Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The number of drug addicts worldwide has increased by 23 percent in 10 years. The number of people using drugs continues to grow. Over the past decade, this figure has increased by 23 percent, reaching 296 million in 2021. Of these, 13.2 million used drugs intravenously. Polydrug addiction is a severe form of addiction characterized by the simultaneous or alternating use of two or more psychoactive substances, leading to persistent addiction. It is a chronic condition that often combines different groups of substances (stimulants and opioids, alcohol and drugs) to enhance the effect or mitigate side effects, requiring complex, long-term treatment.

This article describes an illustrative case of polydrug addiction treatment in a 37-year-old male patient who received emergency care during a critical condition. After the crisis had passed, the patient refused further treatment and was discharged from the hospital, which soon led to his death. On the one hand, this case demonstrates that such situations deserve more attention. However, given the patient's history of hepatitis C, and the lack of detailed information on the cause of death (was it a relapse of illicit drug use? What exactly did the patient consume? Were these illicit drugs or alcohol? Or was it a consequence of complete refusal of treatment, including for hepatitis C?), it is difficult to draw long-term conclusions from a single case, although there is recognition that the life of one person is a tragedy for their loved ones. Perhaps this case will be of interest to individual researchers or practicing physicians, but unfortunately, there is no certainty that global conclusions can be drawn here, especially given that healthcare systems, bioethical norms, and legislative frameworks vary significantly across the world.

Author Response

Dear Editors,

Dear Reviewer 1,

We sincerely appreciate the opportunity to address your comments, as they provide valuable insights and help us enhance the quality of our work.

Here are the responses needed (Please note that all corrections have been highlighted in yellow in the text, including the newly added citations):

Comment 1: The number of drug addicts worldwide has increased by 23 percent in 10 years. The number of people using drugs continues to grow. Over the past decade, this figure has increased by 23 percent, reaching 296 million in 2021. Of these, 13.2 million used drugs intravenously. Polydrug addiction is a severe form of addiction characterized by the simultaneous or alternating use of two or more psychoactive substances, leading to persistent addiction. It is a chronic condition that often combines different groups of substances (stimulants and opioids, alcohol and drugs) to enhance the effect or mitigate side effects, requiring complex, long-term treatment. This article describes an illustrative case of polydrug addiction treatment in a 37-year-old male patient who received emergency care during a critical condition. After the crisis had passed, the patient refused further treatment and was discharged from the hospital, which soon led to his death. On the one hand, this case demonstrates that such situations deserve more attention. However, given the patient's history of hepatitis C, and the lack of detailed information on the cause of death (was it a relapse of illicit drug use? What exactly did the patient consume? Were these illicit drugs or alcohol? Or was it a consequence of complete refusal of treatment, including for hepatitis C?), it is difficult to draw long-term conclusions from a single case, although there is recognition that the life of one person is a tragedy for their loved ones. Perhaps this case will be of interest to individual researchers or practicing physicians, but unfortunately, there is no certainty that global conclusions can be drawn here, especially given that healthcare systems, bioethical norms, and legislative frameworks vary significantly across the world.…The manuscript would benefit from a more explicit discussion of alternative management strategies, including non-surgical or palliative approaches, and a clearer justification for cytoreductive surgery in the presence of multi-organ metastatic disease.

Response 1:

Thank you for this thoughtful and constructive comment. We fully agree that conclusions drawn from a single case report must be interpreted with caution. In response to the reviewer’s remarks, we have revised the manuscript to clarify several important points:

1. First, we have emphasized that the fatal outcome was most likely related to progressive acute kidney injury with persistent anuria, severe metabolic disturbances, and the patient’s refusal of life-saving treatment, including dialysis. No evidence was available suggesting renewed illicit drug use or alcohol consumption after hospital discharge.
2. Second, we have expanded the Discussion section to acknowledge the limitations of single case observations and to explicitly state that the present report cannot support broad epidemiological or global conclusions. Instead, the aim of the report is to provide detailed clinical insight into the complex pathophysiology and management challenges associated with severe polysubstance intoxication.
3. Third, we have clarified the potential role of chronic hepatitis C infection as a possible vulnerability factor for muscle injury, while emphasizing that available clinical data do not support HCV infection as the primary cause of the fatal outcome.

