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Metformin and contrast media — A dangerous combination?
Clinical
Radiology
(1999)54, 29-33
Metformin
and Contrast Media - A Dangerous Combination?
M. M. MCCARTNEY,
F. J. GILBERT, L. E. MURCHISON, K. McHARDY, A. D. MURRAY
D. PEARSON,
Department of Radiology, University of Aberdeen, and the Diabetology Department, Aberdeen Royal Hospitals NHS Trust, Aberdeen, Scotland, UK Received: 29 April 1998 Revised: 23 June 1998 Accepted: 5 August 1998 Metformin is a biguanide used to treat type II diabetes mellitus. Since the recent introduction of this drug into the United States there has been considerable interest in metformin associated lactic acidosis (MALA) following intravenous contrast media. The Royal College of Radiologists published advice in November, 1996 (Advice to Members and Fellows with regard to metformin-induced lactic acidosis and X-ray contrast medium agents, RCR Prcblication) supporting the manufacturers’ advice that metformin should not be used in the 48 h before or after intravenous (i.v.) contrast medium. We performed a systematic review of the literature and this has shown that almost all reported cases of MALA following i.v. contrast medium occurred where there was either pre-existing poor renal function or another contraindication to metformin usage. There has been only one reported case of lactic acidosis following the use of intravenous contrast medium in a patient with normal renal function. We suggest that the Royal College of Radiologists’ advice should be modified and that it is safe to give i.v. contrast medium to patients on metformin with normal renal function. McCartney, M. M.
et al., (1999) Clinical Radiology 54, 29-33. Key words:
contrast media, metformin, lactic acidosis,diabetes.
Metformin is a biguanide used to treat type II diabetes mellitus. It was first introduced in the 1950s along with phenformin and buformin. Phenformin was the most widely used initially and then withdrawn in 1977 due to the frequency of lactic acidosis. In the late 1980s metformin began to be widely used again and is now the most common medication used to treat type II diabetes [ 1,2]. The precise mechanism of action is unknown [l]. Muscle is thought to be the main site of action [3]. There appears to be a change in glucose utilization with an improvement in insulin sensitivity [ 1,3,4]. Gluconeogenesis is inhibited in the liver with a rise in the precursor lactate and it has been shown that lactate levels rise during treatment with metformin, but still lie within the normal range [ 1,3]. As a result, treatment will result in a lower fasting blood glucose, but hypoglycemia will not occur. The plasma half life of metformin is estimated at 1.5-5 h, with at least 90% being excreted in the urine unchanged [ 11. Since the introduction of the biguanides, there have been over 400 reports of associated lactic acidosis [4]. Specifically metformin associated lactic acidosis (MALA) has been reported over 120 times with a mortality of 50% [4]. The relative incidence of MALA is 0.03 per 1000 patient years [3]. In the reported cases there are usually existing contraindications to the prescribing of metformin. The contraindications to metformin are listed in Table 1 [ 1,3,5,6]. The release of metformin into the United States has highlighted the potential problem of intravascular iodinated contrast media usage in patients on metformin. The US manufacturer, 0009-9260/99/010029+05 $12.00/O
Myers Squibb, has stated that metformin should not be used in the 48 h before and after the use of contrast medium and only after normal renal function has been established. In the UK, Lipha Pharmaceuticals has stated that metformin should be withheld for 48 h before the use of contrast medium and reinstituted only when renal function has been found to be normal. The Royal College of kadiologists published advice in November, 1996 [7] stating that metformin should be stopped 48 h before and after the use of contrast medium, although there is an additional statement qualifying that it may be enough to stop metformin 48 h after contrast medium [8]. It is also stated that emergency procedures can be carried out with no delay, but the clinician and local nephrologists should be consulted. In order to implement the advice locally in our institution, a meeting was held with the local radiologists and diabetologists. Table
1 - Contraindications
to metformin
Hypersensitivity to metformin Diabeticcomaandketoacidosis Impairedrenalfunction,evenmild Chronicliverdisease Cardiacfailure Recentmyocardialinfarction Shockor severesystemicdisease Pulmonaryinsufficiency B 12 deficiency 0 1999The RoyalCollegeof Radiologists
30 Table
CLINICAL 2 - Reports
of lactic
Report
1. Hayat,
1974 [9]
et al.,
2. Assan
et aZ.,
3. Assan
et al.,
4. Assan
5. Prinseau
1977 [lo]
1977 [lo]
1977 [lo]
et al. 1977 [ 111
acidosis
after
the use of contrast
RADIOLOGY
medium
Patient
Renal function
Radiology procedure
Outcome
Contraindications to metformin?
