Koyama et al. (2017): Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients

Reference ↗
Title	Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients
Topic	Carnitine
Author	Koyama Y, Moro K, Nakano M, Miura K, Nagahashi M, Kosugi S-i, Tsuchida J, Ikarashi M, Nakajima M, Ichikawa H, Hanyu T, Shimada Y, Sakata J, Kameyama H, Kobayashi T, Wakai T
Year	2017
Journal	Journal of clinical medicine research
DOI	https://doi.org/10.14740/jocmr3113w

Brief summary

The study investigated the influence of carnitine on the inflammatory and insulin response in patients following surgery for gastric or colorectal cancer. Eight patients were randomly assigned to the control group, who received the usual parenteral nutrition after colorectal cancer surgery. In the intervention group, the 8 patients were also given carnitine. The administration took place in both groups over 4 days after surgery and showed no differences in laboratory values, insulin response or other characteristics between the two groups. The additional administration of carnitine does not appear to have any health benefits for the target group, but the results should be interpreted with caution due to the small sample size.

Die Studie untersuchte den Einfluss von Carnitin auf die Entzündungs- und Insulinreaktion bei Patienten nach einer Operation aufgrund eines Magen – oder Kolorektalen Karzinoms. Es wurden 8 Patienten zufällig in die Kontrollgruppe eingeteilt, diese erhielten die übliche Gabe an parentaler Ernährung nach der Operation des Darmkrebses. In der Interventionsgruppe wurde den 8 Patienten zusätzlich Carnitin verabreicht. Die Gabe erfolgte in beiden Gruppen über 4 Tage nach der Operation und zeigte keine Unterschiede in den Laborwerten, der Insulin Reaktion oder anderen Merkmalen zwischen den beiden Gruppen. Die zusätzliche Gabe von Carnitin scheint der Zielgruppe keine gesundheitlichen Vorteile zu bringen, aufgrund der kleinen Stichprobe sind die Ergebnisse aber mit Vorsicht zu interpretieren.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	NI
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Preoperative gastric or colorectal cancer patients without distant metastasis
Exclusion criteria	Liver dysfunction, respiratory dysfunction, cardiac dysfunction, renal failure, ongoing infection, history of recent immunosuppressive or immunologic disease (including preoperative chemo-therapy and/or radiation therapy), or diabetes mellitus
N randomized	16
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	ITT not specified, but no drop-out reported.
Countries of data collection	Japan
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: preoperative phase T1: 1 day after surgery T2-T7: Day 2-7 after surgery Blood samples at T0, T1, T3 and T4; carnitine concentration at T0, T1, T3, T7; C-reactive protein (CRP) at T3 and T7, urine samples at T3 and T7

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal Cancer, Gastrointestinal Cancers - Gastric (Stomach) Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Stage I-III
Comorbidities	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	Open or Laparoscopic surgery for gastric or colorectal cancer + Peripheral postoperative parenteral nutrition (PPN): glucose, amino acid, lipid emulsion
Previous cancer therapies	No therapy
Gender	Mixed
Gender specifications	43.8% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 68 (9.6) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	8
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Carnitin + PPN + Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
Dosage and regime	Peripheral PN (PPN) 100ml (20% lipid emulsion) + carnitine, IV, -1st postoperative day OP to day 4, average administration: 72.6mg/kg daily (SD = 37.3) Duration: 4 days
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	4
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	-999
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	PPN + Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
Dosage and regime	Peripheral PN (PPN) 100ml (20% lipid emulsion)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	4
Side effects / Interactions	NI

Outcomes

Postoperative morbidity/ complications

Outcome type As specificed by the authors	Primary
Outcome specification	Reduction of complication rates: infectious, mechanical, overall after surgery
Type of measurement	NI
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No differences between the arms for complications (in both arms n=2 each; p=0.715) or type of complication (p>0.05)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	This work was supported financially by Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports and Culture, Japan (Project no. 15K10047).
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethical approval obtained.
• Testing of variables for normal distribution.
• Reporting values adjusted for variable distribution.
• Good statistical methodology with adjusted corrections.
• Consideration of baseline values (ANCOVA).

CONTRA:

• At baseline: BMI, TLC, and ChE significantly higher in intervention arm (p < 0.05).
• Measurements of individual variables taken on different days.
• Unclear temporal definition of preoperative phase.
• 14 out of 16 participants had colorectal cancer, mostly stage I.
• Very brief data presentation.
• Very small sample size.
• Short intervention phase.
• BMI: significant preoperative difference between groups, with the difference on postoperative day 7 even larger but no longer significant.
• No reporting of significance values when no difference was found.