Response to reviewers
Response to reviewer # 1:
Major comments:
1. The authors used the Genius batch dialysis system for the initial 4-hour
hemodialysis session. They used less efficient hemodialysis settings than the
settings that are normally used with standard hemodialysis. For instance, the
authors used a relatively low dialysate flow (350 ml/min versus the usual 500
ml/min) and a low dialyser surface area (1.3 m2). The question is why the authors
did not use the regular – more efficient – hemodialysis settings. This probably
would have augmented the lithium clearance even further. With conventional
hemodialysis it is also possible to collect dialysate and estimate the lithium
removal, so that is not an argument. I would advise to comment on this issue of
relative inefficient hemodialysis settings in the discussion.
- The GENIUS batch system was not chosen to collect the used dialysate, it is the standard
treatment method for critically ill patients in our ICU and has been repeatedly used with
success for extracorporeal treatment of intoxications. The maximum blood and
countercurrent dialysate flow rate of this machine is 350 ml/min. Even though we agree
that the elimination of lithium could have been increased by higher dialysate and blood
flow rates, we consider the added benefit of blood and dialysate flow >350 ml/min
unlikely to be of major importance. As the total collected spent dialysate represents an
integral of total removal, we consider it to be a better reflection of removal than (multiple)
spot checks of the dialysate. We now comment this issue in our case presentation.
2. Please specify details on the ‘extended dialysis’. Was this also with the Genius
system and with the low-surface dialyser? What was the reason for not choosing
CVVH or CVVHDF? Was this a logistic choice or a medical choice based on the
presumed superiority of extended dialysis. If so, what are the arguments for the
choice for extended dialysis? Did the authors measure lithium clearance with this
‘extended dialysis’?
- Hemodialysis with the GENIUS batch system is the standard dialysis procedure in our
ICU. The ‘extended dialysis’ modality is a prolonged (up to 18 hours) hemodialysis
treatment, which combines an excellent detoxification and a cardiovascular tolerability
akin to that associated with CVVH (Fliser, Kielstein, Technology Insight: treatment of
renal failure in the intensive care unit with extended dialysis, Nature Clinical Practice
Nephrology (2006)). We did not measure the Lithium clearance during the extended
dialysis treatment session.
3. The authors state that data on the elimination of lithium with extended dialysis
are scarce. This may be true but there are additional reports on continuous
techniques (after initial hemodialysis) that the authors could refer to. In 2009, we
published a case of an adult patient with lithium intoxication who underwent
hemodialysis followed by continuous veno-venous haemodiafiltration (CVVHDF).
Lithium clearances with hemodialysis and CVVHDF were 173 and 61 ml/min,
respectively. Serum lithium levels were rapidly lowered and did not rebound. Two
compartment simulations illustrated that hemodialysis followed by CVVHDF is the
most effective strategy for removing lithium from the intracellular compartment. I
would suggest to refer to this publication (Meertens et al, Heamodialysis followed
by continuous veno-venous haemodiafiltration in lithium intoxication; a case and a
model. Eur J Int Med 2009;20:e70-e73), in any case to make the point that relatively
high lithium clearances can be achieved with CVVHDF.
- We thank the reviewer for this important addition to the case and do now refer to the
suggested article.
Minor comments:
1. Did the authors measure the removal of lithium by the urine? Was the patient
still polyuric during her stay in the intensive care unit? If so, renal clearance of
lithium was probably also substantial.
- The patient was in fact polyuric during the ICU stay. Sadly the lithium excretion by the
urine was not measured in this case as the saved urine aliquot was accidently discarded.
We now acknowledge this limitation more clearly in the discussion.
2. For the convenience of the reader, I would suggest to add a brief section on the
method of the calculation of lithium clearance. Were simultaneous dialysate and
blood samples used for the calculation of clearance? Notably, the lithium clearance
with the Genius system that the authors found (177 ml/min) was identical to the
lithium clearance that we observed (see major remark NR3: 173 ml/min), whereas
I would have expected a lower lithium clearance in their patient because of their
less efficient hemodialysis settings. Could a difference in the method of calculation
of clearance account for this?
Lithium dialyzer clearance was calculated according to the following equation:
Kplasma = QB x (1 – Hct/100) x ((Cart – Cven)/Cart). Pre-dialyser concentrations (Cart) and
postdialyser concentration (Cven) were drawn at a time of minimal ultrafiltration (50
ml/h). We added a brief method section to the manuscript. We think that one explanation
for the identical clearance despite the difference in dialysis coordinates could be due to
the fact that the clearance curve of small molecules like lithium clearance is not stepp
anymore above and beyond dialysate and blood flows of 350 ml/min.
3. Please add a legend to the Figure explaining the abbreviations.
We added a legend explaining the abbreviations.
4. What does GCS mean (in the text and in the Figure)?
GCS stands for Glasgow Coma Scale. We stated the GCS to visualize and quantify the
patient’s state of consciousness. We added a legend explaining the abbreviations to the
figure.
Response to reviewer # 2:
Minor Essential Revisions
The authors deals with a novel topic but require to make certain essential but
minor changes;
1) On page 4 para 1 line 12 “Subsequently is rose to a concentration of 4.2 mmol/l
two hours after admission” needs to be rewritten
Done.
2) On Page 4 para 2 line 5 “to avoid frequent alarms and fixation of the patient”
needs to be rewritten.
Done.