First sign
74, male
Clearance 30 ml/mm
IVU
Dialysis Recovery
Yes - renal function Stopped immediately
Oliguria, 24 h
49, male
Creatinine 178 umolA
IVU
Dialysis Recovery
Yes Metformin 48 h
continued
Anuria, 24 h
Creatinine 320 umol/l
IVU
Dialysis Fluid Expansion Death
Yes Metformin 120 h
continued
Anuria, 24 h
178 umolll creatinine
Aortography
Dialysis Fluid Expansion Died MI 4 weeks later
Yes Metformin
continued
Anuria, hours
IVU
Dialysis Recovery
Probable
48 h
52, male
67, female
66, female
only given
Urea 13.3 mmol/l supplied
only
6. Prinseau
et al.,
1977 [ll]
74, male
Creatinine 178 umol/l
IVU
Dialysis Recovery
Yes
24 h
7. Prinseau
et al.,
1977 [ll]
59, male
Creatinine 151 umol/l
IVU
Died
Yes
72 h (earlier
Yes Metformin
72 h
et al.,
8. Jamet
9. Oksenhendler [I31
1980 [12]
66, female
Creatinine 140 umol/l
IVU
Hypotension Death
et al.,
68, female
Creatinine 220 umol/l
IVU
Dialysis Death
Yes - renal function
Anuria, 3h
1983
continued
10. Westberg
1985 [14]
72, female
Creatinine 205 umol/l
Angiography
Death
Yes - renal function
Unknown
11. Westberg
1985 [14]
75, female
Creatinine 157 umol/l
Angiography
Death
Yes - renal function
Unknown
12. Westberg
1985 [14]
71, male
Creatinine 115 umovl
CT with contrast
Recovery
No
Unknown 24 h
13. Lalau
et al.,
1987 [15]
48, male 5.1 g/day (excessive)
Unknown Concomitant Sepsis and gentamycin
IVU
Dialysis Recovery
Probable
14. Lalau
et al.,
1989 [15]
80, female 2.55 g/day
‘normal’ disease
Carotid Angiography
Dialysis Recovery
Probable Neurological
neurological
Disease
Anuria, hours
15. Lalau
et al.,
1989 [16]
62, male
‘normal’
Tomodensimetric scan
Dialysis Death
Yes - cirrhosis
Unknown
16. Lalau
et al.,
1995 [17]
69, female
Creatinine 199 umol/l
Arteriography
Dialysis Recovered
Yes - Renal function Metformin continued 4 days
Rapid
17. Safadi
et aZ.,
1996 [18]
68, female
‘mild chronic renal failure’
Arteriography
Recovered
Yes
Unknown
68, male
943 umolll
CT with contrast
Dialysis
Yes - Renal function
Unknown
18. Zandijike u91
et al., 1997
It was agreed to conduct an independent systematic review of the literature to determine the strength of the evidence on which the advice was based. METHOD
A comprehensive search strategy to identify reports of intravenous contrast related MALA was undertaken.
signs)
(1) A computerized search was performed using Medline. The keywords used were: ‘lactic acidosis’, ‘intravenous contrast’, ‘renal failure’, ‘metformin’, ‘biguanides’. These were run in pairs, using ‘and’ ligands. (2) Biblographies of the RCR paper and of relevant papers identified by other reference search strategies were interrogated. (3) Drug Information Services were contacted for adverse
METFORMIN
AND
effect profiles and reports under the National ‘yellow card’ system in the UK, and the FDA were contacted in the USA. (4) Myers Squibb and Lipha Pharmaceuticals were contacted for additional reports of adverse effects. (5) Authors of published reports were contacted for unpublished data, i.e., in cases where lactic acidosis occurred with contrast media and renal function was not published.
RESULTS
Initially over 140 references were generated using Medline. Abstracts were assessedfor reports of MALA and any possible association with intravenous iodinated contrast media. All possible reports were ordered and references from these again assessedfor further possible cases.As contrast media may not have been considered at the time to have caused the lactic acidosis, a particular searchwas therefore made for reference to radiological investigations, which may have involved contrast media prior to the presentation of lactic acidosis. The ‘Yellow Card’ scheme in this country had no other cases reported. Authors of published cases sometimes had personal communications of similar incidences. The information gathered has been tabulated (Table 2). A total of 18 cases of MALA after use of contrast media in patients on metformin have been found. In 17 cases, renal dysfunction was known to be present before the administration of contrast medium. Although the diagnosis of lactic acidosis may not have been made for up to 3 days, signs, mainly anuria, were present within 24 h in the majority of cases. These cases had all drawn medical attention early due to the severity of the illness.
