The paracetamol dose administered is part of the "standard of care" and is not a study specific intervention. All paracetamol will be administered over 15 minutes with a volumetric pump.
T0: administration of standard paracetamol (2g) dose after induction of anesthesia, followed by IV 1g / 6hrs postoperatively up to 30 h after first administration.
In addition to paracetamol, the patients receive a IV- dose of ibuprofen (600mg every 8h) and a patient controlled intravenous analgesia pump with piritramide (1mg/ml).
Routine monitoring:
Non-invasive blood pressure (NIBP), electrocardiography (ECG), pulse oximetry (SpO2) with a Surgical Pleth Index (SPI) module (GE-Health care). The SPI index is a measure of the balance between nociception/antinociception.
The first group consists of 40 obese patients undergoing elective laparoscopic surgery. The control group consists of non-obese patients undergoing laparoscopic GI surgery because laparoscopy can alter paracetamol metabolism. Both groups will be stratified to an equal gender composition due to gender differences in paracetamol metabolism. all patients receive the same dose of paracetamol. a second intravenous catheter for blood sampling is placed in a large vein of the contralateral arm.
Liver function (AST, ALT, prothrombin time [PT], c-glutamyl transpeptidase [c-GT] and bilirubin) will be assessed before and after 30 h of paracetamol administration (T <0 and T = 30 h).
Venous blood samples are collected at the following times:
T = 0min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 24 hours, 24 hours 15min, 25 hours 30min, 27 hours and 30 hours.
VAMS VAMS samples are generated from the collected venous blood sample and from capillary blood obtained by a fingerstick. Only at T = 0 no VAMS are produced from capillary blood.
T = 30 min, 60 min, 120 min, 180 min, 360 min, 24h 15 min and 30 hours. (7 finger pricks)
In addition, the VAS pain score and Surgical Pleth index will also be monitored, as well as the consumption of piritramide via a patient-controlled intravenous analgesia pump (PCIA pump), to objectively evaluate pain relief in the current dosing regimen.
Visual Analog Scale and Surgical Pleth Index:
VAS pain scores are measured at rest and after movement (coughing) simultaneously with the SPI.
VAS T = 180min, 240min, 300min, 360min, 24h, 24h15, 25h30min, 27h and 30h SPI T = 180min, 240min, 300min, 360min, 24h, 24h15, 25h30min, 27h and 30h
Patients who are discharged within 24hrs and cannot complete the full measurement cycle are not considered dropouts.
statistical analysis
Fisher exact test for Categorical data. For continuous data with normal distribution: unpaired student t-test or rMANOVA for repeated measures. Mann-Whitney test as non-parametric test and to test the AUC 0-8hr for paracetamol + metabolites. The Wilcoxon rank test to test liver function samples. Acetaminophen and metabolite data are analyzed using non-linear mixed effects modelling NONMEM version 7.2. Bland- Altman and Passing \& Bablok regression analysis for agreement between techniques.
- significance
If this study reveals that 4g/day of paracetamol is insufficient to reach therapeutic plasma levels of paracetamol, then higher doses of paracetomol might be needed. If the results of the VAMS method are comparable to the venous blood samples, than future studies can use capillary samples to explore the concentrations of paracetamol and its toxic metabolites when higher doses of paracetamol are administered.
- Flowchart
Inclusion criteria for obese patients:
- BMI> 35 kg.m-2 undergoing laparoscopic bariatric surgery.
- Patients >18 years old
- ASA physical classification II to III
Inclusion criteria for control patients:
- Patients 18.5 ≤ BMI ≤ 30 kg.m-2 undergoing elective laparoscopic surgery (Nissen procedure, inguinal hernia repair, laparoscopic bowel surgery and cholecystectomy).
