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Case Report
Revised

Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome

[version 2; peer review: 2 approved]
PUBLISHED 20 Jan 2022
Author details Author details
OPEN PEER REVIEW
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Abstract

Introduction: Propofol infusion syndrome (PRIS) is rare but a potentially lethal adverse event. The pathophysiologic mechanism is still unknown.
Patient concerns: A 22-year-old man was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings, acute kidney injury, hyperkalemia and severe rhabdomyolysis.
Diagnosis and interventions: The patient was transferred to our intensive care unit (ICU) on suspicion of PRIS. Administration of noradrenaline and renal replacement therapy and fasciotomy for compartment syndrome of lower legs due to PRIS-rhabdomyolysis were performed.
Outcomes: The patient gradually recovered and was discharged from the ICU on day 30. On day 37, he had repeated sinus bradycardia with pericardial effusion in echocardiography. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle. Electron microscopic investigation of endomyocardial biopsy on day 75 revealed mitochondrial myelinization of the cristae, which indicated mitochondrial damage of cardiomyocytes. He was discharged without cardiac abnormality on day 192.
Conclusions: Mitochondrial damage in both morphological and functional aspects was observed in the present case. Sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.

Keywords

mitochondria, arrhythmia, cardiac failure,Propofol

Revised Amendments from Version 1

We have added some sentences about how Propofol impairs carnitine palmitoyl transport activities and cardiac calcium dynamics, potentially affecting the oxidation of fatty acids. We have included a few sentences explaining the different findings between the past reports and the present study. In addition, we have made some minor changes to the text as suggested by the reviewers.

See the authors' detailed response to the review by Anja Karlstaedt
See the authors' detailed response to the review by Susanne Haen and Petra Fallier-Becker

Abbreviations

PRIS, propofol infusion syndrome; 18F-FDG PET,18F-fluorodeoxyglucose positron emission tomography.

Introduction

Propofol is extensively used in the intensive care units (ICU) for sedation1. Propofol infusion syndrome (PRIS) is widely recognized as an adverse event of this commonly used drug, but is rare and potentially lethal2. The pathophysiologic mechanism is still unknown. However, mitochondrial damage is suggested to be a potential pathogenesis mechanism. Here we report a severe case of PRIS with evidence of mitochondrial damage in both morphological and functional aspects.

Case presentation

A 22-year-old man, who was a healthy university student with Japanese ancestry without preexisting medical and family history, experienced muscle weakness and was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered via a peripheral venous catheter for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings (ST elevation in II, III, and aVF). Blood test revealed acute kidney injury, hyperkalemia and severe rhabdomyolysis (serum creatinine phosphokinase 271,700 IU/L, normal range 68-287 IU/L). He was transferred to our ICU on suspicion of PRIS by excluding other diagnoses. Administration of noradrenaline via a central venous catheter (0.3 µg/kg/min) and hemodialysis were initiated, and fasciotomy by orthopedic surgeons under general anesthesia without propofol was required for compartment syndrome of lower legs due to PRIS-rhabdomyolysis. Noradrenaline was gradually reduced and terminated on day 15. He gradually recovered from cardiac and renal dysfunction according to echocardiography and blood tests and was discharged from the ICU on day 30. On day 37, he repeatedly presented sinus bradycardia and right bundle branch block in continuous electrocardiogram monitoring, eventually requiring temporary pacing via the intracardiac placement of a pacing wire, with a finding of pericardial effusion on echocardiography. Detailed examination including cardiac 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was conducted to evaluate whether these late-phase cardiac events were related to PRIS. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle with a maximum Standardized Uptake Value(SUV) of 3.97 (Figure 1). Blood glucose level before imaging was 90mg/dL. Electron microscopic investigation of the endomyocardial biopsy, which was taken on day 75 to examine the cause of cardiac dysfunction, revealed abnormal findings in the mitochondria of the cardiomyocytes, including myelinization of the cristae (Figure 2), which was interpreted as mitochondrial damage. In addition, apoptotic myocytes were not observed. Since weakness of respiratory muscles and extremities muscles needed mechanical ventilation and rehabilitation, he was treated in the hospital for another 3 months.He was taken off the ventilator and transferred to another hospital on day 192 due to persisting muscle weakness, but with normal cardiac function without arrhythmia. Three-year follow-up revealed that he had normal cardiac function with normal activities of daily living.

6e531e37-47c7-42ca-a7cd-4b1d9f5ebe01_figure1.gif

Figure 1. 18F-fluorodeoxyglucose positron emission tomography.

18F-fluorodeoxyglucose positron emission tomography showed heterogeneous 18F-FDG uptake in left ventricle. Scale bar: 5cm.

6e531e37-47c7-42ca-a7cd-4b1d9f5ebe01_figure2.gif

Figure 2. Electron microscopic investigation of endomyocardial biopsy.

Electron microscopy revealed mitochondrial myelinizations of the cristae in cardiomyocyte. Arrows indicate cardiomyocytes with the mitochondrial injury. Scale bar: 1 µm.