DISCUSSION
At least 16 and probably 17 out of the 18 patients (94%) had contraindications to metformin prior to the administration of contrast medium. These were mainly renal dysfunction, i.e. a creatinine above the normal range, but occasionally intercurrent illness or hepatic dysfunction. These are usually the circumstances which should prompt a clinician to change a patient from a biguanide to a different class of drug due to the risk of MALA (without i.v. contrast media). Serum biochemistry should be measured regularly in metformin users and the drug stopped should renal or hepatic impairment occur (Table 1). A patient presenting as an emergency, for example with sepsis, requiring radiological investigation with the use of intravenous contrast medium would still be able to proceed under the College’s advice. However, the sepsis itself would contraindicate metformin use until medical stabilization occurred. Contrast medium would be given and the metformin restarted when the patient had recovered and renal function returned to normal. It is therefore the prescribing of metformin, not the contrast medium, which is the primary concern, and many diabetologists would use insulin temporarily during an acute illness. Contrast media induced nephrotoxicity (CMN) refers to a condition in which an impairment in renal function (an increase
CONTRAST
MEDIA
31
in serum creatinine by more than 25% or 44 umol/l) occurs within 3 days following intravascular administration of contrast media [21]. It occurs in O-10% of people with normal renal function and in 12-27% if there is pre-existing renal impairment [21]. CMN is dose dependent and is more common following intra-arterial injection than intravenous administration. It is the development of CMN which can result in delayed excretion of metformin and so increase the risk of MALA. However, the chances of contrast medium being associated with lactic acidosis are extremely rare, with only one ‘or possibly two reported cases (cases number 12 and 14 in Table 2) if the guidance for metformin usage is followed and . the contraindications heeded. A modified algorithm is suggested (Table 1). We suggest-that patients on metformin can be given intravenous contrast medium provided the renal function is known to be normal. In patients whose renal function is abnormal or is not known, the metformin should be stopped for 48 h before and after the examination with contrast medium. The creatinine level should be checked prior to resumption of metformin and this drug should only be continued provided the patient has normal renal function. The clinician and diabetologist responsible for the patient should be informed if the patient has abnormal renal function as the prescription of metformin may be inappropriate. The concurrent use of non-steroidal anti-inflammatory drugs or aminoglycosides potentiates the nephrotoxic effects of contrast medium. Therefore in patients on metformin and either of the aforementioned drugs particular attention should be paid to renal function and consideration to withholding metformin for 48 h after contrast medium usage [21]. Old age (over 60 years) also carries increased risk for CMN because of decreased renal function and perfusion and similar consideration should be given to renal function after contrast usage. The St Vincent’s declaration recommends that renal function should be checked annually in patients with diabetes. It is not known for how long normal renal function can be assumed to be normal. The clinician making the request for a radiological procedure involving intravenous contrast should take responsibility for renal function, either by checking the serum creatinine or accepting a normal level within the past year. Patients who have abnormal renal function should not be given intravenous contrast media until the metformin has been stopped for 48 h. The metformin should not be restarted by the clinician until the renal function has returned to normal. In an emergency situation the College’s advice should be adhered to and intravenous contrast administered with metformin stopped at the time of the procedure and restarted at the clinician’s discretion. As intravenous contrast medium is likely to adversely affect renal function for 24-48 h after administration, it is prudent to withhold metformin usage for at least 48 h. Searching for reported rare adverse drug reactions has many difficulties [22]. The methodology for searching for large trials is well established [23]. This is not particularly useful when searching for case reports or rare drug reactions. Publication may not have been made and adverse reports are not always filed. The aetiology of the use of contrast medium in the evolution of lactic acidosis may not have been recognized and may not have been reported on at all, or not in the key word section. Therefore, in this study all potential abstracts and
32
CLINICAL
RADIOLOGY
EMERGENCY RADIOLOGICAL EXAMINATION
ROUTINE RADIOLOGICAL EXAMINATION 1 Recent satisfactory renal function results
1 *Should metformin be stopped due to intercurrent illness or abnormal renal function? /
A normal
unavailable
abnormal
yes
no
4
either
li
ensure creatinine normal
advise stop metformin until safe to restart
proceed with contrast medium administration
proceed with contrast medium as appropriate for renal dysfunction
continue metformin as prescribed
+ proceed as per RCR guidelines
1
stop metformin 24-48 hrs before and after contrast medium administration
/... proceed with contrast medium administration proceed with contrast medium as appropriate for renal dysfunction
continue metformin prescribed
as
f clinician recommended to review metformin prescription
clinician recommended to review metformin prescription
* see Table 1 for contraindications Fig. 1 - Suggested algorithm for use of contrast media in patients on metformin. papers were searched for mention of radiological examinations that had been performed. A degree of misfiling is present on all electronic data searches, estimated at greater than 50% [23] and subsequently reports can be lost. The authors who were contacted kindly helped with information of further cases known to themselves, or to their colleagues. We conclude that the risk of lactic acidosis with intravenous iodinated contrast in patients who are correctly prescribed metformin is so low as to be negligible. We believe that the
Royal College of Radiologists’s advice should be modified to emphasize that in patients who are correctly prescribed metformin, i.e., with normal renal function, metformin does not require to be stopped prior to or after the administration of intravenous contrast medium. It is important that the requesting clinician should state that the patient is on metformin and has normal renal function thus allowing the radiologist to proceed with the administration of contrast. In the emergency situation the intravenous contrast medium should be administered but
METPORMIN
AND CONTRAST
metformin should be stopped and restarted by the clinician when appropriate.