- ASA physical classification I to III
- Patients > 18 yrs
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| obese patients WHO class > 2 | – | –patients with a BMI > 35 undergoing laparoscopic surgery. venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions. |
| non obese and overweight patients | – | –patients with a BMI between 18,5 - 30 undergoing laparoscopic surgery. Venous and capillary blood samples are collected to determine the concentrations of acetaminophen and its metabolites after intravenous administration of a first dose of 2g acetaminophen and after a fifth dose of 1g acetaminophen in steady state conditions. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- control group is the cohort of patients with a BMI between 18,5 and 30 kg/m2. study group is the cohort of patients with a BMI over 35 kg/m2. All patients undergo laparscopic surgery because laparoscopy can affect liver function. since there are gender differences in acetaminophen metabolism, both cohorts were stratified into equal amounts of men and women.
Key inclusion criteria (5 listed)
- Adult ≥ 18 < 70 years old (obese patients) Adult ≥ 18 years old (non-obese patients)
- Able to comprehend, sign, and date the written informed consent document to participate in the clinical trial
- Obese scheduled for laparoscopic bariatric surgery Non obese scheduled for laparoscopic surgery
- Control group BMI ≥18.5 en <30 kg.m-2 or Obese group BMI > 35kg.m-2
- ASA Class I, II or III as assigned by the anaesthesiologist
Key exclusion criteria (9 listed)
- Allergy or inability to tolerate "paracetamol"
- Documented Liver disease or liver enzymes > 3X normal value
- Kidney disease (eGFR < 30ml.min-1)
- Participation in a clinical trial within the past 30 days
- Chronic alcohol abuse or alcohol intake <72hrs
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
acetaminophen
Time frame: first six hours after IV administration of the loading dose of 2g
plasma concentrations and capillary blood concentrations
acetaminophen
Time frame: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-glucuronide metabolite
Time frame: the first six hours after IV administration of a loading dose of 2g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-glucuronide metabolite
Time frame: the first six hours after IV administration of fifth dose of 1 g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-sulphate metabolite
Time frame: the first six hours after IV administration of 2g IV acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen-sulphate metabolite
Time frame: the six hours after IV administration of fifth dose of 1g IV acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen- Cysteine protein adduct
Time frame: the first six hours after IV administration of 2 g loading dose of acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen- Cysteine protein adduct
Time frame: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen- mercapturate protein adduct
Time frame: the first six hours after IV administration loading dose 2g acetaminophen
plasma concentrations and capillary blood concentrations
acetaminophen- mercapturate protein adduct
Time frame: the six hours after IV administration of the fifth dose of 1g acetaminophen
plasma concentrations and capillary blood concentrations
5 secondary outcomes
pain score using Visual analog scale at rest
Time frame: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
pain score using Visual analog scale after movement
Time frame: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
surgical pleth index (SPI) at rest
Time frame: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
surgical pleth index (SPI) after movement
Time frame: hours after starting acetaminophen: 3,4,5,6, 24, 24:15, 25:30,27,30
patient controlled intravenous analgesia: piritramide consumption
Time frame: first 30 hours after starting acetaminophen or until discharge from the hospital
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2024.
- Results publication: PubMed 26818482van Rongen A, Valitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, van Dongen EPA, van den Anker JN, Knibbe CAJ. Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen. Clin Pharmacokinet. 2016 Jul;55(7):833-847. doi: 10.1007/s40262-015-0357-0.
- Individual participant dataSharing planned: No
Related trials for Acetaminophen Toxicity
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.
Luc De Baerdemaeker, Md,PhD principal investigator
University Hospital, Ghent
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 Acetaminophen Toxicity and Obesity, Morbid, run by University Hospital, Ghent at 1 site in Belgium.
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 5 inclusion and 9 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: status not confirmed, as of the sponsor's last update on 12 Aug 2024. 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 Belgium. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Luc De Baerdemaeker, MD, PhD (09 332 3281, luc.debaerdemaeker@ugent.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
acetaminophen (time frame: first six hours after IV administration of the loading dose of 2g). The study lists 10 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 NCT06549062, which also lists 1 linked publication.
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 12 Aug 2024.