Veilig gebruik van contrastmiddelen

Initiatief: NVvR Aantal modules: 48

Meerdere onderzoeken met contrastmiddelen bij patiënten met normale of gereduceerde nierfunctie

Uitgangsvraag

Wat is een veilig tijdsinterval bij patiënten met een verminderde nierfunctie tussen twee radiologische of cardiologische onderzoeken?

 

Wat is een veilig tijdsinterval bij patiënten met een verminderde nierfunctie en:

  1. Twee onderzoeken met jodiumhoudend contrastmiddel (CM)?
  2. Twee onderzoeken met gadoliniumhoudend CM?
  3. Twee onderzoeken met jodiumhoudend- en gadoliniumhoudend CM?

 

Deze vraag bevat de volgende subgroepen:

  • Electieve CT/Angio/MRI bij patiënten met een normale nierfunctie (eGFR >60 ml/min/1.73m2)
  • Electieve CT/Angio/MRI bij patiënten matig verminderde nierfunctie (eGFR 30-60 ml/min/1.73m2)
  • Electieve CT/Angio/MRI bij patiënten met ernstig verminderde nierfunctie (eGFR < 30 ml/min/1.73m2)
  • CT/Angio/MRI bij spoedeisende of levensbedreigende situaties

Aanbeveling

1. Veilig tijdsinterval tussen radiologische of cardiologische onderzoeken met jodiumhoudende CM

 

Overweeg een wachttijd tussen electieve CM-versterkte CT of (coronair) angiografie onderzoeken met meerdere jodiumhoudende CM-toedieningen bij patiënten met een normale nierfunctie (eGFR>60 ml/min/1.73m2) van:

  • Optimaal 12 uur (bijna complete eliminatie van vorig toegediend jodiumhoudend CM)
  • Minimaal 4 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen electieve CM-versterkte CT of (coronair) angiografie onderzoeken met meerdere jodiumhoudende CM-toedieningen bij patiënten met een matig verminderde nierfunctie (eGFR 30-60 ml/min/1.73m2) van:

  • Optimaal 48 uur (bijna complete eliminatie van vorig toegediend jodiumhoudend CM)
  • Minimaal 16 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen electieve CM-versterkte CT of (coronair) angiografie onderzoeken met meerdere jodiumhoudende CM-toedieningen bij patiënten met een ernstig verminderde nierfunctie (eGFR <30 ml/min/1.73m2) van:

  • Optimaal 168 uur (bijna complete eliminatie van vorig toegediend jodiumhoudend CM)
  • Minimaal 60 uur (als de klinische indicatie een snelle follow up vereist

Bij spoedeisende of levensbedreigende situaties, houd minder wachttijd aan tussen CM-versterkte onderzoeken met opeenvolgende jodiumhoudende CM-toedieningen.

 

2. Veilig tijdsinterval tussen radiologische onderzoeken met gadoliniumhoudende CM

 

Overweeg een wachttijd tussen electieve CM-versterkte MRI onderzoeken met meerdere gadoliniumhoudende CM bij patiënten met een normale nierfunctie (eGFR>60 ml/min/1.73m2) van:

  • Optimaal 12 uur (bijna complete eliminatie van het vorig toegediende gadoliniumhoudende CM)
  • Minimaal 4 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen electieve CM-versterkte MRI onderzoeken met meerdere gadoliniumhoudende CM-toedieningen bij patiënten met een matig verminderde nierfunctie (eGFR 30-60 ml/min/1.73m2) van:

  • Optimaal 48 uur (bijna complete eliminatie van vorig toegediend gadoliniumhoudend CM)
  • Minimaal 16 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen electieve CM-versterkte MRI onderzoeken met meerdere gadoliniumhoudende CM-toedieningen bij patiënten met een ernstig verminderde nierfunctie (eGFR <30 ml/min/1.73m2) van:

  • Optimaal 168 uur (bijna complete eliminatie van vorig toegediende gadoliniumhoudende CM)
  • Minimaal 60 uur (als de klinische indicatie een snelle follow up vereist)

Bij spoedeisende of levensbedreigende situaties, houd minder wachttijd aan tussen contrast- versterkte onderzoeken met opeenvolgende gadoliniumhoudende CM-toedieningen.

 

3. Veilig tijdsinterval tussen radiologische of cardiologische onderzoeken met jodiumhoudende en gadoliniumhoudende CM

 

Bij CT of (coronair) angiografie met jodiumhoudend CM en MRI met gadoliniumhoudend CM op dezelfde dag in electieve situaties, is het beter om met het MRI-onderzoek te starten, behalve als het CT onderzoek voor de nieren, ureters of blaas bedoeld is (CT Urografie).

 

Overweeg een wachttijd tussen een electieve MRI met gadoliniumhoudend CM en een CT of (coronair) angiografie met jodiumhoudend CM bij patiënten met een normale nierfunctie (eGFR >60 ml/min/1.73m2) van:

  • Optimaal 6 uur (bijna complete eliminatie van vorig toegediende gadoliniumhoudende CM)
  • Minimaal 2 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen een electieve MRI met gadoliniumhoudend CM en een CT of (coronair) angiografie met jodiumhoudend CM bij patiënten met een matig verminderde nierfunctie (eGFR 30-60 ml/min/1.73m2) van:

  • Optimaal 48 uur (bijna complete eliminatie van vorig toegediende gadoliniumhoudende CM)
  • Minimaal 16 uur (als de klinische indicatie een snelle follow up vereist)

Overweeg een wachttijd tussen een electieve MRI met gadoliniumhoudend CM en een CT of (coronair) angiografie met jodiumhoudend CM bij patiënten met een ernstig verminderde nierfunctie (eGFR <30 ml/min/1.73m2) van:

  • Optimaal 168 uur (bijna complete eliminatie van vorig toegediende gadoliniumhoudende CM)
  • Minimaal 60 uur (als de klinische indicatie een snelle follow up vereist)

Bij CT of (coronair) angiografie met jodiumhoudend CM en MRI met gadoliniumhoudend CM op dezelfde dag in spoedeisende of levensbedreigende situaties, voer beide onderzoeken direct achter elkaar uit zonder wachttijd.

Overwegingen

 

1. Pharmacokinetics and Elimination of Iodine-based CM

The physicochemical data of currently used ICM have been summarized in Supplemental Table S1 at the end of this guideline.