Acknowledgements. We would like to thank Professor PD Lalau, Associate Professor, Service d’Endocrinologie - Nutrition Hospital Sud, Cedex 1, France, Professor G Westberg, University of Gotebeg, Sweden, and Professor A Dachman, University of Chicago, USA, for their help with this study.
REFERENCES 1 Hermann LF, Melander A. Biguanides: Basic Actions and Clinical Uses. In: Alberti KGMM, Zimmet P, DeFronzo RA, et al., eds. International Textbook of Diabetes Mellitus, 2nd ed. Chichester: John Wiley and Sons, 1997:841-864. 2 Monson JP. Metformin and lactic acidosis, Prescribers Journal 1993;33:170-173. 3 Bailey CT, Turner RC. Metformin. New England Journal of Medicine 1996;334:575-579. 4 Sirtori CR, Pasik C. Reevaluation of a biguanide metformin: Mechan ism of action and tolerability. Pharmacological Research 1994;30: 187-228. 5 Association of British Pharmaceutical Industry Compendium of Data Sheets, 1998:664-665. 6 Data Sheet, Metformin Hydrochloride. Bristol Myers Squibb, London 1997. 7 Royal College of Radiologists: Advice to Members and Fellows with regard to Metformin-Induced Lactic Acidosis and X-Ray Contrast Medium Agents. RCR Publication, November 1996. 8 Rasuli P, French G, Hammond DI. New contraindication to intravenous contrast material. Letter. Radiology 1996;201:289-290. 9 Hayat JC. The treatment of lactic acidosis in the diabetic patient by Petitoneal Dialysis Using Sodium Acetate. A Report of Two Cases. Diabetologica 1974;10:485-487. 10 Assan R, Heuelin Ch, Ganeval D, et al. Metformin induced Lactic Acidosis in the presence of Acute Renal Failure. Diabetologia 1977;13:211-217. 11 Prinseau .I: Jardin F, Sanchez A, et al. Acute renal failure after intravenous urography in diabetics. Incidence of lactic acidosis in metformin treatment. Annales de Medecine Interne. 1977;128:173177. 12 Jamet P, Lebas de Lacour B, Christoforov B, et al. Acidose lactique mortelle apres urographie intra-veineuse chez une diabetique recevant de la metformine. Semaine des Hopitaux 1980;56:473-474. 13 Oksenhendler G, Petit J, Choisnet N, et al. Apropos d’un cas d’acidose lactique apres urographie intraveinuse chez une diabetique insuffisante renale traitee par la metformine. Annales Francais Anestesiques 1983;2:249. 14 Westberg G. Discontinue metformin before contrast X-ray examination. Lakartidningen (Journal of the Swedish Medical Association) 1995;92:2520. 15 Lalau JD, Westeel PF, Debussche X, et al. Bicarbonate haemodialysis:
16
17
18
19 20 21 22 23 24
25 26 27 28 29
30 31 32 33
34 35
36 37
MEDIA
33
an adequate treatment for lactic acidosis caused by metformin. Intensive Care Medicine 1987;13:383-387. Lalau JD, Andrejak M, Moriniere Ph, et al. Haemodialysis in the treatment of diabetics treated by metformin: a study of metformin elimination. International Journal of Clinical Pharmacology 1989;6: 285-288. Lalau JD, Lacroix C, Compagnon P, et al. Role of Metformin Accumulation in Metformin associated lactic acidosis. Diabetes Cure 1995;18:779-784. Safadi R, Dranitzki-Elahal M, Popovtzer M, et al. Metformin induced lactic acidosis associated with acute renal failure. American Journal of Nephrology 1996;16:520-522. Zandijike, Demey HE, Bossaert LL. Metformin induced lactic acidosis. Tijdshr. voor Geeskunde 1991;3:543-546. Diabetic Guidelines, St Vincent Guidelines, World Health Organisation, 1992. Morcos SK. Contrast media induced nephrotoxicity, questions and answers. The British Journal of Radiology 1998;71:357-365. Edwards IR. Editorial: Adverse drug reactions: finding the needle in the haystack. British Medical Journal 1997;315:500. Chalmers I, Altman D. Systematic Reviews. 