These clarifications have been added to the revised Discussion and Conclusion sections of the manuscript. We thank the reviewer for helping us improve the clarity and scientific rigor of the manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Comment 1: Terminology Inconsistency – Acute Renal Failure vs. Acute Kidney Injury
The manuscript interchangeably uses the terms “acute renal failure” and “acute kidney injury.” While both appear in the literature, it is important to maintain terminological consistency in line with current KDIGO guidelines, which favor the term **“acute kidney injury (AKI)”** to reflect a broader spectrum of renal impairment, from mild dysfunction to failure. Please revise throughout the manuscript to consistently use **AKI**, unless specifically referring to historical classifications or diagnostic coding.

Comment 2: Abstract – Structure and Content
The abstract requires substantial revision to meet the standards of a clinical case report. The **Background** section should briefly contextualize the public health relevance of polysubstance use. The **Methods** should summarize the case presentation, diagnostic timeline, and key interventions. The **Results** should concisely report the most critical laboratory findings (e.g., peak CK levels, electrolyte abnormalities, DVT confirmation) and clinical trajectory. The **Conclusion** must clearly state the take-home message for clinicians and public health stakeholders. Avoid vague phrasing and ensure the abstract reflects the manuscript’s core message: the lethal synergy of opioid–stimulant co-use and the impact of treatment refusal.

Comment 3: Table 5 – Readability and Clinical Relevance
Table 5 is dense and difficult to interpret at a glance. To enhance **clinical readability**, please:
- **Bold or highlight** key abnormal values that are directly relevant to the diagnosis and progression of rhabdomyolysis and AKI (e.g., CK, potassium, creatinine, myoglobinuria).
- Consider adding a **brief narrative summary** beneath the table (or in the results section) that explains the most clinically significant trends, for example:  “Serum creatine kinase rose sharply from 63,444 U/L on Day 1 to 161,050 U/L by Day 4, reflecting massive and progressive muscle necrosis despite initial resuscitation.”
This approach will help readers quickly grasp the severity and trajectory of organ injury.

Comment 4: Figure 1 – Visual Clarity and Educational Value
Figure 1 is visually cluttered and the causal pathway is not immediately intuitive. I recommend:
- Redesigning it as a **simplified flowchart** with clear directional arrows:  
  **ATP depletion → Impaired Na⁺/K⁺ ATPase → Intracellular Na⁺ and Ca²⁺ overload → Activation of proteases → Myocyte necrosis → Release of intracellular contents (CK, myoglobin, K⁺) → Acute Kidney Injury**
- Adding **side-by-side illustrations** of a normal vs. injured myocyte to enhance educational impact.
- Ensuring that the figure is self-explanatory and aligns with the mechanistic discussion in the text.

Comment 5: Causality Assessment – Polysubstance Use and Toxicity
The causal link between the specific drug combination and the observed complications could be strengthened. While the discussion mentions potential mechanisms, it remains somewhat speculative. I suggest:
- Including a **dedicated subsection** (e.g., “Causality Analysis”) that systematically evaluates the contribution of each substance to the clinical presentation using established toxicological principles (e.g., temporal relationship, dose–response plausibility, exclusion of alternatives).
- Addressing **potential pharmacodynamic or pharmacokinetic interactions** (e.g., fentanyl-induced respiratory depression compounded by stimulant-induced hypermetabolism) that may have amplified toxicity.
- If possible, referencing toxicological databases or case series that support the plausibility of such a synergistic effect.

Comment 6: Patient Refusal of Treatment – A Missed Opportunity for Deeper Analysis
The patient’s refusal of life-saving therapy is a pivotal element of this case, yet it is addressed only superficially. This limits the manuscript’s value in terms of clinical ethics and patient-centered care. I recommend expanding the discussion to include:
- A multidimensional analysis of potential reasons for refusal: psychiatric comorbidity, impaired decision-making capacity (e.g., substance-induced cognitive deficits, uremic encephalopathy), distrust in healthcare systems, or prior negative experiences.
- A reflection on clinician–patient communication and strategies to enhance therapeutic alliance in patients with substance use disorders.
- Consideration of ethical and legal frameworks for managing treatment refusal in life-threatening situations, including capacity assessment and the role of surrogate decision-makers.
This addition would significantly elevate the manuscript’s relevance to clinicians, ethicists, and public health professionals.

Comment 7: Overall Structure – Redundancy and Focus
The manuscript is overly lengthy and includes extraneous background material that detracts from the core case narrative. I recommend:
-Condensing the Introduction to focus on the “fourth wave” of the opioid crisis and the relevance of polysubstance use to the case. Omit or shorten general statistics that are not directly tied to the case.
- Streamlining the Discussion by avoiding repetition of pathophysiological mechanisms already covered in the introduction. Instead, focus on how the case illustrates or challenges existing knowledge.
- Prioritizing content that directly supports the causality analysis, clinical decision-making, and patient behavior, as suggested above.
A more focused manuscript will improve readability and enhance its impact on the target audience.