 

For ICM the use of an open, 2-compartment model is justified. No third compartment for storage can be identified. In patients with normal renal function the renal elimination half- value times are between 1.8 and 2.3 h (average 2.0h) Almost all the administered contrast medium will be cleared in 6 half-lives, or 12 h, and already over 75% will be cleared in 2 half- lives, or 4 h.

 

In patients with moderate renal impairment (eGFR 30-60 ml/min/1,73m2), the renal elimination half-lives increase to 7 h, so it will need a maximum 42 h for near-complete clearance, and about 14 h for 75% clearance. In severe renal impairment (eGFR < 30 ml/min/1,73m2) renal elimination half-lives vary widely between 10-27 h, so in the worst case it will need a maximum 162 h (6,75 days) for near-complete clearance, and about 55 h (2,3 days) for 75% clearance (Table 1).

 

Table 1 Renal Excretion of Iodine-Based Contrast Media 

Name

Structure

Ionicity

Renal Excretion

 

 

 

 

 

 

 

 

(Elimination T½; hours - Near complete elimination in 6 x T½)

Normal Renal Function

Moderately Reduced RF

Severely Reduced RF

(eGFR > 60

ml/min)

(eGFR 30-60

ml/min)

(eGFR < 30

ml/min)

Iohexol

Monomeric

Nonionic

2.0

NA

27.2

Iopromide

Monomeric

Nonionic

1.8

NA

NA

Iomeprol

Monomeric

Nonionic

2.3

6.9

15.1

Ioversol

Monomeric

Nonionic

2.1

NA

NA

Iobitridol

Monomeric

Nonionic

NA

NA

NA

Iodixanol

Dimeric

Nonionic

2.2

NA

23.0

 Sources: See references in text above

 

2. Pharmacokinetics and Elimination of Gadolinium-based CM 

The physicochemical data of currently available GBCA have been summarized in Supplemental Table S2 at the end of this guideline.

 

For general MRI, currently only stable macrocyclic GBCA are allowed. Using the optimized open 3-compartment model, in patients with normal renal function the renal elimination half-lives are between 1.3 and 1.8 h (average 1.6h) and the residual excretion time will be in

 

the order of 6 h. Almost all the administered contrast medium will be cleared in 6 half-lives, or 10-12 h, and already over 75% will be cleared in a little more than 2 half-lives, or 4 h.

 

In patients with moderate renal impairment (eGFR 30-60 ml/min/1,73m2), the renal elimination half-lives increase to 4-7 h, so it will need a maximum 42 h for near-complete clearance, and about 14 h for 75% clearance. As the residual excretion depends on thermodynamic stability, it will not be significantly prolonged in these patients.

 

The situation is worse for patients with severe renal impairment (eGFR < 30 ml/min/1,73m2). Renal elimination half-lives are between 10-30 h, so it will need a maximum 180 h (7,5 days) for near-complete clearance, and about 60 h (2,5 days) for 75% clearance. It is thus far unclear if the residual excretion is prolonged in these patients (Table 2).

 

Table 2 Renal Excretion of Gadolinium-Based Contrast Agents 

Name

Ligand

Structure

Ionicity

Renal Excretion

 

 

 

 

 

 

 

 

(Elimination T½; hours – Near complete elimination in 6 x T½)

Normal RF

Moderately Reduced RF

Severely Reduced RF

(eGFR > 60

ml/min)

(eGFR 30-60

ml/min)

(eGFR < 30

ml/min)

Gadopentetate

DTPA

Linear

Ionic

1.6

4.0

30.0

Gadobenate

BOPTA

Linear

Ionic

1.2-2.0

5.6

9.2

Gadoxetate

EOB- DTPA

Linear

Ionic

1.0

2.2

20.0

Gadoteridol

HP- DO3A

Macrocyclic

Nonionic

1.6

6.9

9.5

Gadobutrol

BT- DO3A

Macrocyclic

Nonionic

1.8

5.8

17.6

Gadoterate

DOTA

Macrocyclic

Ionic

1.6

5.1

13.9

Gadopiclenol

NA

Macrocyclic

Nonionic

1.6-1.9

3.8

11.7

 Sources: from references in text above

 

For approved linear hepatobiliary GBCA, moderate renal impairment leads to an increase in renal elimination half-value times of 2-5 h, corresponding to a maximum 30h for near- complete and 10h for 75% clearance. Severe renal impairment leads to an increase in renal elimination half-value times of 10-20 h, corresponding to 60-120 h for near-complete and 20-40 h for 75% clearance. Residual excretion half-lives are in the order of 30-48h.

 

3. Combined Enhanced imaging with an ICM and a GBCA

In oncology diagnosis and follow-up, contrast-enhanced MRI examinations with GBCA and contrast-enhanced CT examinations with ICM are often combined, sometimes on the same day. The presence of ICM will influence the (results of) MRI examination and the presence of GBCA will influence the (results of) CT examination. The degree of these effects will determine the optimal order of examinations. The pharmacokinetics of both types of CM will dictate how waiting times between examinations should be scheduled.

 

Combining CT and MRI: Effects of GBCA on CT studies

 

Multiple in vitro studies have demonstrated the effect of GBCA in CT. At equal mass concentration, GBCA will have a higher CT attenuation than ICM due to the higher atomic number of Gadolinium (64) compared to iodine (53) (Bloem, 1989; Engelbrecht, 1996; Gierada, 1999; Kim, 2003; Quinn, 1994; Schmitz, 1995; Schmitz, 1997; Zwicker, 1991).

 

Yet, in clinical practice the molar concentration used for ICM is much higher than for GBCA. For instance, iopromide 300 mgI/ml equals 2,94 mmol/ml, compared to GBCA with 0.5-1.0 mmol/ml. Excellent detailed phantom studies from Sweden focusing on equal attenuation have shown that in CT at 80-140kVp a solution of 0.5M GBCA is iso-attenuating to a solution of ICM with 91-116 mg I/mL for a chest phantom, and to 104- 125 mg I/mL for an abdominal phantom. Due to a different X-ray tube filtration, in DSA at 80-120 kVp a solution of 0.5M GBCA is iso-attenuating to 73-92 mg I/mL (Nyman, 2002 and 2011).

 

Many clinical studies have used GBCA for CT or angiography in renal insufficiency patients or in patients with (severe) hypersensitivity reactions to ICM. The GBCA injection frequently needs high doses of 0.3-0.5 mmol/kg for good vascular enhancement (Kaufman 1996), which is relatively short-lived. Such doses may be useful for vascular imaging or interventions but are usually not suitable for optimal imaging of the abdominal organs. Good overviews of the results can be found in multiple reviews (Spinosa, 2002; Strunk, 2004).