1st ed. London: BMJ Publishing Group 1995. Lebon P, Beau J, Jacobs C, et al. Insuffisance renale aigue apres urographie intravenouse chez le diabetique. Annales Medicine Interne, 1976;127:712-717. Dawson P, Trewhella M. Opinion. Intravascular Contrast Agents and Renal Failure. Clinical Radiology 1990;41:373-375. Lucis OJ. The status of Metformin in Canada. Canadian Medical Association Journal 1983;128:24-26. Pon GD, Smyth SH, Roach DJ et al. Metformin and Contrast Media: Genuine Risk or Witch Hunt? Letter. Radiology 1996;201:879. Rotter A. New contraindication to intravenous contrast material. Letter. Radiology 1995;197:545-546. Nugent RA, Flak B. Contrast enhanced imaging studies contraindicated in patients receiving metformin. Letter. Canadian Association ofRadiologists Journal 1996;4:225. Pearlman BL, Fenres AZ, Emmett M. Metformin induced lactic acidosis. American Journal ofMedicine 1996;101:109-110. Dawson P. The non-ionic isotonic contrast agents. European Radiology, Supplement 2, 1996;6:20-24. Dachman AH. New contraindication to intravenous contrast material. Letter. Radiology 1995;197:545. Ellis JS, Cohan RH, Sonnad S, et al. Selective use of Radiographic Low-Osmolality Contrast Media in the 1990s. Radiology 1996;200: 297-311. Homsby VPL. Intravascular Injection of Iodinated Contrast Media. Clinical Radiology 1996;51:820. Broom J, Ross IS, Whiting PH. Lactic Acidosis due to Metformin Therapy in a low risk patient. Postgraduate Medical Journal 1989; 65:57. Tymms DJ, Letherdale BA. Lactic Acidosis due to Metfonnin Therapy in a low risk patient. Postgraduate Medical Journal 1988;64:230-231. Nawaz S, Cleveland P, Gaines PA, et al. Clinical Risk Associated with Contrast Angiography in Metformin treated Patients: A Clinical Review. Clinical Radiology 1998;53:342-344.
Radiology
(1999)54, 29-33
Metformin
and Contrast Media - A Dangerous Combination?
M. M. MCCARTNEY,
F. J. GILBERT, L. E. MURCHISON, K. McHARDY, A. D. MURRAY
D. PEARSON,
Department of Radiology, University of Aberdeen, and the Diabetology Department, Aberdeen Royal Hospitals NHS Trust, Aberdeen, Scotland, UK Received: 29 April 1998 Revised: 23 June 1998 Accepted: 5 August 1998 Metformin is a biguanide used to treat type II diabetes mellitus. Since the recent introduction of this drug into the United States there has been considerable interest in metformin associated lactic acidosis (MALA) following intravenous contrast media. The Royal College of Radiologists published advice in November, 1996 (Advice to Members and Fellows with regard to metformin-induced lactic acidosis and X-ray contrast medium agents, RCR Prcblication) supporting the manufacturers’ advice that metformin should not be used in the 48 h before or after intravenous (i.v.) contrast medium. We performed a systematic review of the literature and this has shown that almost all reported cases of MALA following i.v. contrast medium occurred where there was either pre-existing poor renal function or another contraindication to metformin usage. There has been only one reported case of lactic acidosis following the use of intravenous contrast medium in a patient with normal renal function. We suggest that the Royal College of Radiologists’ advice should be modified and that it is safe to give i.v. contrast medium to patients on metformin with normal renal function. McCartney, M. M.
et al., (1999) Clinical Radiology 54, 29-33. Key words:
contrast media, metformin, lactic acidosis,diabetes.
