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Re: MS 8230298576402320
The prognostic value of blood pH and lactate and metformin concentrations in severe
metformin-associated lactic acidosis
by Farshad Kajbaf and Jean-Daniel Lalau
Reply to Reviewers and to the Editor
Reply to Reviewer 1
The authors thank the Reviewer for his/her helpful comments.
1. The reviewer is right in saying that a comment on patients’ age as a risk factor is
necessary, particularly given the wide age range (39-83). However, we state that the
survivors and non-survivors did not differ significantly in terms of age.
2. The “protective effect of metformin” is indeed a central point in the Discussion section
and we hope now to have presented it more effectively. References for animal and
clinical studies supporting the hypothesis of a “protective” effect of metformin (i.e. its
action on the vasculature and mitochondrial function) are indeed provided.
3. As required, some definite articles have been deleted.
Reply to Reviewer 2
The authors thank the Reviewer for his/her helpful comments. However, the authors disagree
with the Reviewer in several respects.
1. As requested (regarding the inclusion criteria), we now provide more information
about how the pharmacovigilance database was built and, consequently, how the study
patients were selected. We now state that the database is a compilation of all the cases
worldwide brought to Merck Serono’s attention during the study period. Most entries
are indirect, i.e. cases for which information was transmitted to Merck Serono by local
or national health authorities. Other cases are documented through spontaneous
declarations (from physicians, pharmacists, patients, etc.) or via the medical literature.
There was no bias in the selection of cases from the database as a whole, since all
available data meeting the study criteria were taken into account.
2. When discussing metformin concentrations, the Reviewer touches on the trickiest
point. We did not use or discuss “strict criteria” for the metformin assay method, since
our only exclusion criterion was the presence of an undetectable plasma metformin
concentration (when measured). With a limit of detection of 0.02 mg/l, a therapeutic
range (measured in patients with well-tolerated metformin therapy) of 0.5  0.4 mg/L,
an extreme value in metformin-associated lactic acidosis of more than 200 mg/L, and,
more importantly, high metformin concentrations (more than 60 mg/L) not necessarily
accompanied by hyperlactatemia, our experience prompts us to consider that the crux
of the problem is the ability to distinguish moderate elevation from marked elevation,
rather than to distinguish subnormal values from undetectable values.
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3. Reasons for metformin accumulation were in fact stated. Metformin may accumulate
by overdose alone, by defective renal elimination alone or a combination of the two.
These situations are mentioned in Table 2 (“kidney failure”, qualified as either “acute”
or “chronic”; “overdose”, qualified as either “metformin alone” or “multidrug
(including metformin)”).
4. When discussing metformin concentrations, the Reviewer touches on the second
trickiest point. In principal, the presence of chronic organ failure (which should be
considered as an associated condition) and/or an acute complication (i.e. a triggering
factor) is critical information and should therefore be stated (in Table 2). In fact, this
type of distinction is somewhat speculative; for example, chronic liver failure is
actually a triggering factor in acute metformin accumulation (because of defective
lactate clearance by the liver).
5. Since the cases were sourced from 32 different countries, it is indeed possible that the
level of care in the ICU varied. However, for the Reviewer’s information, 74.7% of
the reports came from Europe and most of the latter came from France.
6. Indeed, the criteria for organ failure were not stated. In this respect, we refer to our
reasoning in point 4. Further, we performed a personal and thus somewhat arbitrary
analysis of the reports. This is why we were careful to entitle Table 2 “… presumed
main triggering medical conditions…”.
7. Indeed, details of treatments are important in the prognosis of lactic acidosis.
However, even though more data is always valuable, the present work is not a review
on “metformin-associated lactic acidosis” per se; it is an investigation of mortality,
with a single, simple question: is mortality as high as commonly reported?