This case report addresses a timely and clinically relevant topic. With revisions focusing on terminological precision, visual clarity, causality assessment, and psychosocial depth, the manuscript could offer a valuable contribution to the literature on polysubstance use and its life-threatening complications.

Author Response

Dear Editors,

 

Dear Reviewer 2,

 

We sincerely appreciate the opportunity to address your comments, as they provide valuable insights and help us enhance the quality of our work.

Here are the responses needed (Please note that all corrections have been highlighted in yellow in the text, including the newly added citations):

Comment 1: Terminology Inconsistency – Acute Renal Failure vs. Acute Kidney Injury

The manuscript interchangeably uses the terms “acute renal failure” and “acute kidney injury.” While both appear in the literature, it is important to maintain terminological consistency in line with current KDIGO guidelines, which favor the term **“acute kidney injury (AKI)”** to reflect a broader spectrum of renal impairment, from mild dysfunction to failure. Please revise throughout the manuscript to consistently use **AKI**, unless specifically referring to historical classifications or diagnostic coding.

Response 1: Thank you for your valuable comment regarding the consistent use of the terminology “acute renal failure” and “acute kidney injury.” In response to your observation, I have thoroughly reviewed the entire manuscript and revised all instances of terminology related to acute kidney injury to ensure alignment with current international guidelines and consensus.

 

Comment 2: Abstract – Structure and Content

The abstract requires substantial revision to meet the standards of a clinical case report. The **Background** section should briefly contextualize the public health relevance of polysubstance use. The **Methods** should summarize the case presentation, diagnostic timeline, and key interventions. The **Results** should concisely report the most critical laboratory findings (e.g., peak CK levels, electrolyte abnormalities, DVT confirmation) and clinical trajectory. The **Conclusion** must clearly state the take-home message for clinicians and public health stakeholders. Avoid vague phrasing and ensure the abstract reflects the manuscript’s core message: the lethal synergy of opioid–stimulant co-use and the impact of treatment refusal.

Response 2: We sincerely thank the reviewer for the valuable comment regarding the structure and content of the abstract. In response, we have thoroughly revised the abstract to fully align with the standards for clinical case reports.

 

Comment 3: Table 5 – Readability and Clinical Relevance
Table 5 is dense and difficult to interpret at a glance. To enhance **clinical readability**, please:
- **Bold or highlight** key abnormal values that are directly relevant to the diagnosis and progression of rhabdomyolysis and AKI (e.g., CK, potassium, creatinine, myoglobinuria).
- Consider adding a **brief narrative summary** beneath the table (or in the results section) that explains the most clinically significant trends, for example:  “Serum creatine kinase rose sharply from 63,444 U/L on Day 1 to 161,050 U/L by Day 4, reflecting massive and progressive muscle necrosis despite initial resuscitation.” This approach will help readers quickly grasp the severity and trajectory of organ injury.

Response 3:

We sincerely thank the reviewer for the constructive comment regarding Table 5. In response, we have revised the table to bold all key abnormal values directly relevant to rhabdomyolysis and acute kidney injury, including creatine kinase, potassium, creatinine, and myoglobinuria, to enhance clinical readability. Additionally, we have included a concise narrative summary beneath the table highlighting the most clinically significant trends.

 

Comment 4: Figure 1 – Visual Clarity and Educational Value
Figure 1 is visually cluttered and the causal pathway is not immediately intuitive. I recommend:
- Redesigning it as a **simplified flowchart** with clear directional arrows:   
  **ATP depletion → Impaired Na⁺/K⁺ ATPase → Intracellular Na⁺ and Ca²⁺ overload → Activation of proteases → Myocyte necrosis → Release of intracellular contents (CK, myoglobin, K⁺) → Acute Kidney Injury**
- Adding **side-by-side illustrations** of a normal vs. injured myocyte to enhance educational impact.
- Ensuring that the figure is self-explanatory and aligns with the mechanistic discussion in the text.

Response 4:

We thank the reviewer for the valuable comment regarding Figure 1. In response, we have revised the figure to simplify the flow of the causal pathway, using clear directional arrows and streamlined labeling, while maintaining its full informational content. The figure is now self-explanatory and directly aligned with the mechanistic discussion in the text, facilitating rapid comprehension of the sequence of events leading from ATP depletion to acute kidney injury. We believe these changes enhance both the clarity and educational value of the figure, without compromising its scientific rigor.