Metformin is a biguanide used to treat type II diabetes mellitus. It was first introduced in the 1950s along with phenformin and buformin. Phenformin was the most widely used initially and then withdrawn in 1977 due to the frequency of lactic acidosis. In the late 1980s metformin began to be widely used again and is now the most common medication used to treat type II diabetes [ 1,2]. The precise mechanism of action is unknown [l]. Muscle is thought to be the main site of action [3]. There appears to be a change in glucose utilization with an improvement in insulin sensitivity [ 1,3,4]. Gluconeogenesis is inhibited in the liver with a rise in the precursor lactate and it has been shown that lactate levels rise during treatment with metformin, but still lie within the normal range [ 1,3]. As a result, treatment will result in a lower fasting blood glucose, but hypoglycemia will not occur. The plasma half life of metformin is estimated at 1.5-5 h, with at least 90% being excreted in the urine unchanged [ 11. Since the introduction of the biguanides, there have been over 400 reports of associated lactic acidosis [4]. Specifically metformin associated lactic acidosis (MALA) has been reported over 120 times with a mortality of 50% [4]. The relative incidence of MALA is 0.03 per 1000 patient years [3]. In the reported cases there are usually existing contraindications to the prescribing of metformin. The contraindications to metformin are listed in Table 1 [ 1,3,5,6]. The release of metformin into the United States has highlighted the potential problem of intravascular iodinated contrast media usage in patients on metformin. The US manufacturer, 0009-9260/99/010029+05 $12.00/O
Myers Squibb, has stated that metformin should not be used in the 48 h before and after the use of contrast medium and only after normal renal function has been established. In the UK, Lipha Pharmaceuticals has stated that metformin should be withheld for 48 h before the use of contrast medium and reinstituted only when renal function has been found to be normal. The Royal College of kadiologists published advice in November, 1996 [7] stating that metformin should be stopped 48 h before and after the use of contrast medium, although there is an additional statement qualifying that it may be enough to stop metformin 48 h after contrast medium [8]. It is also stated that emergency procedures can be carried out with no delay, but the clinician and local nephrologists should be consulted. In order to implement the advice locally in our institution, a meeting was held with the local radiologists and diabetologists. Table
1 - Contraindications
to metformin
Hypersensitivity to metformin Diabeticcomaandketoacidosis Impairedrenalfunction,evenmild Chronicliverdisease Cardiacfailure Recentmyocardialinfarction Shockor severesystemicdisease Pulmonaryinsufficiency B 12 deficiency 0 1999The RoyalCollegeof Radiologists
30 Table
CLINICAL 2 - Reports
of lactic
Report
1. Hayat,
1974 [9]
et al.,
2. Assan
et aZ.,
3. Assan
et al.,
4. Assan
5. Prinseau
1977 [lo]
1977 [lo]
1977 [lo]
et al. 1977 [ 111
acidosis
after
the use of contrast
RADIOLOGY
medium
Patient
Renal function
Radiology procedure
Outcome
Contraindications to metformin?
First sign
74, male
Clearance 30 ml/mm
IVU
Dialysis Recovery
Yes - renal function Stopped immediately
Oliguria, 24 h
49, male
Creatinine 178 umolA
IVU
Dialysis Recovery
Yes Metformin 48 h
continued
Anuria, 24 h
Creatinine 320 umol/l
IVU
Dialysis Fluid Expansion Death
Yes Metformin 120 h
continued
Anuria, 24 h
178 umolll creatinine
Aortography
Dialysis Fluid Expansion Died MI 4 weeks later
Yes Metformin
continued
Anuria, hours
IVU
Dialysis Recovery
Probable
48 h
52, male
67, female
66, female
only given
Urea 13.3 mmol/l supplied
