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Authors (names, affiliations, contributions)

Description Hyperoxic Vasconstriction (working title) B. Smit, MSc, Dept. of Intensive Care, VU University medical centre Y.M. Smulders, Prof, M.D., Ph.D., Dept. of Internal Medicine, VU University medical centre H.J.S. de Grooth, MSc, Dept. of Intensive Care, VU University medical centre A.R.J. Girbes, Prof, M.D., Ph.D., Dept. of Intensive Care, VU University medical centre H.M. Oudemans - van Straaten, Prof, M.D., Ph.D., Dept. of Intensive Care, VU University medical centre E.C. Eringa, Ph.D., Dept. of Physiology, VU University medical centre C. Hooijmans, Ph.D., Dept. of SYRCLE and Anesthesiology, Radboud University Medical Center A.M.E. Spoelstra - de Man, M.D., Ph.D., Dept. of Intensive Care, VU University medical centre


Other contributors (names, affiliations, contributions) Contact person + e-mail address


Funding sources/sponsors


Conflicts of interest Date and location of protocol registration Registration number (if applicable) N.A. Stage of review at time of registration Search B. Objectives Background Hospitalized patients often receive oxygen supplementation, which may lead to a supraphysiological oxygen tension (hyperoxia). Although not equivocal, studies in humans and animals show that hyperoxia causes a reduction in cardiac output and an increase in What is already known about this systemic vascular resistance, the latter suggesting disease/model/intervention? Why is it vasoconstriction. Besides the potential hindrance of organ important to do this review? perfusion due to vasoconstriction, the mechanism responsible for said constriction may be harmful to the patient. The magnitude and mechanism of the vasoconstriction is not well known. Both are required to better understand if the effect of hyperoxia is potentially harmful. Research question


7. 8. 9.


None B. Smit, Department of Intensive Care, VU University medical centre and ZonMw None

Check for approval

11. 12.

Specify the disease/health problem of interest Specify the population/species studied


Specify the intervention/exposure


Specify the control population


Specify the outcome measures


State your research question (based on items 11-15)

Hyperoxia induced alterations in hemodynamics/vascular tone PICO1: Animals PICO2: Isolated arteries/arterioles PICO1: Normobaric hyperoxia/hyperoxic superfusion PICO2: Hyperoxic superfusion PICO1: Normoxia/normoxic superfusion PICO2: Normoxic superfusion PICO1: Change in vascular tone PICO2: Change in vascular tone PICO1: What is the effect of normobaric hyperoxia or hyperoxic superfusion on hemodynamics or vascular tone in animals, in comparison to normoxia or normoxic superfusion? PICO2: What is the effect of hyperoxic superfusion on vascular tone of isolated arteries and arterioles, in comparison to normoxic superfusion?

C. Methods Search and study identification


Identify literature databases to search (e.g. Pubmed, Embase, Web of science)

x MEDLINE via PubMed □Web of Science □SCOPUS x EMBASE □Other, namely: □Specific journal(s), namely:


Define electronic search strategies (e.g. use the step by step search guide15 and animal search filters20, 21)

When available, please add a supplementary file containing your search strategy: [insert file name]

Identify other sources for study identification

x Reference lists of included studies □Books x Reference lists of relevant reviews □Conference proceedings, namely: □Contacting authors/ organisations, namely: □Other, namely:







Define search strategy for these other The reference lists of included studies will be screened for sources unknown articles based on title. Study selection Define screening phases (e.g. pre1. Title screening for obvious irrelevant studies screening based on title/abstract, full 2. Abstract screening text screening, both) 3. Full text screening Specify (a) the number of reviewers All screening phases will be performed by two reviewers. per screening phase and (b) how Discrepancies will be resolved by discussion. discrepancies will be resolved Define all inclusion and exclusion criteria based on: All PICOs: Inclusion criteria: Controlled studies, repeated measures Type of study (design) Exclusion criteria: Case reports, reviews, observational studies Type of animals/population (e.g. age, PICO1 gender, disease model) Inclusion criteria: Adult animals

Exclusion criteria: Disease models without healthy control, focus on lung, brain, fetal, retinal vasculature or ductus arteriosus, no focus on vasoactivity



27. 28. 29.


Type of intervention (e.g. dosage, timing, frequency)

