You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


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Introduction
============

Metformin is a biguanide-derived drug commonly used in the treatment of type 2 diabetes since the 1960s. It acts by inhibiting glucose absorption from the intestine, reducing gluconeogenesis in the liver, and increasing the use of peripheral glucose \[[@REF1]\]. As metformin is eliminated from the proximal tubules without metabolization, it may accumulate in the body during renal insufficiency. Most metformin-induced toxicities are seen due to acute or chronic renal diseases, advanced liver problems, or simultaneously occurring acute diseases \[[@REF2]\].

The reported side effects of metformin are frequently associated with the gastrointestinal tract. However, metformin-induced metabolic acidosis, which is a serious complication with a mortality rate of 50%, may rarely occur. This complication is known to be associated with lactic acid elevation \[[@REF3]\].

In this case report, we aimed to present the management of a patient who developed metabolic acidosis without lactic acidosis after metformin use in the intensive care unit.

Case presentation
=================

A 74-year-old male patient applied to the emergency department because of a femur fracture. He was admitted to the orthopedics and traumatology department with an operation plan. The comorbidities of the patient were type 2 diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and benign prostatic hyperplasia. His medications were benidipine hydrochloride 8 mg, theophylline, tamsulosin HCl 0.4 mg, ipratropium bromide monohydrate + salbutamol sulfate 20/100 mcg, formoterol + budesonide 12/200 mcg, tiotropium bromide monohydrate 18 mcg, salbutamol inhaler 2.5 mg, and metformin 1000 mg twice a day.

In the preoperative cardiology examination, the ejection fraction of the patient was evaluated as 60% and the left ventricular systolic function was normal. The hemoglobin level was 10.4 g/dL in laboratory blood tests, and no other abnormality was detected. The metformin treatment was stopped 24 hours before the operation. In the operating room, the patient underwent spinal anesthesia with 10 mg bupivacaine and 20 mcg fentanyl. The surgery lasted for 90 minutes. The patient had 150 ml hemorrhage and received saline 1000 ml infusion with 500 ml polyglycine. Hemodynamic values were stable throughout the operation and the patient was taken to the intensive care unit (ICU) for postoperative observation. The cardiac and respiratory examination of the patient was repeated in the ICU. Mild acidosis and hypoxia were detected in the admission arterial blood gas (ABG) examination (Table [1](#TAB1){ref-type="table"}). The patient\'s albumin level was 2 g/dL and human albumin 20% replacement treatment was applied. In the postoperative twelfth hour, metabolic acidosis with increased compensated anion clearance (30 mEq/L) was detected in the ABG analysis. The lactate level was within normal limits (Table [1](#TAB1){ref-type="table"}). Urea and creatinine values were normal in the control blood tests and the hourly urine output of the patient was above 0.5 ml/kg. The hourly blood glucose measurements were between 80 and 140 mg/dL within the first 12 hours. Since a hemoglobin level of 8.4g/dL was detected, the patient received a unit of erythrocyte suspension. Although a bolus dose of bicarbonate 8.4% was administered intravenously, metabolic acidosis and the severe base deficit of the patient did not improve. So, intravenous bicarbonate infusion was initiated. As no additional reason for the persistent metabolic acidosis was detected, metformin was thought to be the cause of the metabolic situation of the patient.

At the postoperative twenty-fourth hour, the patients\' metabolic acidosis was resolved and the bicarbonate infusion was terminated. Although there was high anion-gap (AG) metabolic acidosis, the lactate level of the patient was within normal ranges during this period. The patient was discharged from the ICU on the postoperative third day.

Table [1](#TAB1){ref-type="table"} shows the ABG values after admission to the ICU.