only
6. Prinseau
et al.,
1977 [ll]
74, male
Creatinine 178 umol/l
IVU
Dialysis Recovery
Yes
24 h
7. Prinseau
et al.,
1977 [ll]
59, male
Creatinine 151 umol/l
IVU
Died
Yes
72 h (earlier
Yes Metformin
72 h
et al.,
8. Jamet
9. Oksenhendler [I31
1980 [12]
66, female
Creatinine 140 umol/l
IVU
Hypotension Death
et al.,
68, female
Creatinine 220 umol/l
IVU
Dialysis Death
Yes - renal function
Anuria, 3h
1983
continued
10. Westberg
1985 [14]
72, female
Creatinine 205 umol/l
Angiography
Death
Yes - renal function
Unknown
11. Westberg
1985 [14]
75, female
Creatinine 157 umol/l
Angiography
Death
Yes - renal function
Unknown
12. Westberg
1985 [14]
71, male
Creatinine 115 umovl
CT with contrast
Recovery
No
Unknown 24 h
13. Lalau
et al.,
1987 [15]
48, male 5.1 g/day (excessive)
Unknown Concomitant Sepsis and gentamycin
IVU
Dialysis Recovery
Probable
14. Lalau
et al.,
1989 [15]
80, female 2.55 g/day
‘normal’ disease
Carotid Angiography
Dialysis Recovery
Probable Neurological
neurological
Disease
Anuria, hours
15. Lalau
et al.,
1989 [16]
62, male
‘normal’
Tomodensimetric scan
Dialysis Death
Yes - cirrhosis
Unknown
16. Lalau
et al.,
1995 [17]
69, female
Creatinine 199 umol/l
Arteriography
Dialysis Recovered
Yes - Renal function Metformin continued 4 days
Rapid
17. Safadi
et aZ.,
1996 [18]
68, female
‘mild chronic renal failure’
Arteriography
Recovered
Yes
Unknown
68, male
943 umolll
CT with contrast
Dialysis
Yes - Renal function
Unknown
18. Zandijike u91
et al., 1997
It was agreed to conduct an independent systematic review of the literature to determine the strength of the evidence on which the advice was based. METHOD
A comprehensive search strategy to identify reports of intravenous contrast related MALA was undertaken.
signs)
(1) A computerized search was performed using Medline. The keywords used were: ‘lactic acidosis’, ‘intravenous contrast’, ‘renal failure’, ‘metformin’, ‘biguanides’. These were run in pairs, using ‘and’ ligands. (2) Biblographies of the RCR paper and of relevant papers identified by other reference search strategies were interrogated. (3) Drug Information Services were contacted for adverse
METFORMIN
AND
effect profiles and reports under the National ‘yellow card’ system in the UK, and the FDA were contacted in the USA. (4) Myers Squibb and Lipha Pharmaceuticals were contacted for additional reports of adverse effects. (5) Authors of published reports were contacted for unpublished data, i.e., in cases where lactic acidosis occurred with contrast media and renal function was not published.
RESULTS
Initially over 140 references were generated using Medline. Abstracts were assessedfor reports of MALA and any possible association with intravenous iodinated contrast media. All possible reports were ordered and references from these again assessedfor further possible cases.As contrast media may not have been considered at the time to have caused the lactic acidosis, a particular searchwas therefore made for reference to radiological investigations, which may have involved contrast media prior to the presentation of lactic acidosis. The ‘Yellow Card’ scheme in this country had no other cases reported. Authors of published cases sometimes had personal communications of similar incidences. The information gathered has been tabulated (Table 2). A total of 18 cases of MALA after use of contrast media in patients on metformin have been found. In 17 cases, renal dysfunction was known to be present before the administration of contrast medium. Although the diagnosis of lactic acidosis may not have been made for up to 3 days, signs, mainly anuria, were present within 24 h in the majority of cases. These cases had all drawn medical attention early due to the severity of the illness.