 

Comment 5: Causality Assessment – Polysubstance Use and Toxicity

The causal link between the specific drug combination and the observed complications could be strengthened. While the discussion mentions potential mechanisms, it remains somewhat speculative. I suggest:

- Including a **dedicated subsection** (e.g., “Causality Analysis”) that systematically evaluates the contribution of each substance to the clinical presentation using established toxicological principles (e.g., temporal relationship, dose–response plausibility, exclusion of alternatives).
- Addressing **potential pharmacodynamic or pharmacokinetic interactions** (e.g., fentanyl-induced respiratory depression compounded by stimulant-induced hypermetabolism) that may have amplified toxicity.

- If possible, referencing toxicological databases or case series that support the plausibility of such a synergistic effect.

Response 5:

We thank the reviewer for the valuable suggestions regarding the assessment of causality. In response, we have revised the Discussion section to include a systematic evaluation of the potential contribution of each substance to the observed clinical presentation, based on established toxicological principles such as temporal relationship, dose–response plausibility, and exclusion of alternative causes. Additionally, we have addressed potential pharmacodynamic and pharmacokinetic interactions that may have amplified toxicity, for example, the synergistic effects of fentanyl and stimulants leading to accelerated muscle injury and acute kidney injury. These additions strengthen the scientific rigor of the discussion and provide a clearer mechanistic explanation of the observed clinical severity, without requiring additional laboratory or comparative toxicological analyses. We believe that these revisions adequately address the reviewer’s concerns and enhance the completeness and credibility of the manuscript.

 

Comment 6: Comment 6: Patient Refusal of Treatment – A Missed Opportunity for Deeper Analysis
The patient’s refusal of life-saving therapy is a pivotal element of this case, yet it is addressed only superficially. This limits the manuscript’s value in terms of clinical ethics and patient-centered care. I recommend expanding the discussion to include:

- A multidimensional analysis of potential reasons for refusal: psychiatric comorbidity, impaired decision-making capacity (e.g., substance-induced cognitive deficits, uremic encephalopathy), distrust in healthcare systems, or prior negative experiences.

- A reflection on clinician–patient communication and strategies to enhance therapeutic alliance in patients with substance use disorders.

- Consideration of ethical and legal frameworks for managing treatment refusal in life-threatening situations, including capacity assessment and the role of surrogate decision-makers.
This addition would significantly elevate the manuscript’s relevance to clinicians, ethicists, and public health professionals.

Response 6: We appreciate the reviewer’s insightful comment regarding the critical importance of the patient’s refusal of life-saving therapy. In response, we have expanded the discussion to provide a more comprehensive, multidimensional analysis, addressing potential reasons for refusal (psychiatric comorbidities, substance-induced cognitive impairment, uremic encephalopathy, and prior negative experiences with healthcare), clinician–patient communication strategies to enhance therapeutic alliance, and ethical/legal considerations, including capacity assessment and the role of surrogate decision-makers. We believe these revisions enhance the manuscript’s relevance to clinicians, ethicists, and public health professionals by integrating clinical ethics, patient-centered care, and the complex challenges of managing high-risk intoxications.

 

Comment 7: Overall Structure – Redundancy and Focus

The manuscript is overly lengthy and includes extraneous background material that detracts from the core case narrative. I recommend:

-Condensing the Introduction to focus on the “fourth wave” of the opioid crisis and the relevance of polysubstance use to the case. Omit or shorten general statistics that are not directly tied to the case.

- Streamlining the Discussion by avoiding repetition of pathophysiological mechanisms already covered in the introduction. Instead, focus on how the case illustrates or challenges existing knowledge.
- Prioritizing content that directly supports the causality analysis, clinical decision-making, and patient behavior, as suggested above.

A more focused manuscript will improve readability and enhance its impact on the target audience.

Response 7:

We thank the reviewer for highlighting the importance of manuscript focus and conciseness. In response, we have substantially condensed the overall text to ensure that attention remains on the core case. The Introduction has been streamlined to emphasize the “fourth wave” of the opioid crisis and the relevance of polysubstance use to the presented case. The Discussion has been optimized by avoiding repetition of pathophysiological mechanisms already addressed in the Introduction; instead, we focus on how the case illustrates or challenges existing knowledge. Priority was given to content directly supporting causality analysis, clinical decision-making, and patient behavior, as suggested. We believe these revisions enhance clarity, readability, and the manuscript’s impact on the target audience.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am completely satisfied with the revised version of the manuscript. So, I recommend accepting the article for publication in its current form.

Reviewer 2 Report

Comments and Suggestions for Authors

All my concerns have been addressed, so, I am haapy to suggest acceptance of revised version for publication.