Hajimohammadebrahim-Ketabforoush et al. (2019): Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial

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Title	Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial
Topic	Vitamin D
Author	Hajimohammadebrahim-Ketabforoush, M, Shahmohammadi, M, Khoundabi, B, Shariatpanahi, ZV
Year	2019
Journal	World Neurosurgery
DOI	https://doi.org/10.1016/j.wneu.2019.05.250

Brief summary

This study examined the effect of high-dose vitamin D3 before tumor surgery on the subjective perception of pain and the use of painkillers after surgery in 60 patients with brain tumors and low vitamin D levels. Three days after the operation, there were no significant differences between patients who had been injected with 300,000 IU 2-14 days before the operation and the control patients in terms of subjective pain perception and painkiller use. Numerous criticisms can be made of this study, e.g. significant differences between the intervention and control arms at the start of the study, inadequate descriptions of the interventions in the intervention and control arms, and unclear calculations.

Diese Studie untersuchte bei 60 Patienten mit Gehirntumoren und zu niedrigem Vitamin D Spiegel die Wirkung von hochdosiertem Vitamin D3 vor der Tumoroperation auf die subjektive Schmerzwahrnehmung und den Schmerzmittelgebrauch nach der Operation. Jeweils 3 Tage nach der Operation zeigten sich zwischen Patienten, die 2-14 Tage vor der Operation 300,000 IU injiziert bekamen und den Kontrollpatienten keine bedeutsamen Unterschiede hinsichtlich subjektiver Schmerzwahrnehmung und Schmerzmittelgebrauch. An dieser Studie lassen sich zahlreiche Kritikpunkte nennen, z.B. bedeutsame Unterschiede zwischen Interventions- und Kontrollarm zum Beginn der Studie, unzureichende Beschreibungen der Interventionen in Interventions- und Kontrollarm, sowie unklare Berechnungen.

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	No
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	At least 18 years of age with newly diagnosed brain tumor with serum level of 25 (OH) vitamin D ≤20 ng/dL
Exclusion criteria	Having another trial participation session, including previous participation in the pilot trial, pregnant or lactating women, hypercalcemia, hyperphosphatemia, tuberculosis, sarcoidosis, history of nephrolithiasis, history of hyperparathyroidism, medications interfering with vitamin D metabolism, renal insufficiency, patients having psychological diseases, abnormal mental function, and unconscious patients
N randomized	71
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.	PP Analysis
Specifications on analyses	NI
Countries of data collection	Iran
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: before operation T1-T3: on day 1-3 after operation T4: on day 5 after operation

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	Brain and Central Nervous System (CNS) Cancers
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	NI
Specifications on cancer stages	NI
Comorbidities	Headache, hypertension, diabetes
Current cancer therapies	Surgery
Specifications on cancer therapies	The patients undergoing general anesthesia were induced with thiopental sodium 5e7 mg/kg, fentanyl 5 mg/kg, midazolam 0.02 mg/kg, lidocaine 1 mg/kg, atracurium 0.5 mg/kg, endotracheal intubation, and maintained with propofol 50e150 mg/kg/min in a 3 L/min oxygen/air mixture. Eventually, the patient’s awakening was induced with neostigmine and atropine to an extent of 0.07 mg/kg and 0.02 mg/kg, respectively.
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: 16 (53.3%) male Control arm: 14 (46.7%) male
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean (SD): 48.2 (15.3) Control arm: mean (SD): 4.3 (15.2)

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	35
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	Missed follow-up
Intervention	Vitamin D
Dosage and regime	Intramuscular injection of 300,000 IU vitamin D 2-14 days (with an average of 5 days) before surgery + all participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
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.	-999
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	36
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	6
Drop-out reasons	Missed follow-up
Intervention	Nothing
Dosage and regime	All participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
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.	-999
Side effects / Interactions	NI

Outcomes

Pain

Outcome type As specificed by the authors	NI
Outcome specification	Postoperative pain (doses of analgesic medication consumption)
Type of measurement	VAS (Visual Analogue Scale), Observation
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 significant differences in VAS scores; No significant differences in doses of analgesic medication consumption
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".	NI

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

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	NA
Type of measurement	Blood Test
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".	Increase in 25(OH) D on the fifth postoperative day in intervention arm was statistically significant compared with the control arm (p = 0.001)
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".	NI

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

Funding and Conflicts of Interest

Funding	Financially supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	No
- Possibility of placebo effects	Yes, one arm without any treatment.
- Other reasons	No

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	Yes
Correction for multiple testing	NA
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	No
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	No
Side effects considered in result interpretation	No
Ethics votum	Yes

Additional Notes

PRO

• Ethics vote;
• Pre/post level control of vitamin D (25 (OH) D level, mean (SD): Arm A: T0: 15.9 (3.8), T4: 22.5 (4.3), Arm B: T0:14.5 (3.6), T4: 13.7 (3.8); A vs. B: p<0.001)

CONTRA

• No power analysis
• Unclear blinding
• Descriptive differences regarding tumor pathology
• Unclear randomization
• Insufficient description of interventions in arm A and B
• Unclear calculations (e.g. no information on control variables in the model)
• Poor report quality