Discussion and conclusions

Mitochondrial damage is suggested as a potential pathogenesis of PRIS24. Mitochondrial damage was observed as a morphological finding in an electron microscopic evaluation of the heart in an autopsy case of PRIS5. We found myelinization of the cristae in cardiomyocyte on day 75; however, similar findings were not observed in postmortem electron microscopical image of mitochondria of PRIS in the previous report5. Different clinical course and timepoints may alter mitochondrial conditions. The autopsy study measured blood levels of short-chain acylcarnitines, while we have no blood sample available for the measurement. Further studies measuring blood levels of short-chain acylcarnitines would strengthen the case results. Similarly, mitochondrial damage was observed in the endomyocardial biopsy two months after the onset in the present case. Mitochondrial damage can also be detected as a functional impairment of fatty acid utilization with alternatively increased glucose utilization6. Propofol is known to inhibit the effects of carnitine palmityl transferase 1 (CPT 1), which transports long-chain fatty acids into the mitochondria3. Thus, propofol potentially impairs carnitine palmitoyl transport activities and cardiac calcium dynamics, affecting the oxidation of fatty acids3. The uptake of a glucose analog (18F-FDG) in left ventricle on day 67 (Figure 1) in the present case implies a shift in the energy substrate of cardiomyocytes from fatty acid to glucose, suggesting mitochondrial damage. To the best of our knowledge, this is the first to report a case of PRIS with evidence of mitochondrial damage in both morphological and functional aspects, which is the strength of this case report. The evidence of increased glucose uptake by 18F-FDG PET and mitochondrial damage by electron microscopic investigation was not repeatedly evaluated during the time-course but a single time-point (18F-FDG PET on day 67 and endomyocardial biopsy 75), which is a potential limitation. Additional timepoints data in future studies would reveal that these flux changes occur due to mitochondrial damage or pharmacologic modulation of key regulatory enzymes and transporters. Since the mitochondrial damage was detected 2 month later after PRIS onset, sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

Consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

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Version 2
VERSION 2 PUBLISHED 16 Jul 2020
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how to cite this article
Karasawa S, Nakada Ta, Mori N et al. Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome [version 2; peer review: 2 approved]. F1000Research 2022, 9:712 (https://doi.org/10.12688/f1000research.24567.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 20 Jan 2022
Revised
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3
Cite
Reviewer Report 08 Mar 2022
Anja Karlstaedt, Cedars Sinai Medical Center, Los Angeles, CA, USA 
Approved
VIEWS 3
The authors have addressed all my concerns and appropriately revised the manuscript. ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Karlstaedt A. Reviewer Report For: Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome [version 2; peer review: 2 approved]. F1000Research 2022, 9:712 (https://doi.org/10.5256/f1000research.112729.r120539)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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6
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Reviewer Report 27 Jan 2022
Petra Fallier-Becker, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Tuebingen, Germany 
Susanne Haen, Institute of pahtology and neuropathology, University of Tuebingen, Tuebingen, Germany 
Approved
VIEWS 6
The revisions ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Fallier-Becker P and Haen S. Reviewer Report For: Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome [version 2; peer review: 2 approved]. F1000Research 2022, 9:712 (https://doi.org/10.5256/f1000research.112729.r120540)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 16 Jul 2020
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23
Cite
Reviewer Report 27 Nov 2020
Anja Karlstaedt, Cedars Sinai Medical Center, Los Angeles, CA, USA 
Approved with Reservations
VIEWS 23
Karasawa et al. present a case report titled "Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome." The authors describe the case of a 22-year-old man of Japanese descent who developed a propofol infusion syndrome (PRIS) as ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Karlstaedt A. Reviewer Report For: Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome [version 2; peer review: 2 approved]. F1000Research 2022, 9:712 (https://doi.org/10.5256/f1000research.27101.r74771)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 20 Jan 2022
    Satoshi Karasawa, Department of Emergency and Critical Care Medicine,, Graduate School of Medicine,Chiba University, 1-8-1 Inohana, Chuo, 260-8677, Japan
    20 Jan 2022
    Author Response
    Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic.

    1. The authors need to provide ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 20 Jan 2022
    Satoshi Karasawa, Department of Emergency and Critical Care Medicine,, Graduate School of Medicine,Chiba University, 1-8-1 Inohana, Chuo, 260-8677, Japan
    20 Jan 2022
    Author Response
    Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic.

    1. The authors need to provide ... Continue reading
Views
25
Cite
Reviewer Report 12 Nov 2020
Susanne Haen, Institute of pahtology and neuropathology, University of Tuebingen, Tuebingen, Germany 
Petra Fallier-Becker, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Tuebingen, Germany 
Approved with Reservations
VIEWS 25
The concentration of several short-chain acylcarnitines in the patient's blood is missing.

Furthermore,the authors showed an electron microscopical image of mitochondria in the heart muscle with "myelinization of the cristae" but they don't write anything about the ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Haen S and Fallier-Becker P. Reviewer Report For: Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome [version 2; peer review: 2 approved]. F1000Research 2022, 9:712 (https://doi.org/10.5256/f1000research.27101.r74264)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 20 Jan 2022
    Satoshi Karasawa, Department of Emergency and Critical Care Medicine,, Graduate School of Medicine,Chiba University, 1-8-1 Inohana, Chuo, 260-8677, Japan
    20 Jan 2022
    Author Response
    Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic. Unfortunately, we have no samples available to ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 20 Jan 2022
    Satoshi Karasawa, Department of Emergency and Critical Care Medicine,, Graduate School of Medicine,Chiba University, 1-8-1 Inohana, Chuo, 260-8677, Japan
    20 Jan 2022
    Author Response
    Thank you for taking your time to review and comment on our manuscript. Sorry for the delay in response due to COVID-19 pandemic. Unfortunately, we have no samples available to ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 16 Jul 2020
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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