Outcome measures

Language restrictions Publication date restrictions Other

Sort and prioritize your exclusion criteria per selection phase

PICO2 Inclusion criteria: Isolated arteries or arterioles from adult animals Exclusion criteria: Lung, brain, fetal, retinal vasculature or ductus arteriosus, no focus on vasoactivity PICO1 Inclusion criteria: Short term normobaric, normocapnic hyperoxia (FIO2 > .21), superfusion with a buffer having a PO2 > 55 mmHg or ~7-21% O2 Exclusion criteria: Hyperbaria, oxygen toxicity/lung damage, long term hyperoxia (hours-days), nonphysiological change in gas fraction/tension other than O2, exposure to hypoxia PICO2 Inclusion criteria: Acute change in oxygen tension of the buffer surrounding the vessel, superfusion with a buffer having a PO2 > 55 mmHg or ~7-21% O2 , use of a pressure or wire-myograph Exclusion criteria: Vessels preconditioned by hypoxia PICO1 Inclusion criteria: Arterial diameter Exclusion criteria: Nerve activity, plasma concentrations, exercise related parameters (i.e. maximal contraction force, endurance), tissue biopsies PICO2 Inclusion criteria: Diameter, tension Exclusion criteria: Pressure drop as outcome, vascular reactivity No language restrictions No publication date restrictions None Selection phase 1 1. Titles that are obviously not related to hyperoxia or oxygen Selection phase 2: 1. Type of study: Review, Case report, In-vitro 2. No focus on blood vessels 3. Long term hyperoxia (>6 hours) 4. Non physiological change in gas fraction/tension other than O2 5. Studies focussing on pregnancy or labour 6. Studies in foetuses/neonates/children 7. Unsuitable control a. No normoxic control

b. Non-brain, lung, eye vessels c. No data from healthy control

31. 32.






Selection phase 3: - Same as phase 2 - Not the identified outcomes (see 26) Study characteristics to be extracted (for assessment of external validity, reporting quality) Study ID (e.g. authors, year) 1st Author, last author, year, language Randomisation, blinding, quality control (e.g. endothelium Study design characteristics (e.g. integrity check), animal age, animal weight, animal sex, experimental groups, number of number of animals/vessels in experimental and control animals) group PICO1 Species, strain, method of oxygen administration, type of study (e.g. intra-vital), anaesthesia Animal model characteristics (e.g. species, gender, disease induction) PICO2 Vessel type, vessel size, measurement setup (e.g. pressure or wire myography) PICO1 FIO2s, %O2, PaO2s, PO2s used, duration, buffer used Intervention characteristics (e.g. intervention, timing, duration) PICO2 %O2 used, PO2s used, duration, buffer used PICO1 and PICO2 Arterial diameter: baseline value, value at maximal Outcome measures exposure, % difference from baseline Tension: baseline value, value at maximal exposure, % difference from baseline Number of non-responding animals/vessels, mention of Other (e.g. drop-outs) variability in responses, in case of multiple exposure levels also the type of response (e.g. linear, sigmoidal) Assessment risk of bias (internal validity) or study quality Specify (a) the number of reviewers assessing the risk of bias/study quality Two reviewers will assess risk of bias and study quality. in each study and (b) how Discrepancies will be resolved by discussion. discrepancies will be resolved

□By use of SYRCLE's Risk of Bias tool x By use of SYRCLE’s Risk of Bias tool, adapted as follows: 4



Define criteria to assess (a) the internal validity of included studies (e.g. selection, performance, detection and attrition bias) and/or (b) other study quality measures (e.g. reporting quality, power)

Collection of outcome data For each outcome measure, define the type of data to be extracted (e.g. continuous/dichotomous, unit of

- to be extended with some reporting quality items

□By use of CAMARADES' study quality checklist, e.g □By use of CAMARADES' study quality checklist, adapted -

as follows:

x Other criteria, namely: Arterial diameter; continuous, µm Tension; continuous, grams







44. 45. 46.





1. Direct extraction of data from tables or text Methods for data extraction/retrieval 2. Extraction from graphs using digital screen ruler (e.g. first extraction from graphs using 3. Contacting the authors. A maximum of two attempts a digital screen ruler, then contacting will be made. After the second attempt, we will wait 2 authors) weeks for an answer. Specify (a) the number of reviewers One reviewer will extract the data, and a second reviewer extracting data and (b) how will randomly check the extracted data. Discrepancies will discrepancies will be resolved be resolved by discussion. Data analysis/synthesis If possible, a meta-analysis will be performed for all Specify (per outcome measure) how you are planning to combine/compare outcome measures. If a meta-analysis is not possible the data (e.g. descriptive summary, (too few or too heterogeneous datasets) the data will be meta-analysis) reported by descriptive summary. A meta-analysis will be performed if there are at least 3 Specify (per outcome measure) how it studies reporting on a specific outcome measure. will be decided whether a metaSubgroup analyses are only conducted in case of minimal analysis will be performed 5 independent comparisons If a meta-analysis seems feasible/sensible, specify (for each outcome measure): The effect measure to be used (e.g. Outcome parameters will be analysed as standardized mean difference, standardized mean mean difference difference, risk ratio, odds ratio) The statistical model of analysis (e.g. Random effects model random or fixed effects model) The statistical methods to assess I2 heterogeneity (e.g. I2, Q) PICO1 Animal species Sex Vascular region Route of administration Which study characteristics will be examined as potential source of PICO2 heterogeneity (subgroup analysis) Animal species Sex Vessel origin Vessel type (systemic or resistance) Presence of flow Any sensitivity analyses you propose To be discussed to perform Correction of p-value for the number of subgroup analyses Other details meta-analysis (e.g. by Bonferroni-Holmes correction for multiple comparisons correction for multiple testing, with the same control group by dividing the number of correction for multiple use of control control animals by the number of comparisons with the group) control group The method for assessment of Funnel plot publication bias

Final approval by (names, affiliations):


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