#12

Search #9 AND #11

#11

Search randomized controlled trial OR randomized controlled trials OR controlled clinical trial OR controlled clinical trials OR random* OR trial OR trials OR groups OR double blind method OR double blind methods OR single blind method OR single blind methods OR clinical trial OR clinical trials OR research design OR controlled study OR controlled studies OR "clinical study" OR "clinical studies" OR control OR controlled OR controls

#10

Search #8 AND (animals[mh] NOT humans[mh])

#9

Search #8 NOT (animals[mh] NOT humans[mh])

#8

Search #7 NOT (editorial[pt] OR letter[pt] OR case reports[pt] OR news[pt] OR newspaper article[pt])

#7

Search #3 OR #5 OR #6

#6

Search #4 AND (neoplasm*[ti] OR tumor*[ti] OR tumour*[ti] OR cancer*[ti]) AND (recur*[ti] OR risk*[ti] OR metasta*[ti])

#5

Search #2 AND #4 AND neoplasm[mh] AND adverse effects[sh]

#4

Search opioid* OR opiate* OR morphine* OR alfentanil OR alphadolone OR alphaxalone OR benoxinate OR benzocaine OR "benzyl alcohol" OR bumecain OR bupivacaine OR butamben OR carbizocaine OR carticaine OR chloralose OR chloroprocaine OR cyclopropane OR desflurane OR diazepam OR dibucaine OR diphenhydramine OR dyclonine OR emla OR enflurane OR entonox OR etidocaine OR etomidate OR ether OR fentanyl OR halothane OR heptacaine OR innovar OR isoflurane OR ketamine OR levobupivacaine OR lidocaine OR lignocaine OR "magnesium sulfate" OR mepivacaine OR methohexital OR methoxyflurane OR methyleugenol OR midazolam OR minaxolone OR "nitrous oxide" OR norflurane OR pentacaine OR phenoxyethanol OR pregnanolone OR prilocaine OR procaine OR propanidid OR propisomide OR propofol OR propoxycaine OR proxymetacaine OR remifentanil OR romifidine OR ropivacaine OR sevoflurane OR "sodium oxybate" OR sufentanil OR "tec solution" OR tetracaine OR tetrahydrodeoxycorticosterone OR tetrodotoxin OR thiamylal OR thiopental OR tiletamine OR tribromoethanol OR tricaine OR trichloroethylene OR trimecaine OR urethane OR anesthe*[ti] OR anaesthe*[ti] OR analges*[ti]

#3

Search #1 AND #2

#2

Search neoplasm recurrence, local[mh] OR neoplasm invasiveness[mh] OR neoplasm metastasis[mh] OR cocarcinogenesis[mh]

#1

Search "anesthesia and analgesia"[mh:noexp] OR anesthesia[mh] OR analgesia[mh:noexp] OR analgesia, epidural[mh] OR analgesia, patient‐controlled[mh] OR anesthetics[majr] OR anesthetics/adverse effects OR anesthetics/immunology OR anesthetics/pharmacology OR analgesics[majr] OR analgesics/adverse effects OR analgesics/immunology OR analgesics/pharmacology OR adjuvants, anesthesia[mh]

#14

#11 AND #13

#13

'randomized controlled trial' OR 'randomized controlled trials' OR 'controlled clinical trial' OR 'controlled clinical trials' OR random*:ab,ti OR 'double blind procedure' OR 'double blind procedures' OR 'single blind procedure' OR 'single blind procedures' OR 'clinical trial' OR 'clinical trials' OR 'controlled study' OR 'controlled studies' OR 'clinical study'/de OR 'major clinical study'/exp

#12

#10 AND [animals]/lim NOT [humans]/lim

#11

#10 NOT ([animals]/lim NOT [humans]/lim)

#10

#9 NOT ('editorial'/de OR 'letter'/de OR 'case report'/de)

#9

#3 OR #6 OR #7 OR #8

#8

anesthe*:ti OR anaesthe*:ti OR analges*:ti AND metasta*:ti

#7

anesthe*:ti OR anaesthe*:ti OR analges*:ti AND (neoplasm*:ti OR tumor*:ti OR tumour*:ti OR cancer*:ti) AND (recur*:ti OR risk*:ti OR metasta*:ti)

#6

#4 AND #5

#5

'cancer recurrence'/exp OR 'recurrent cancer'/exp OR 'tumor recurrence'/exp OR 'metastasis'/de OR 'cocarcinogenesis'/de OR 'cancer invasion'/exp

#4

'anesthesiological techniques'/exp/mj OR 'anesthetic agent'/exp/mj OR 'analgesic agent'/exp/mj OR 'local anesthetic agent'/exp/mj OR 'anesthesia complication'/exp/mj