 

Nowadays, such high doses cannot be used anymore. Animal studies have shown that for equal attenuation, GBCA are more nephrotoxic and more costly than low-dose or diluted ICM (Elmsthål, 2006; Nyman, 2011). In addition to the risk of NSF and Gadolinium deposition, these are the major reasons that current ESUR guidelines strongly discourage the use of GBCA for radiographic examinations (Thomsen, 2002).

 

Due to the short-lived effect of GBCA injection in CT, this vascular enhancement is less cumbersome in clinical practice when combining contrast-enhanced CT and MRI examinations on the same day. One exception is that the kidneys will concentrate the gadolinium, so that the renal collecting systems, ureters, and bladder will show CT enhancement for a significant period.

 

Combining CT and MRI: Effects of ICM on MRI studies

 

In vitro experiments in MR Arthrography may serve as a model of these effects. Mixing of ICM with GBCA will lead to some shortening of the T1 (spin-lattice) relaxation time, and a more profound shortening of the T2 (spin-spin) relaxation time. This results in an increase in T1w signal and a decrease in T2w signal. The magnitude of the effect is greater for higher GBCA concentrations. The presence of ICM shifts the peak SI towards lower GBCA concentrations. Overall, in small joint spaces the enhancement was decreased (Andreisek, 2008; Choi, 2008; Ganguly, 2007; Kopka, 1994; Montgomery, 2002).

 

Similar effects can also be seen in routine MRI examinations, but to a lesser degree. The shortening effect on T1 and T2 times, with increase in T1w signal and a decrease in T2w signal, depends on the concentration of the ICM and on the side chains in the molecular structure of the specific ICM that is used (effect is for ioxithalamate > iotrolan > iopamidol > iodixanol, iohexol or iomeprol) (Hergan, 1995; Jinkins, 1992; Kopka, 1994; Morales, 2016). Very recently it was shown that adding an overdose of ICM to macrocyclic GBCA led to a significant increase in R1 relaxation and the combination was excreted more slowly, possibly because of the formation of chemical adducts between the lipophilic three-iodo-benzene rings of the ICM and the tetra-aza-cycle of the macrocyclic GBCA (DiGregorio, 2022). Increasing concentrations of ICM will also influence diffusion weighted imaging, with increased signal and decreased ADC values (Ogura, 2009), and on functional imaging with shortening of the T2* times used in BOLD MRI (Wang, 2014).

 

The effects of ICM in MRI can be longer-living and will be more disturbing on subsequent contrast-enhanced MRI.

 

Recommendations

 

1. Safe time intervals in enhanced imaging with iodine-based contrast media

 

Based on the following, the Committee can recommend the following waiting times between successive administrations of iodine-based contrast media in contrast-enhanced CT (or (coronary) angiography) to avoid accumulation of iodine-based contrast media with potential safety issues:

Consider a waiting time between elective contrast-enhanced CT or (coronary) angiography with successive iodine-based contrast media administrations in patients with normal renal function (eGFR >60 ml/min/1.73m2) of:

  • Optimally 12 hours (near complete clearance of the previously administered iodine-based contrast media)
  • Minimally 4 hours (if clinical indication requires rapid follow-up)

 

Consider a waiting time between elective contrast-enhanced CT or (coronary) angiography with successive iodine-based contrast media administrations in patients with moderately reduced renal function (eGFR 30-60 ml/min/1.73m2) of:

  • Optimally 48 hours (near complete clearance of the previously administered iodine- based contrast media)
  • Minimally 16 hours (if clinical indication requires rapid follow-up)

 

Consider a waiting time between elective contrast-enhanced CT or (coronary) angiography with successive iodine-based contrast media administrations in patients with severely reduced renal function (eGFR < 30 ml/min/1.73m2) of:

  • Optimally 168 hours (near complete clearance of the previously administered iodine-based contrast media)
  • Minimally 60 hours (if clinical indication requires rapid follow-up)

 

In emergency or life-threatening situations, employ less waiting time between contrast- enhanced CT (or coronary angiography) with successive iodine-based contrast media administrations.

 

2. Safe time intervals in enhanced imaging with gadolinium-based contrast agents

 

Based on the review above, the Committee recommends the following waiting times between contrast-enhanced MRI with successive administrations of gadolinium-based contrast agents, to avoid accumulation of gadolinium-based contrast agents with potential safety issues:

Consider a waiting time between elective contrast-enhanced MRI with successive gadolinium-based contrast agent administrations in patients with normal renal function (eGFR >60 ml/min/1.73m2) of:

  • Optimally 12 hours (near complete clearance of the previously administered gadolinium-based contrast agent)
  • Minimally 4 hours (if clinical indications require rapid follow-up)

 

Consider a waiting time between elective contrast-enhanced MRI with successive gadolinium-based contrast agent administrations in patients with moderately reduced renal function (eGFR 30-60 ml/min/1.73m2) of:

  • Optimally 48 hours (near complete clearance of the previously administered gadolinium-based contrast agent)
  • Minimally 16 hours (if clinical indications require rapid follow-up)

 

Consider a waiting time between elective contrast-enhanced MRI with successive gadolinium-based contrast agent administrations in patients with severely reduced renal function (eGFR < 30 ml/min/1.73m2) of:

  • Optimally 168 hours (near complete clearance of the previously administered gadolinium-based contrast agent)
  • Minimally 60 hours (if clinical indications require rapid follow-up)

 

In emergency or life-threatening situations, employ less waiting time between contrast- enhanced MRI with successive gadolinium-based contrast agent administrations.

 

3. Safe time intervals in combined enhanced imaging with an iodine-based contrast medium and a gadolinium-based contrast agent

 

Based on the review above, the Committee recommends the following waiting times between contrast-enhanced MRI and contrast-enhanced CT or (coronary) angiography, to avoid interference of the contrast medium used in the first contrast-enhanced examination on the other contrast-enhanced examination, and to avoid accumulation of contrast media with potential safety issues:

When combining contrast-enhanced CT or (coronary) angiography with an iodine-based contrast medium and contrast-enhanced MRI with a gadolinium-based contrast agent on the same day in elective situations, it is better to start with the MRI examination, unless the CT examination is intended for the kidneys, ureters, or bladder (CT Urography).

