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\begin{document}

\title{Is Continous Dialysis Effective to Treat Metformin Toxicity?}



\author[1]{Jehat Kılıc}%
\author[2]{Mahsum Ozan}%
\author[1]{Ihsan Solmaz}%
\author[3]{Delyadıl Karakaş KILIÇ}%
\author[1]{süleyman özçaylak}%
\author[1]{Ferhat Bingöl}%
\author[1]{Nuh Berekatoğlu}%
\affil[1]{Diyarbakir Gazi Yasargil Training and Research Hospital}%
\affil[2]{Diyarbakır Gazi Yaşargil Eğitim ve Araştırma Hastanesi}%
\affil[3]{Dicle University}%


\vspace{-1em}



  
  \date{June 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Case presentation In this case, we are presenting 26-year-old young
patients, who took 60-gram metformin plus 900 mg pioglitazone,
presenting with abdominal pain, nausea, confusion, and lethargy. And
lactic acidosis was treated with continuous hemodialysis
\textgreater{}15 hours. Our aim, in this case, is to highlight the
importance of continuous hemodialysis in the treatment of metformin
poisoning. Discussion Metformin is an oral antidiabetic drug which is
used as a first line treatment in the treatment of DM. Metformin
poisoning is a rare condition seen by clinicians. One of the severe side
effects of metformin poisoning is lactic acidosis and it can be fatal
without on-time treatment due to acidosis-related complications.
Conclusion Metformin toxication is a rare condition seen in clinical
practice. Metformin associated lactic acidosis is one of the expected
complication. The continous dialysis can be effective to treat the
lactic acidosis caused by metformin toxication. What's already known
about this topic? Lactic acidosis might be caused by metformin toxicity.
Without on-time treatment for metformin toxicity, it can cause
life-threatening condition. What does this article add? The treatment of
hemodialysis, especially continous hemodialysis, might be beneficial to
treat the patients with metformin toxicity. Key words: Metformin
Toxicity, Dialysis, Lactic acidosis%
\end{abstract}%



\sloppy


\textbf{Is Continous Dialysis Effective to Treat Metformin Toxicity?}

\textbf{Abstract}

\textbf{Case presentation}

In this case, we are presenting 26-year-old young patients, who took
60-gram metformin plus 900 mg pioglitazone, presenting with abdominal
pain, nausea, confusion, and lethargy. And lactic acidosis was treated
with continuous hemodialysis \textgreater{}15 hours. Our aim, in this
case, is to highlight the importance of continuous hemodialysis in the
treatment of metformin poisoning.

\textbf{Discussion}

Metformin is an oral antidiabetic drug which is used as a first line
treatment in the treatment of DM. Metformin poisoning is a rare
condition seen by clinicians. One of the severe side effects of
metformin poisoning is lactic acidosis and it can be fatal without
on-time treatment due to acidosis-related complications.

\textbf{Conclusion}

Metformin toxication is a rare condition seen in clinical practice.
Metformin associated lactic acidosis is one of the expected
complication. The continous dialysis can be effective to treat the
lactic acidosis caused by metformin toxication.

\textbf{What's already known about this topic?}

Lactic acidosis might be caused by metformin toxicity. Without on-time
treatment for metformin toxicity, it can cause life-threatening
condition.

\textbf{What does this article add?}

The treatment of hemodialysis, especially continous hemodialysis, might
be beneficial to treat the patients with metformin toxicity.

\textbf{Key words:} Metformin Toxicity, Dialysis, Lactic acidosis

\textbf{Introduction:} Metformin is an oral anti-diabetic drug, which is
a biguanide used to treat Diabetes Mellitus(1). Biguanides can be used
as a monotherapy or combination with other drugs. Metformin increases
the sensitivity of insulin, decreases the output of glucose from the
liver, and increases the uptake of glucose by muscles(2). Common side
effects are gastrointestinal such as metallic taste, bloating, abdominal
discomfort, nausea, mild anorexia, and diarrhea(2). And one of the major
side effects of metformin is lactic acidosis(3).

\textbf{Case :} A 26-year-old young patient after digesting 60 g
metformin plus 900 mg pioglitazone for the suicidal purpose was admitted
to the emergency ward. He presented with abdominal pain and discomfort,
nausea, agitation, confusion, and lethargy 3 hours after digestion of
drugs. His vital signs were as follows: blood pressure:115/85, pulse:110
beat/min, respiratory rate: 18 RR/min, oxygen saturation in room air:
96\%. His laboratory results were glucose:123 mg/dL, creatinine:1,75
mg/dL, urea:27 mg/dL, alanine transferase(ALT):29 U/L, aspartate
transferase(AST):17 U/L. Arterial blood gas (ABG) analysis showed
acidosis pH:7.15, which was caused by elevated lactate levels. The
lactate level was 7,8 mmol/L. The anion gap was calculated at 11
mmol/L(6 hours after the suicide attempt)(Table 1). The patient was
transferred to the intensive care unit(ICU). At the time of admission to
ICU, confusion, and lethargy worsened and blood glucose levels lowered
to 64 mg/dL. IV dextrose (1 g/kg) was administered. IV saline was
administered due to polyuria. A central venous catheter was performed
and continuous dialysis was initiated. Hemodialysis was performed with
Fresenius 4008 S device, 1.5 m2 high-flux FX-60 membrane (Fresenius),
300 ml/min blood flow rate, 500 mL/min dialysis fluid rate, 32 mmol/L
bicarbonate, without ultrafiltration. At the 4th hour of dialysis, the
patient was more oriented and cooperated. Continous dialysis was
performed for 15 hours. Lactate levels lowered and at the 48th hours
following admission to ICU, lactate levels were completely normalized.
The patient was discharged 3 days after admission to the hospital.