###### ABG values after admission to the ICU

ABG: arterial blood gas; ICU: intensive care unit

  ----------------------------- ------------------ --------------------
  Arterial blood gas analysis   Admission values   12^th ^hour values
  pH                            7.33               7.34
  PaCO~2 ~(mmHg)                39                 21
  PaO~2~(mmHg)                  55                 98
  SaO~2~                        89 %               97 %
  HCO~3~(mmol/L )               20.6               11.3
  Lactate (mmol/L )             1.5                0.7
  Chlorine (mmol/L )            107.5              102.3
  ----------------------------- ------------------ --------------------

  -------- ----- -----
  Sodium   136   138
  -------- ----- -----

Discussion
==========

Acid-base disorders are a commonly seen problem in the ICU. When the metabolic status of the patients is assessed in the ICU, it is seen that only 35% have a normal acid-base balance. Metabolic acidosis occurs either by the accumulation of a constant acid in the blood or by the loss of blood bases. In order to distinguish these reasons, the term AG was defined.

The AG value is the difference between the total major cations and anions in the plasma \[[@REF4]\]. The most common cause of high AG metabolic acidosis is lactic acidosis. In addition, hypoxia, high doses of aspirin, methanol, ethylene glycol, paraldehyde, toluene, azotemic renal failure, ethanol, liver failure, ketoacids, fasting, and diabetes can also cause metabolic acidosis with high AG \[[@REF5]\]. Despite the increased AG, the lactate levels of our patient ranged between 0.5 and 1.5 mmol/L. 

Our patient was slightly hypoxic at admission to the ICU, however, mild acidosis and hypoxia were detected in the admission arterial blood gas (ABG) examination. At the twelfth hour of intensive care, metabolic acidosis progressed despite heating and fluid replacement. So, we ruled out hypoxia from the etiology of metabolic acidosis. The use of metformin was considered the most likely cause of acidosis; hence, the patient did not have known aspirin or substance use or renal or hepatic insufficiency and had normal blood glucose levels. However, urinary output and urea creatinine levels were normal.

Although the most common side effects of metformin use are gastrointestinal problems, such as nausea and vomiting; hyperlactatemia and metabolic acidosis are rare but potentially serious side effects that can cause mortality \[[@REF6]\]. These risks are thought to increase in cases of kidney or liver dysfunction, chronic heart or respiratory failure, sepsis and severe dehydration \[[@REF7]\].

Metformin-associated lactic acidosis (MALA) is a rare but very dangerous complication of metformin use \[[@REF8]\]. The presence of co-morbidities that may cause lactic acidosis is the most important factor that makes the differential diagnosis difficult. A meta-analysis by Inzucchi and colleagues reported a strong association between metformin and MALA development in patients with stable chronic kidney disease. MALA often develops in the case of concomitant acute disease, which can lead to acute renal failure \[[@REF9]\].

However, so far, there is no case report regarding metabolic acidosis without lactic acidosis due to metformin use in the current literature. Despite the presence of type 2 diabetes in our patient, there was no kidney or liver failure and no increase in laboratory lactate levels.

In the case of MALA, the most important step in the treatment is ensuring adequate intravenous hydration. In addition, the use of targeting oxygen-sensing prolyl hydroxylase domain enzyme (PHD) has recently been proposed. Oyaizu-Toramaru and colleagues reported that the inhibition of PHD activates the transcription factor called hypoxia-inducible factor (HIF), which increases lactate excretion and gluconeogenesis in which lactate is used as a substrate \[[@REF10]\]. Angioi et al. have reported that they applied continuous low-efficiency dialysis and bicarbonate to 28 patients with MALA and got positive results. We didn't consider dialysis in the treatment of our patient because lactic acid levels were within the normal ranges. However, bicarbonate infusion was applied to correct the resistant acidosis.

In our patient, the termination of metformin use, increasing hemoglobin levels above 10 g/dL to improve oxygen delivery, and bicarbonate infusion for 24 hours successfully treated the metabolic status.

Conclusions
===========

Metformin-induced metabolic acidosis with increased lactic acidosis is a well-known complication of metformin treatment, with a high mortality rate. In addition, clinicians should also consider that metformin-induced metabolic acidosis may develop without lactate elevation. In such cases, metformin treatment should be terminated and bicarbonate infusion should be initiated.

The authors have declared that no competing interests exist.

Consent was obtained by all participants in this study