 

In patients with normal renal function the interference of the contrast medium used in the first contrast-enhanced examination on the second contrast-enhanced examination will predominantly determine the suggested waiting times.

Consider a waiting time between elective contrast-enhanced MRI with a gadolinium-based contrast agent and contrast-enhanced CT or (coronary) angiography with an iodine- based contrast medium in patients with normal renal function (eGFR >60 ml/min/1.73m2) of:

  • Optimally 6 hours (near complete clearance of the effects of the previously administered gadolinium-based contrast agent)
  • Minimally 2 hours (if the clinical indication requires rapid follow-up)

 

In patients with reduced renal function the avoidance of accumulation of contrast media with potential safety issues will predominantly determine the suggested waiting times (as in sections 1 and 2 above).

Consider a waiting time between elective contrast-enhanced MRI with a gadolinium-based contrast agent and contrast-enhanced CT or (coronary) angiography with an iodine- based contrast medium in patients with moderately reduced renal function (eGFR 30-60 ml/min/1.73m2) of:

  • Optimally 48 hours (near complete clearance of the previously administered gadolinium-based contrast agent)
  • Minimally 16 hours (if the clinical indication requires rapid follow-up)

 

Consider a waiting time between elective contrast-enhanced MRI with a gadolinium-based contrast agent and contrast-enhanced CT or (coronary) angiography with an iodine- based contrast medium in patients with severely reduced renal function (eGFR < 30 ml/min/1.73m2) of:

  • Optimally 168 hours (near complete clearance of the previously administered gadolinium-based contrast agent)
  • Minimally 60 hours (if the clinical indication requires rapid follow-up)

 

When combining contrast-enhanced CT or (coronary) angiography with an iodine-based contrast medium and contrast-enhanced MRI with a gadolinium-based contrast agent on the same day in emergency or life-threatening situations, employ no waiting time and perform back-to-back examinations.

 

 

Onderbouwing

The pharmacokinetics of contrast media (CM) will dictate how waiting times between CT or MRI examinations should be scheduled. There are few dedicated studies about the optimal time between successive doses of CM in repeated contrast-enhanced studies (Kwon, 2021) or when contrast-enhanced CT or (coronary) angiography and contrast-enhanced MRI studies are done in succession.

Systematic literature analysis

For this chapter it was decided not to perform a systematic literature analysis.

 

Narrative literature analysis

Results will be discussed separately for the previously described subgroups:

  1. Pharmacokinetics and Elimination of Iodine-based CM
  2. Pharmacokinetics and Elimination of Gadolinium-based CM
  3. Combined CT and MRI Examinations with ICM and GBCA 

 

1. Pharmacokinetics and Elimination of Iodine-based CM

Most studies on iodine-based CM (ICM) have employed an open, 2-compartiment model for pharmacokinetic analyses. The first compartment is the plasma in which the molecules are being diluted and the second compartment is the extravascular extracellular space of the tissues where there is an effective capillary permeability, i.e., outside the brain. In this classical model the plasma concentration decays by distribution of the CM from plasma to the extracellular volume (distribution phase, slope a), and by elimination of the CM from plasma to urine by renal excretion (elimination phase, slope b).

 

The elimination phase is of interest as it defines the time when a second administration of the same product can be performed safely, with no risk of accumulation and potential toxicity (such as contrast-associated acute kidney injury). In theory, near-complete elimination to 1,5% of the original concentration is achieved within 6 elimination half-lives (T½ b) (Bourin, 1997; Dean, 1993).

 

Results in Animal Studies

 

In most animal studies the open, 2-compartment model describes the pharmacokinetics of ICM well. All ICM behave similarly in early distribution and excretion. In animal studies distribution volumes ranged 180-250 ml/kg, or between 21-25% of body weight. This indicates distribution within the extracellular fluid only. Renal excretion is species dependent, and is higher for rats, rabbits, and dogs, compared to monkeys and humans due to their higher weight normalized GFR. Elimination half-life times in rat studies range 20-25 minutes, in dogs 50-62 minutes, and in monkeys 71-83 minutes (Bourrinet, 1994; Coveney, 1989; Dencausse, 1996; Gardeur, 1980; Heglund, 1995; Lorusso, 1994; Morin, 1988; Mützel,1980; Mützel, 1983).

 

The excretion in urine within 4h is 60-85% and within 24h is 86-95%, depending on the animal species. The urinary excretion is complete within 48h. Excretion in faeces is species- dependent, less than 1% for dogs and up to 7% for rats (Bourrinet, 1994; Coveney, 1989; Dencausse, 1996; Gardeur, 1980; Heglund, 1995; Lorusso, 1994; Morin, 1988; Mützel, 1980; Mützel, 1983).

 

After oral ingestion, 1-2% of the ICM reaches the systemic circulation and is eliminated rapidly via the kidneys. The rest is eliminated in unchanged form with the faeces (Bourrinet, 1994; Mützel, 1983).

 

Results in Human Studies – Normal Renal Function

 

Pharmacokinetics in humans also worked well using an open 2-compartment model.

The distribution volumes in healthy volunteers and young patients were between 165-280 ml/kg, indicating a distribution in the extracellular volume. Distribution half-lives are rapid, in the range of 15-22 minutes. For currently available nonionic ICM, the elimination half- value times range 1.8-2.3 hours (Bourin, 1997; Edelson, 1984; Fountaine, 1996; Krause, 1994; Lorusso, 2001; McKinstry, 1984; Olsson, 1983; Spencer, 1996; Svaland, 1992; Wilkins, 1989), but may already increase to 3.25-4h in volunteers and patients of older age (Hartwig, 1989).

 

Excretion in urine is quick and independent of dose. About 80% of the dose will be eliminated within 4h, and 93-98% is excreted in 24h. There is limited faecal excretion, usually < 2-4%. Nonionic ICM are not metabolized, and there is no binding to plasma proteins.

 

The elimination half-lives for older ionic high-osmolar ICM that are still in use as oral ICM for fluoroscopy or CT are shorter than for current nonionic low-osmolar CM used for intravascular administration, in the range of 1.3-1.8h (Difazio, 1978; Feldman, 1984; Gardeur, 1980).