\textbf{Table 1:} The results of ABG\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
ABG following suicide attempt & pH & pCO2 (mmHg) & HCO3 (mmol/L) &
Lactate (mmol/L) & Base Excess (BE) (mmol/L)\tabularnewline
\midrule
\endhead
6th hour (ABG at the time of admission) & 7,15 & 48,5 & 13,8 & 7,8 &
-11\tabularnewline
11th hours (2 hours after initiation of dialysis) & 7,11 & 50,8 & 13,2 &
20 & -12,2\tabularnewline
14th hour & 7,25 & 45,1 & 17,8 & 12,2 & -6,7\tabularnewline
17th hour & 7,38 & 40,3 & 23,3 & 7,2 & -0,7\tabularnewline
20th hour & 7,46 & 34,7 & 25,4 & 6 & 1,2\tabularnewline
22th hour & 7,40 & 32,9 & 21,5 & 7,9 & -3,9\tabularnewline
24th hour (After 15-hour dialysis) & 7,40 & 38,3 & 23,5 & 6,7 &
-0,7\tabularnewline
48th hour & 7,40 & 44,8 & 26,5 & 1,8 & 3\tabularnewline
\bottomrule
\end{longtable}

\textbf{Discussion:} Metformin is an oral anti-diabetic drug used in the
treatment of type 2 DM as a first-line treatment. It is absorbed from
the upper part of the intestine and is excreted unmetabolized from the
kidney via transporters in the proximal tubules. Elimination of
metformin from the kidney takes 5 hours in those who have good renal
function. But it can be accumulated in patients with acute or chronic
kidney disease(4). One of the major complications of metformin is lactic
acidosis despite the fact that it is rarely seen in patients with normal
kidney function. Lactic acidosis is generally seen in patients with
glomerular filtration rate lower than 30 mm/min. Moreover, It can be
also seen in patients with metformin poisoning(5-6).
Metformin-associated lactic acidosis(MALA) is a rare condition. Without
diagnosis and on-time treatment, it might have detrimental consequences.
The diagnosis of MALA is based on lactic acidosis following metformin
exposure. Metformin levels assessment is not easy and available in most
centers. And because metformin is mostly intracellular toxin, measuring
levels of metformin has no value to diagnose MALA(7). The mainstay of
MALA treatment is supportive. Gastrointestinal clearing with activated
charcoal and treatment with sodium bicarbonate or hemodialysis are
suggested. The treatment is to remove the offending agent, balance
acid-base status in the normal range, and buffer to acidosis by removing
lactate through dialysis. Although removal of metformin by dialysis is
uncertain due to high volume (63--646 l/kg) and it is mostly
intracellular toxin, dialysis has importance to treat the complications
of lactic acidosis(7-8). In one of the biggest studies conducted by
Peter and et al., there was no significant difference in dialyzed and
undialyzed MALA patients in terms of mortality. But the patients in the
dialyzed group had the higher simplified acute physiology score II
(SAPSII) and need for vasopressor compared to undialyzed group. Dialyzed
group were more disadvantaged compared to undialyzed group in terms of
SAPS II and the need for vasopressor. Because of these two factors,
there was no difference in terms of mortality between the two groups.
This indicates that dialysis might be beneficial in the treatment of
MALA(7).\textbf{Conclusion:} Continuous dialysis might be beneficial in
patients with MALA not to remove the metformin but especially to treat
the lactic acidosis, which might be detrimental and life-threatening.

\textbf{Data Availability Statement}

All datasets are available from the corresponding author upon reasonable
request.

\textbf{References}

1-) Bailey CJ, Day C. Traditional plant medicines as treatments for
diabetes. Diabetes Care 1989; 12:553.

2-) Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574.

3-) Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and
nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
Cochrane Database Syst Rev 2010; :CD002967.

4-) Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ,
Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams
KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011
Feb;50(2):81-98.

5-)Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose
metabolism in the splanchnic bed. Br J Pharmacol 1992; 105:1009.

6-)Vecchio S, Giampreti A, Petrolini VM, et al. Metformin accumulation:
lactic acidosis and high plasmatic metformin levels in a retrospective
case series of 66 patients on chronic therapy. Clin Toxicol (Phila)
2014; 52:129.

7-)Peters N, Jay N, Barraud D, et al. Metformin-associated lactic
acidosis in an intensive care unit.~\emph{Crit Care} . 2008;12(6):R149.
doi:10.1186/cc7137

8-) Ayoub P, H\selectlanguage{ngerman}étu PO, Cormier M, et al. Toxicokinetics of Metformin
During Hemodialysis.~\emph{Kidney Int Rep} . 2017;2(4):759-762.
Published 2017 Mar 7. doi:10.1016/j.ekir.2017.02.017

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