8. The Reviewer considers that it is “impossible to document the prognostic value of any
marker from such a retrospective, worldwide, poorly documented database”. This
criticism is rather harsh, particularly given that the same drawbacks applied to the
publication from the Reviewer’s group (Seidowsky et al: “Metformin-associated lactic
acidosis: A prognosis and therapeutic study, Crit Care 2009), a retrospective study
performed in the sole case of metformin overdose - thus merely in metformin-induced
lactic acidosis, where the criterion for metformin accumulation was just above the
therapeutic metformin range. We are not seeking to argue for arguing's sake but
simply wish to emphasize how difficult it is to provide informative studies in “true”
MALA, which is far from being a single entity. At this stage, it seems reasonable to
avoid the wording “prognostic” (factors) in a retrospective study, because of the risk
of confusion between future and past. Strictly speaking, the wording “factors
associated with… (outcome)” is more rigorous than “prognostic factors”.
Ultimately, we could circumvent this problem by changing the title of our work to
read “Blood pH and lactate and metformin concentrations in severe MALA”.
Shortening the title would also usefully focus the reader's attention on the key word,
i.e. “severe”. We kindly request the Editor’s advice in this respect.
9. The Reviewer considers that the “study does not bring additional information,
compared to other previously published reports showing that metformin level per se
has no prognostic value”. We again disagree in this respect. Apart from the Reviewer's
own work (cited above and performed in the particular context of metformin
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overdose), the only reasonably documented, rather large series of MALA originates
from our group (Lalau/Race, 1999, n = 49). The present study is not comparable but,
in contrast, stands apart. Comparing acidosis with arterial pH either just at the criterion
of 7.35 or as low as 6.28, and hyperlacatemia either at 5 mmol/L or up to 55.7 mmol/L
should not be done in terms of degree (i.e. severity) but merely in terms of nature.
Furthermore, one cannot legitimately raise the hypothesis of a protective effect of
metformin in low-severity cases. In contrast, the demonstration of survival in cases
with a mean pH that is incompatible with a favorable outcome under other
circumstances argues in favor of a protective effect.
10. The Reviewer is right to state that “numerous studies in the ICU setting have already
shown that initial pH and lactate levels are poorly predictive of vital prognosis and in
some situations, such as diabetic cetoacidosis” and that sequential levels and clearance
of lactate are much more informative. Nevertheless, given the conventional view of
MALA (i.e. “metformin-associated lactic acidosis is rare but is still associated with a
high rate of mortality”), the observation that a pH as low as 6.28 and a lactate
concentration as high as 55.7 mmol/L are not necessarily associated with a poor
outcome is impressive.
11. Indeed, we do not provide a “reference documenting which definite pH level predicts
death in patients admitted in the ICU”. However, (i) we are not aware of an obvious,
critical threshold (this is why overall scores are instead used); (ii) we are more
interested by the course of each individual, in rather rare situations; and (iii) most
importantly, this type of an analysis would be rather speculative in the heterogeneous
setting of MALA.
12. The Reviewer writes that the main finding, i.e. the “low predictive value metformin
blood levels” is presented without further explanation. In fact, we raised two
hypotheses, regarding the severity of co-morbidities and the role of metformin itself.
We can further refine the first hypothesis as follows: for similar arterial lactate levels
in MALA and metformin-independent lactic acidosis, high plasma metformin
concentrations are associated with less serious concurrent disease. For the second
hypothesis, please see the following point.
13. As requested, references on clinical and preclinical studies supporting the hypothesis
of a “protective” effect of metformin – i.e. its action on vasculature and mitochondrial
function - are now provided,.
14. The addition of new references (including the Reviewer’s own work) has reduced the
proportion of our own citations.
Reply to the Editor
The authors thank the Editor for his help in improving the manuscript.
1. As required, the protocol is currently being reviewed by an investigational review
board committee (Espace Ethique Hospitalier Amiens Picardie, Amiens, France). The
opinion will be issued on Oct. 14, 2012.
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2. As requested, the Friedsecke reference has been removed from the abstract.
Authors’ contribution
3. An Authors’ contribution section had been provided but has now been improved.
4. The manuscript has been read and edited by a native English speaker, DPhil in
Biochemistry from the University of Oxford, first author of peer-reviewed articles and
a professional medical writer).
5. Lastly, we require the Editor’s advice about the discussion of point 8 in response to
Reviewer 2.
All changes are underlined in italic type in the revised text.