 

Results in Human Studies – Renal Insufficiency

 

In patients with renal impairment the half-lives of the ICM increase progressively. The literature on pharmacokinetics of currently available ICM in patients with renal insufficiency is scarce and patient categories vary. In moderate renal insufficiency (eGFR 30- 60 ml/min/1.73m2) the elimination half-lives increase up to 6.9h, and in severe renal insufficiency (eGFR < 30 ml/min/1.73m2) the half-lives vary for several ICM from 10.0h to 27.0h, depending on the degree of insufficiency. When renal function is impaired, biliary excretion will increase somewhat (Corradi, 1990; Lorusso, 2001; Nossen, 1995).

 

The summarized data are largely dependent on the study populations and settings and should be taken as a relative indication.

 

 

2. Pharmacokinetics and Elimination of Gadolinium-based CM

Most of the early elimination of extracellular GBCA is via renal excretion, and for the hepatobiliary GBCA (gadobenate or gadoxetate) there is additional biliary excretion.

 

The elimination phase is of interest as it defines the time when a second administration of the same or another GBCA can be performed safely, with lower risk of accumulation and potential toxicity (such as nephrogenic systemic fibrosis or gadolinium deposition). In theory, near-complete elimination to 1,5% of the original concentration is achieved within 6 elimination half-lives (T½ b) (Bourin, 1997; Dean, 1993).

 

Results in Animal Studies – Normal renal and biliary function

 

All extracellular GBCA behave similarly in early distribution and excretion, except for brain. Elimination half-lives in rat studies range 16-23 min and in rabbit and dog studies 45-60 min for all clinically administered GBCA doses (Allard, 1988; Harpur, 1993; Lorusso, 1999; Robic, 2019; Tombach, 2002; Tweedle, 1988; Vittadini, 1988; Vogler, 1995), with decreases in elimination with increasing age or presence of diabetes of rats (Michel, 1992). The decrease is first rapid and then progressively slower. Steady-state distribution volumes range 210-230 ml/kg, indicating distribution in the extracellular fluid (Allard, 1988; Harpur, 1993; Lorusso, 1999; Robic, 2019; Tombach, 2002; Tweedle, 1988; Vittadini, 1988; Vogler, 1995). More than 95% of the contrast is recovered in urine within 24h after administration. Only small fractions are excreted with bile into the faeces, usually < 4% within 24h.

 

For the hepatobiliary GBCA gadobenate and gadoxetate, there is additional biliary excretion. Like the renal elimination, this is species-dependent, and is high for rats and rabbits. The administration of these CM is associated with a choleretic effect. About 30-35% is eliminated with bile into faeces for gadobenate (Lorusso, 1999; Vittadini, 1988), and 63-68% for gadoxetate (Schuhmann-Gampieri, 1997). Biliary excretion has a capacity-limiting step with increasing doses, and maximum excretion is about 5 µmol/min · kg.

 

Clearance of macrocyclic GBCA from the brain is a slow process, both for cerebrum and cerebellum. Half-lives for elimination were 1.8-2.0 weeks in the first 6 weeks, and 6.3-8.3 weeks thereafter, slightly slower in cerebellum than in cerebrum (Frenzel, 2021).

 

Results in Animal Studies – Renal and Hepatobiliary Insufficiency

 

Only few studies with hepatobiliary GBCA have been done in rats with combinations of reduced renal and biliary function. With reduced biliary elimination there will be an increased renal elimination and vice versa. Injection of bromosulfophthalein (BSP) or bile duct ligation can reduce biliary excretion of gadobenate to 1-5%, with concomitant increase in urinary excretion of 66-83% (De Haën, 1995). Renal artery or bile duct ligation reduced elimination half value times of gadoxetate, but significantly more after renal artery ligation. Between 1-3% of CM remained in the body in these animals (Mühler, 1994 and 1995).

 

Results in Human Studies – Normal Renal and Biliary Function

 

Pharmacokinetic analyses of extracellular GBCA in volunteers showed renal clearances matching the glomerular filtration rate. The reported excretion half-lives range from 1.3 to

1.8h. Steady state distribution volumes are in range of 180-250 ml/kg. Clearance from plasma is rapid with 75-85% of the CM cleared within 4h, and 94-98% cleared within 24h (Hao, 2019; Le Mignon, 1990; McLachlan, 1992; Staks, 1994; Tombach, 2002 Van Wagoner

1993, Weinmann, 1984).

 

For the hepatobiliary gadoxetate the terminal half-lives ranged from 1.0h for young to 1.8h for older volunteers, with a balanced renal and biliary excretion. The biliary excretion is only saturated for high doses, not used in clinical practice (Gschwend, 2011; Hamm, 1995; Schuhmann-Gampieri, 1992). Due to the lower biliary excretion, gadobenate has a profile that is more like the extracellular GBCA. The half-value times were 1.2h for clinically used doses with distribution volumes of 170-218 ml/kg (Spinazzi, 1999).

 

Results in Human Studies – Renal and Hepatobiliary Insufficiency

 

In patients with renal impairment the half-lives of the extracellular GBCA increase progressively. However, the summarized data are dependent on the study populations and settings and should be taken as a relative indication.

 

In patients with mild renal insufficiency (eGFR 60-90 ml/min/1.73m2) the half-life for the new GBCA gadopiclenol increased to 3.2h (Bradu, 2021). In moderate renal insufficiency (eGFR 30-60 ml/min/1.73m2) the increase in half-lives was between 3.8 and 6.9h, depending on the amount of renal impairment, with higher values for lower eGFR. This is equivalent with a factor of 2.5-3.5x that of volunteers with normal renal function. In severe renal insufficiency (eGFR < 30 ml/min/1.73m2), excluding dialysis, half-lives are between 9.5-30h, equivalent to 6-18x the value of volunteers with normal renal function (Bradu, 2021, Chachuat, 1992; Joffe, 1998; Schuhmann-Gampieri, 1991; Swan, 1999; Tombach, 2000 and 2001, Yoshikawa, 1997).

 

In the hepatobiliary GBCA, a combination of renal and hepatic impairment has been studied, as bile duct excretion is able to compensate for some renal function deterioration.

Moderate hepatic impairment did not change the plasma half-life, but severe hepatic impairment (like Child-Pugh C cirrhosis) led to slight increases of 2.6h for gadoxetate and

2.2h for gadobenate (Davies, 2002; Gschwend, 2011). For gadoxetate, moderate renal impairment could be compensated with a half-life of only 2.2h, but severe renal impairment led to a half-value time of 20h (Gschwend, 2011). In gadobenate moderate renal impairment increased the half-life to 5.6h and severe impairment to 9.2h. This is much more like the other extracellular GBCA (Swan, 1999).