DISCUSSION
At least 16 and probably 17 out of the 18 patients (94%) had contraindications to metformin prior to the administration of contrast medium. These were mainly renal dysfunction, i.e. a creatinine above the normal range, but occasionally intercurrent illness or hepatic dysfunction. These are usually the circumstances which should prompt a clinician to change a patient from a biguanide to a different class of drug due to the risk of MALA (without i.v. contrast media). Serum biochemistry should be measured regularly in metformin users and the drug stopped should renal or hepatic impairment occur (Table 1). A patient presenting as an emergency, for example with sepsis, requiring radiological investigation with the use of intravenous contrast medium would still be able to proceed under the College’s advice. However, the sepsis itself would contraindicate metformin use until medical stabilization occurred. Contrast medium would be given and the metformin restarted when the patient had recovered and renal function returned to normal. It is therefore the prescribing of metformin, not the contrast medium, which is the primary concern, and many diabetologists would use insulin temporarily during an acute illness. Contrast media induced nephrotoxicity (CMN) refers to a condition in which an impairment in renal function (an increase
CONTRAST
MEDIA
31
in serum creatinine by more than 25% or 44 umol/l) occurs within 3 days following intravascular administration of contrast media [21]. It occurs in O-10% of people with normal renal function and in 12-27% if there is pre-existing renal impairment [21]. CMN is dose dependent and is more common following intra-arterial injection than intravenous administration. It is the development of CMN which can result in delayed excretion of metformin and so increase the risk of MALA. However, the chances of contrast medium being associated with lactic acidosis are extremely rare, with only one ‘or possibly two reported cases (cases number 12 and 14 in Table 2) if the guidance for metformin usage is followed and . the contraindications heeded. A modified algorithm is suggested (Table 1). We suggest-that patients on metformin can be given intravenous contrast medium provided the renal function is known to be normal. In patients whose renal function is abnormal or is not known, the metformin should be stopped for 48 h before and after the examination with contrast medium. The creatinine level should be checked prior to resumption of metformin and this drug should only be continued provided the patient has normal renal function. The clinician and diabetologist responsible for the patient should be informed if the patient has abnormal renal function as the prescription of metformin may be inappropriate. The concurrent use of non-steroidal anti-inflammatory drugs or aminoglycosides potentiates the nephrotoxic effects of contrast medium. Therefore in patients on metformin and either of the aforementioned drugs particular attention should be paid to renal function and consideration to withholding metformin for 48 h after contrast medium usage [21]. Old age (over 60 years) also carries increased risk for CMN because of decreased renal function and perfusion and similar consideration should be given to renal function after contrast usage. The St Vincent’s declaration recommends that renal function should be checked annually in patients with diabetes. It is not known for how long normal renal function can be assumed to be normal. The clinician making the request for a radiological procedure involving intravenous contrast should take responsibility for renal function, either by checking the serum creatinine or accepting a normal level within the past year. Patients who have abnormal renal function should not be given intravenous contrast media until the metformin has been stopped for 48 h. The metformin should not be restarted by the clinician until the renal function has returned to normal. In an emergency situation the College’s advice should be adhered to and intravenous contrast administered with metformin stopped at the time of the procedure and restarted at the clinician’s discretion. As intravenous contrast medium is likely to adversely affect renal function for 24-48 h after administration, it is prudent to withhold metformin usage for at least 48 h. Searching for reported rare adverse drug reactions has many difficulties [22]. The methodology for searching for large trials is well established [23]. This is not particularly useful when searching for case reports or rare drug reactions. Publication may not have been made and adverse reports are not always filed. The aetiology of the use of contrast medium in the evolution of lactic acidosis may not have been recognized and may not have been reported on at all, or not in the key word section. Therefore, in this study all potential abstracts and
32
CLINICAL
RADIOLOGY
EMERGENCY RADIOLOGICAL EXAMINATION
ROUTINE RADIOLOGICAL EXAMINATION 1 Recent satisfactory renal function results
1 *Should metformin be stopped due to intercurrent illness or abnormal renal function? /
A normal
unavailable
abnormal
yes
no
4
either
li
ensure creatinine normal
advise stop metformin until safe to restart
proceed with contrast medium administration
proceed with contrast medium as appropriate for renal dysfunction
continue metformin as prescribed
+ proceed as per RCR guidelines
1
stop metformin 24-48 hrs before and after contrast medium administration
/... proceed with contrast medium administration proceed with contrast medium as appropriate for renal dysfunction
continue metformin prescribed
as
f clinician recommended to review metformin prescription
clinician recommended to review metformin prescription
* see Table 1 for contraindications Fig. 1 - Suggested algorithm for use of contrast media in patients on metformin. papers were searched for mention of radiological examinations that had been performed. A degree of misfiling is present on all electronic data searches, estimated at greater than 50% [23] and subsequently reports can be lost. The authors who were contacted kindly helped with information of further cases known to themselves, or to their colleagues. We conclude that the risk of lactic acidosis with intravenous iodinated contrast in patients who are correctly prescribed metformin is so low as to be negligible. We believe that the
Royal College of Radiologists’s advice should be modified to emphasize that in patients who are correctly prescribed metformin, i.e., with normal renal function, metformin does not require to be stopped prior to or after the administration of intravenous contrast medium. It is important that the requesting clinician should state that the patient is on metformin and has normal renal function thus allowing the radiologist to proceed with the administration of contrast. In the emergency situation the intravenous contrast medium should be administered but
METPORMIN
AND CONTRAST
metformin should be stopped and restarted by the clinician when appropriate.
Acknowledgements. We would like to thank Professor PD Lalau, Associate Professor, Service d’Endocrinologie - Nutrition Hospital Sud, Cedex 1, France, Professor G Westberg, University of Gotebeg, Sweden, and Professor A Dachman, University of Chicago, USA, for their help with this study.
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