3) On page 4 para 2 line 9 “as well as 15 minutes, 30 minutes, 1 hour, 2 hours and
3.5 hours after treatment initiation” suggested to be written as “as well as within
an interval of 15 minutes, 30 minutes, 1 hour, 2 hour, and 3.5 hours after treatment
initiation”.
Done.
4) On page 4 para 2 line 10 “To prevent an early contamination of fresh” needs to
be clarify more.
The separation of the fresh and used dialysate in the GENIUS dialysis is due to differences
in temperature and solute content between the fresh and used dialysate. In the absence
of uremia the solute content of the used dialysate is not very high, which could lead to an
earlier mixing of fresh and used dialysate as reported by DHONDT et al. Am J Kid Dis
2005.
5) On page 5 para 2 line 3 “Flow” should be written as “flow”.
Done.
6) Check the whole case report for capitalization of “Lithium”; there are places in
which there is unnecessarily capitalization.
Done.
7) On page 5 last para and last line “Monitoring was no longer required and the
patient could be transferred to the psychiatric hospital”; are you suggesting that the
patient be transferred to the psychiatric hospital or was it already done; if it has
been done check the grammar of sentence.
We changed the wording to “transferred”.
Response to reviewer # 3:
Major compulsory revisions:
Despite this is a case report, I found interesting and useful for giving advice other
physicians. However, authors have to soften their message since reports cannot
provide any clear recommendations. In consequence I would change in conclusions
the word "can" for "could/may".
We changed the wording as suggested.
Minor essential revisions:
N/A.
Discretionary revisions:
"Presence on admission of low creatinine clearance, low blood sodium
concentration, and/or high lithium levels correlated with a higher number of
dialysis sessions in severe lithium poisoning" (Hemodialysis International 2012;
16:407–413). Consider include this within your discussion.
We thank the reviewer for this suggestion and included the article in our discussion part.
Response to reviwer # 4:
The authors contend theirs is a novel case because it demonstrates the
effectiveness of intermittent hemodialysis followed by slow prolonged dialysis in
removing a significant amount of lithium – quantified – from a patient with high
serum levels, and presumably deep tissue levels. While the case shows the
effectiveness of this treatment for this patient, it does not make clear what is novel:
is it the time, the technology or just the calculation of the total lithium removed?
There are a few case reports of lithium toxicity treated with continuous renal
replacement therapy and recommendations that include following high flow
intermittent therapy with slow continuous therapy. There is also a small study in
the literature comparing the effectiveness of the GENIUS system compared to
continuous veno-venous hemodiafiltration (CVVHDF).
- In fact there several manuscripts published, comparing the different RRT modalities in
lithium detoxification. (Bailey, Comparison of intermittent haemodialysis, prolonged
intermittent renal replacement therapy and continuous renal replacement
haemofiltration for lithium toxicity: a case report. Crit Care 2011) Lithium clearance
seems highly dependent to the blood flow rate of the chosen modality. However, we here
present a case of different combined RRT modalities (IHD+SLED) that underlines these
former findings by measuring the total eliminated amount of lithium in the total spent
dialysate.
The authors do not show why it is important to know the total amount of lithium
collected. Did that help them determine how long it would take to remove enough
lithium to bring the serum concentration down into a safe range? And are they
proposing this as a way to help guide clinicians in the future? Why is this system
more effective than standard intermittent treatments at high blood flow and
dialysate flow rates? Put another way, is it significant that the subsequent slow low
efficiency dialysis lasted as long as it did, and did this somehow improve the patient
outcome? And what is the significance of this particular dialysis technology to the
outcome of this case?
The measurement of lithum in the collectd spent dialsate is though to be interesting solely
from a academic point of view. We do not suggest that monitoring of dialysate lithium
would be clinically important, yet it helps to compare the decline in blood levels to the
absolute amount removed by dialysis. The use of SLED seemed to be prudent to prevent
the well known rebound of lithium after intermittent hemodialysis. This occurs as as
lithium equilibrates from intracellular to extracellular compartments.
Other questions: how does the fact that the patient was on chronic lithium affect
removal of the acute load? It would seem that the length of lithium therapy and
serum levels would be important to know.
The patient had a history of chronic bipolar disorder and was treated with lithium for
years prior to admission. We included this information in the manuscript. The case does
not allow to differentiate between the effect of acute and chronic lithium intoxication.
What is the author’s estimate of the volume of distribution of lithium in this
patient?
The estimated volume of distribution of lithium in this patient was 23.4 l/kg body weight
Do we have any sense of native lithium clearance beyond that the patient was
polyuric?
What was the serum lithium concentration at the end of the firs treatment?
How long between treatments? And what was the serum lithium concentration at
the start of the next treatment? Did the authors calculate native lithium clearance
([ULi/PLi]V). Finally, was this continuous release lithium or fast release?
The patient was in fact polyuric during the ICU stay. Sadly the lithium excretion in the
urine was not measured in this case as the saved urine aliquot was accidently discarded.
We now acknowledge this limitation more clearly in the discussion.
These are major revisions that authors must address, in my opinion. I think the case
has merit for publication overall. There is not much data on the optimal dialysis
regimen for extracorporeal removal of lithium, and publishing this account would
provide another alternative. The authors have obtained appropriate consent from
the patient. The work of others has been appropriately cited. And the work does
not appear to have been published elsewhere to judge by a search of the literature
on PubMed.