 

Results in Systematic Reviews

 

Already in the late 1980s, biodistribution studies suggested that an open 3-compartment model may better fit the pharmacokinetic data of GBCA than the 2-compartment model. The first compartment is the plasma and the second and third compartments are the extravascular extracellular space of the tissues where there is an effective capillary permeability. The second and third compartments of the model are related to rapidly and slowly equilibrating tissues (storage compartment) (Wedeking, 1988 and 1990).

 

In a large systematic review of pharmacokinetic data, the 3-compartiment, open model better fitted the data, with 3 phases of GBCA decay from plasma. Apart from the distribution phase (a) and rapid (renal) elimination phase (b), there is a slow residual excretion phase (g). After IV administration of GBCA, plasma levels of gadolinium fall rapidly, indicating a short distribution phase with an average half-life of 0.2 ± 0.1 h. Then, levels will decrease slower as renal elimination prevails, with half-lives 1.7 ± 0.5 h when measured in plasma and 2.6 ± 0.6 h in urine (Lancelot, 2016).

 

The third phase of decay from the storage compartment can only be demonstrated in urine at a time when concentrations in plasma have become undetectable. Calculated rate constant g values are 0.107/h for gadoterate, and 0.012/h for gadobenate, and 0.029/h for gadoxetate. The half-life for this residual excretion phase is about 5-8 times longer for currently approved linear GBCA (approximately 25 h) compared to a macrocyclic GBCA (6 h), with risk of dechelation or transmetallation. This residual phase is species-independent and its rate constant g is closely related to the thermodynamic stability of the GBCA molecule. The relative contribution of this slow elimination is not insignificant, being 21-35% for linear GBCA vs. 10% for macrocyclic GBCA. The exact locations of this third compartment are not completely clear, but Gd retention/deposition can be found in the brain, spleen, liver, kidney, skin, and bones (Lancelot, 2016).

 

 

3. Combined Enhanced imaging with an ICM and a GBCA

In oncology diagnosis and follow-up, contrast-enhanced MRI examinations with GBCA and contrast-enhanced CT examinations with ICM are often combined, sometimes on the same day. The presence of ICM will influence the (results of) MRI examination and the presence of GBCA will influence the (results of) CT examination. The degree of these effects will determine the optimal order of examinations. The pharmacokinetics of both types of CM will dictate how waiting times between examinations should be scheduled.

 

Combining CT and MRI: Effects of GBCA on CT studies

 

Multiple in vitro studies have demonstrated the effect of GBCA in CT. At equal mass concentration, GBCA will have a higher CT attenuation than ICM due to the higher atomic number of Gadolinium (64) compared to iodine (53) (Bloem, 1989; Engelbrecht, 1996;

Gierada, 1999; Kim, 2003; Quinn, 1994; Schmitz, 1995; Schmitz, 1997; Zwicker, 1991).

 

Yet, in clinical practice the molar concentration used for ICM is much higher than for GBCA. For instance, iopromide 300 mgI/ml equals 2,94 mmol/ml, compared to GBCA with 0.5-1.0 mmol/ml. Excellent detailed phantom studies from Sweden focusing on equal attenuation have shown that in CT at 80-140kVp a solution of 0.5M GBCA is iso-attenuating to a solution of ICM with 91-116 mg I/mL for a chest phantom, and to 104- 125 mg I/mL for an abdominal phantom. Due to a different X-ray tube filtration, in DSA at 80-120 kVp a solution of 0.5M GBCA is iso-attenuating to 73-92 mg I/mL (Nyman, 2002 and 2011).

 

Many clinical studies have used GBCA for CT or angiography in renal insufficiency patients or in patients with (severe) hypersensitivity reactions to ICM. The GBCA injection frequently needs high doses of 0.3-0.5 mmol/kg for good vascular enhancement (Kaufman 1996), which is relatively short-lived. Such doses may be useful for vascular imaging or interventions but are usually not suitable for optimal imaging of the abdominal organs. Good overviews of the results can be found in multiple reviews (Spinosa, 2002; Strunk, 2004).

 

Nowadays, such high doses cannot be used anymore. Animal studies have shown that for equal attenuation, GBCA are more nephrotoxic and more costly than low-dose or diluted ICM (Elmsthål, 2006; Nyman, 2011). In addition to the risk of NSF and Gadolinium deposition, these are the major reasons that current ESUR guidelines strongly discourage the use of GBCA for radiographic examinations (Thomsen, 2002).

 

Due to the short-lived effect of GBCA injection in CT, this vascular enhancement is less cumbersome in clinical practice when combining contrast-enhanced CT and MRI examinations on the same day. One exception is that the kidneys will concentrate the gadolinium, so that the renal collecting systems, ureters, and bladder will show CT enhancement for a significant period.

 

Combining CT and MRI: Effects of ICM on MRI studies

 

In vitro experiments in MR Arthrography may serve as a model of these effects. Mixing of ICM with GBCA will lead to some shortening of the T1 (spin-lattice) relaxation time, and a more profound shortening of the T2 (spin-spin) relaxation time. This results in an increase in T1w signal and a decrease in T2w signal. The magnitude of the effect is greater for higher GBCA concentrations. The presence of ICM shifts the peak SI towards lower GBCA concentrations. Overall, in small joint spaces the enhancement was decreased (Andreisek, 2008; Choi, 2008; Ganguly, 2007; Kopka, 1994; Montgomery, 2002).

 

Similar effects can also be seen in routine MRI examinations, but to a lesser degree. The shortening effect on T1 and T2 times, with increase in T1w signal and a decrease in T2w signal, depends on the concentration of the ICM and on the side chains in the molecular structure of the specific ICM that is used (effect is for ioxithalamate > iotrolan > iopamidol > iodixanol, iohexol or iomeprol) (Hergan, 1995; Jinkins, 1992; Kopka, 1994; Morales, 2016). Very recently it was shown that adding an overdose of ICM to macrocyclic GBCA led to a significant increase in R1 relaxation and the combination was excreted more slowly, possibly because of the formation of chemical adducts between the lipophilic three-iodo-benzene rings of the ICM and the tetra-aza-cycle of the macrocyclic GBCA (DiGregorio, 2022). Increasing concentrations of ICM will also influence diffusion weighted imaging, with increased signal and decreased ADC values (Ogura, 2009), and on functional imaging with shortening of the T2* times used in BOLD MRI (Wang, 2014).

 

The effects of ICM in MRI can be longer-living and will be more disturbing on subsequent contrast-enhanced MRI.

For this chapter it was decided not to perform a systematic literature analysis, and therefore no search question with PICO was formulated.

 

Search and select (Methods)

The guideline authors decided to perform an explorative search. The explorative search was performed in the databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until April 13th, 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 441 hits.

Studies were selected based on the following criteria: any contrast medium (IBM, GBCA or other), study reported on pharmacokinetics or biodistribution parameters, and any study design (clinical, preclinical, in vitro etc.). The authors also added pharmacokinetics studies from their own database and articles found through cross-referencing.

 

No systematic literature analysis was performed. Instead, the authors made an overview of all available literature. A narrative literature analysis can be found below.

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  88. Wedeking P, Eaton S, Covell DG, Nair S, Tweedle MF, Eckelman WC. Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA)2- and 99mTc(DTPA) in rats. Magn Reson Imaging 1990; 8: 567-575.
  89. Weinmann HJ, Laniado M, Mützel W. Pharmacokinetics of GdDTPA/dimeglumine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 1984; 16: 167-172.
  90. Wilkins RA, Whittington JR, Brigden GS, Lahiri A, Heber ME, Hughes LO. Safety and pharmacokinetics of ioversol in healthy volunteers. Invest Radiol 1989; 24: 781-788.
  91. Yoshikawa K, Davies A. Safety of Prohance in special populations. Eur Radiol 1997; 7 (Suppl 5): S246-S250.
  92. Zwicker C, Langer M, Langer R, Keske U. Comparison of iodinated and noniodinated contrast media in computed tomography. Invest Radiol. 1991; 26 (Suppl 1): S162-S164; discussion S165-S166.

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 28-11-2022

Laatst geautoriseerd  : 28-11-2022

Geplande herbeoordeling  :

Validity

The Radiological Society of the Netherlands (NVvR) will determine around 2027 if this guideline (per module) is still valid and applicable. If necessary, the scientific societies will form a new guideline group to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be a reason to commence revisions. The Radiological Society of the Netherlands is the owner of this guideline and thus primarily responsible for the actuality of the guideline. Other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging voor Radiologie
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Maag-Darm-Leverartsen
  • Nederlandse Vereniging voor Cardiologie
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Neurologie
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Patiëntenfederatie Nederland
  • Nederlandse Vereniging voor Allergologie en Klinische Immunologie
  • Nederlandse Vereniging voor Endocrinologie
  • Nederlandse Vereniging voor Vaatchirurgie

Algemene gegevens

General Information

The Kennisinstituut van de Federatie Medisch Specialisten (www.kennisinstituut.nl) assisted the guideline development group. The guideline was financed by Stichting Kwaliteitsgelden Medisch Specialisten (SKMS) which is a quality fund for medical specialists in The Netherlands.

Samenstelling werkgroep

Guideline development group (GDG)

A multidisciplinary guideline development group (GDG) was formed for the development of the guideline in 2020. The GDG consisted of representatives from all relevant medical specialization fields which were using intravascular contrast administration in their field.

 

All GDG members have been officially delegated for participation in the GDG by their scientific societies. The GDG has developed a guideline in the period from June 2020 until November 2022. The GDG is responsible for the complete text of this guideline.

 

Guideline development group

  • Dekkers I.A. (Ilona), clinical epidemiologist and radiologist, Leiden University Medical Center, Leiden
  • Geenen R.W.F. (Remy), radiologist, Noordwest Ziekenhuisgroep, Alkmaar
  • Kerstens M.N. (Michiel), internist-endocrinologist, University Medical Centre Groningen
  • Krabbe J.G. (Hans), clinical chemist-endocrinologist, Medisch Spectrum Twente, Enschede
  • Rossius M.J.P. (Mariska), radiologist, Erasmus Medical Centre, Rotterdam
  • Uyttenboogaart M. (Maarten), neurologist and neuro-interventionalist, University Medical Centre Groningen
  • van de Luijtgaarden K.M. (Koen), vascular surgeon, Maasstad Ziekenhuis, Rotterdam
  • van der Molen A.J. (Aart), chair guideline development group, radiologist, Leiden University Medical Center, Leiden
  • van der Wolk S.L. (Sabine), gynaecologist-obstetrician, Haga Ziekenhuis, Den Haag
  • van de Ven A.A.J.M. (Annick), internist-allergologist-immunologist, University Medical Centre Groningen (until 1.7.2022)
  • van der Houwen, T.B. (Tim), internist-allergologist-immunologist, Amsterdam University Medical Center (from 1.7.2022)

Invited experts

  • van Maaren M.S. (Maurits), internist-allergologist-immunologist, Erasmus MC, Rotterdam

Belangenverklaringen

Conflicts of interest

The GDG members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that were related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested from the administrative office of Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl) and were summarised below.

 

Last name

Function

Other positions

Personal financial

interests

Personal relations

Reputation management

Externally financed

research

Knowledge valorisation

Other interests

Signed

Actions

Dekkers IA

Radiologist, LUMC

Clinical Epidemiologist

 

Member of contrast media safety committee, European Society of Urogenital Radiology (no payment)

 

Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no

payment)

No

No

No

No

No

Received consultancy fees from Guerbet, 2019-

2022

July 24th, 2020, Reaffirmed October 12th, 2022

No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention specific medication, not of working mechanism, nor of side effects.

Geenen RWF

Radiologist, Noordwest ziekenhuisgroep

/Medisch specialisten

Noordwest

Member of contrast media safety

committee, European

Society of Urogenital

Radiology (no payment)

No

No

No

No

No

No

April 11th, 2020, Reaffirmed October 12th,

2022

No restrictions

Houwen T, van der

Internist - Immunologist - Allergologist, Amsterdam UMC, also seconded allergologist in Huid Medisch

Centrum

None

None

None

None

None

None

None

July 11th, 2022 Reaffirmed October 12th, 2022

No restrictions

Kerstens MN

Internist- endocrinologist, UMCG

Chairman Bijniernet (no payment)

No

No

No

No

No

No

July 1st, 2020, reaffirmed October 25th,

2022

No restrictions

Krabbe JG

Clinical chemist, Medisch Spectrum Twente

No

No

No

No

No

No

No

September 1st, 2020,

Reaffirmed October 13th, 2022

No restrictions

Luijtgaarden KM, van de

Vascular surgeon, Maasland Ziekenhuis

No

No

No

No

No

No

No

August 1st, 2020,

reaffirmed October 26th, 2022

No restrictions

Molen AJ, van der

Radiologist LUMC

Member of contrast media safety committee, European Society of Urogenital Radiology (no

payment)

 

Member, Gadolinium Research and Education Committee, European Society of Magnetic Resonance in Medicine, and Biology (no

payment)

No

No

No

No

No

Received consultancy fees from Guerbet, 2019-

2022

July, 24th, 2020 Reaffirmed October 12th, 2022

No restrictions: received in part 3 of the guideline speaker fees, but this guideline does not mention

Specific medication, not

of working mechanism, nor of side effects.

Rossius MJP

Radiologist Erasmus Medical Centre

Medical coordinator (no payment)

No

No

No

No

No

No

April 7th, 2020, Reaffirmed October 13th,

2022

No restrictions

Uyttenboogaart M

Neurologist and neuro- interventionalist UMCG

Advisor International Federation of Orthopaedic Manipulative Physical Therapist / Nederlandse Vereniging Manuele Therapie

No

No

Subsidy Hart Stichting for CONTRAST

(Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology: financing of 2 PhD students by the Hart Stichting / PPS

Allowance

Work package leader CONTRAST

(Consortium of New Treatments in Acute Stroke): WP8 Stroke logistics and Epidemiology

No

No

June 30th, 2020, reaffirmed October 26th, 2022

No restrictions: the CONTRAST

consortium wp8 is only about organisation and treatment of stroke.

Stroke is not in this guideline.

Ven AAJM, van de

Internist- allergologist- immunologist, UMCG

Education and research related to work as internist-

allergist

No

No

No

No

No

No

April 7th, 2020, Reaffirmed October 19th, 2022

No restrictions

Wolk S, van der

Gynaecologist- obstetrician, Haga Ziekenhuis

No

No

No

No

No

No

No

June 30th, 2021, reaffirmed October 25th,

2022

No restrictions

Inbreng patiëntenperspectief

Input of patient’s perspective

The guideline does not address a specific adult patient group, but a diverse set of diagnoses. Therefore, it was decided to invite a broad spectrum of patient organisations for the stakeholder consultation. The stakeholder consultation was performed at the beginning of the process for feedbacking on the framework of subjects and clinical questions addressed in the guideline, and during the commentary phase to provide feedback on the concept guideline. The list of organisations which were invited for the stakeholder consultation can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). In addition, patient information on safe use of contrast media in pregnancy and lactation was developed for Thuisarts.nl, a platform to inform patients about health and disease.

Implementatie

Implementation

During different phases of guideline development, implementation and practical enforceability of the guideline were considered. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found in the ‘Appendices to modules’. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found in the ‘Appendices to modules’.

Werkwijze

Methodology

AGREE

This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0 by the advisory committee of the Quality Counsel (www.kwaliteitskoepel.nl). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreetrust.org), a broadly accepted instrument in the international community and based on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).

 

Identification of subject matter

During the initial phase of the guideline development, the GDG identified the relevant subject matter for the guideline. The framework is consisted of both new matters, which were not yet addressed in part 1 and 2 of the guideline, and an update of matters that were subject to modification (for example in case of new published literature). Furthermore, a stakeholder consultation was performed, where input on the framework was requested.

 

Clinical questions and outcomes

The outcome of the stakeholder consultation was discussed with the GDG, after which definitive clinical questions were formulated. Subsequently, the GDG formulated relevant outcome measures (both beneficial and harmful effects). The GDG rated the outcome measures as critical, important and of limited importance (GRADE method). Furthermore, where applicable, the GDG defined relevant clinical differences.

 

Search and select

For clinical questions, specific search strategies were formulated, and scientific articles published in several electronic databases were searched. First, the studies that potentially had the highest quality of research were reviewed. The GDG selected literature in pairs (independently of each other) based on the title and abstract. A second selection was performed by the methodological advisor based on full text. The databases used, selection criteria and number of included articles can be found in the modules, the search strategy in the appendix.

 

Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search. For systematic reviews, a combination of the AMSTAR checklist and PRISMA checklist was used. For RCTs the Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University were used, and for cohort studies/observational studies the risk of bias tool by the CLARITY Group at McMaster University was used. The risk of bias tables can be found in the separate document Appendices to modules.

 

Summary of literature

The relevant research findings of all selected articles were shown in evidence tables. The evidence tables can be found in the separate document Appendices to modules. The most important findings in literature were described in literature summaries. When there were enough similarities between studies, the study data were pooled.

 

Grading quality of evidence and strength of recommendations

The strength of the conclusions of the included studies was determined using the GRADE- method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org) (Atkins, 2004). GRADE defines four levels for the quality of scientific evidence: high, moderate, low, or very low. These levels provide information about the certainty level of the literature conclusions (http://www.guidelinedevelopment.org/handbook).

 

The evidence was summarized in the literature analysis, followed by one or more conclusions, drawn from the body of evidence. The level of evidence for the conclusions can be found above the conclusions. Aspects such as expertise of GDG members, local expertise, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects are discussed in the paragraph justifications. The recommendations provide an answer to the clinical question or help to increase awareness and were based on the available scientific evidence and the most relevant justifications.

 

Appendices

Internal (meant for use by scientific society or its members) quality indicators were developed with the guideline and can be found in the separate document Appendices to modules. In most cases, indicators were not applicable. For most questions, additional scientific research on the subject is warranted. Therefore, the GDG formulated knowledge gaps to aid in future research, which can be found in the separate document Appendices to modules.

 

Commentary and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The list of parties that participated in the commentary phase can be requested from the Kennisinstituut van de Federatie Medisch Specialisten (secretariaat@kennisinstituut.nl). The commentaries were collected and discussed with the GDG. The feedback was used to improve the guideline; afterwards the GDG made the guideline definitive. The final version of the guideline was offered to the involved scientific societies for authorization and was authorized.

 

Literature

Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010; 182(18): E839-E842.

Medisch Specialistische Richtlijnen 2.0. Adviescommissie Richtlijnen van de Raad Kwaliteit, 2012. Available at: [URL].

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available at: [URL].

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106- 1110. Erratum published in: BMJ 2008;336(7654).

Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten, 2020.

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Andere veiligheidsmaatregelen