#3

#1 AND #2

#2

'cancer recurrence'/exp/mj OR 'recurrent cancer'/exp/mj OR 'tumor recurrence'/exp/mj OR 'metastasis'/mj OR 'cocarcinogenesis'/mj OR 'cancer invasion'/exp/mj

#1

'anesthesiological techniques'/exp OR 'anesthetic agent'/exp OR 'analgesic agent'/exp OR 'local anesthetic agent'/exp OR 'anesthesia complication'/exp

#9

#8 AND #7
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#8

Topic=(random* OR "controlled clinical trial" OR "controlled clinical trials" OR "double blind method" OR "double blind methods" OR "single blind method" OR "single blind

methods" OR "clinical trial" OR "clinical trials" OR "research design" OR "controlled study" OR "controlled studies" OR "clinical study" OR "clinical studies")
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#7

#5 OR #6
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#6

Title=(anesthe* or anaesthe* or analges*) AND Title=(metasta*)
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#5

#3 and #4
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#4

Topic=(neoplasm* or tumor* or tumour* or cancer*) AND Topic=(recur* or risk* or metasta*)
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#3

#1 OR #2
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#2

Title=("magnesium sulfate" OR mepivacaine OR methohexital OR methoxyflurane OR methyleugenol OR midazolam OR minaxolone OR "nitrous oxide" OR norflurane OR

pentacaine OR phenoxyethanol OR pregnanolone OR prilocaine OR procaine OR propanidid OR propisomide OR propofol OR propoxycaine OR proxymetacaine OR remifentanil

OR romifidine OR ropivacaine OR sevoflurane OR "sodium oxybate" OR sufentanil OR "tec solution" OR tetracaine OR tetrahydrodeoxycorticosterone OR tetrodotoxin OR

thiamylal OR thiopental OR tiletamine OR tribromoethanol OR tricaine OR trichloroethylene OR trimecaine OR urethane)
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

#1

Title=(anesthe* OR anaesthe* OR analges* OR opioid* OR opiate* OR morphine* OR alfentanil OR alphadolone OR alphaxalone OR benoxinate OR benzocaine OR "benzyl
alcohol" OR bumecain OR bupivacaine OR butamben OR carbizocaine OR carticaine OR chloralose OR chloroprocaine OR cyclopropane OR desflurane OR diazepam OR

dibucaine OR diphenhydramine OR dyclonine OR emla OR enflurane OR entonox OR etidocaine OR etomidate OR ether OR fentanyl OR halothane OR heptacaine OR innovar OR isoflurane OR ketamine OR levobupivacaine OR lidocaine OR lignocaine)
Databases=SCI‐EXPANDED, SSCI, A&HCI Timespan=All years

# 11

#10 AND Document Type=(Article OR Meeting OR Meeting Paper) AND Taxa Notes=(Humans)

Databases=PREVIEWS Timespan=All Years

# 10

#9 AND Document Type=(Article OR Meeting OR Meeting Paper)

Databases=PREVIEWS Timespan=All Years

# 9

#8 AND #7

Databases=PREVIEWS Timespan=All Years

# 8

Topic=(random* OR "controlled clinical trial" OR "controlled clinical trials" OR "double blind method" OR "double blind methods" OR "single blind method" OR "single blind methods" OR "clinical trial" OR "clinical trials" OR "research design" OR "controlled study" OR "controlled studies" OR "clinical study" OR "clinical studies")

Databases=PREVIEWS Timespan=All Years

# 7

#6 OR #5

Databases=PREVIEWS Timespan=All Years

# 6

Title=(anesthe* or anaesthe* or analges*) AND Title=(metasta*)

Databases=PREVIEWS Timespan=All Years

# 5

#3 and #4

Databases=PREVIEWS Timespan=All Years

# 4

Topic=(neoplasm* or tumor* or tumour* or cancer*) AND Topic=(recur* or risk* or metasta*)

Databases=PREVIEWS Timespan=All Years

# 3

#1 OR #2

Databases=PREVIEWS Timespan=All Years

# 2

Title=("magnesium sulfate" OR mepivacaine OR methohexital OR methoxyflurane OR methyleugenol OR midazolam OR minaxolone OR "nitrous oxide" OR norflurane OR pentacaine OR phenoxyethanol OR pregnanolone OR prilocaine OR procaine OR propanidid OR propisomide OR propofol OR propoxycaine OR proxymetacaine OR remifentanil OR romifidine OR ropivacaine OR sevoflurane OR "sodium oxybate" OR sufentanil OR "tec solution" OR tetracaine OR tetrahydrodeoxycorticosterone OR tetrodotoxin OR thiamylal OR thiopental OR tiletamine OR tribromoethanol OR tricaine OR trichloroethylene OR trimecaine OR urethane)

Databases=PREVIEWS Timespan=All Years

# 1

Title=(anesthe* OR anaesthe* OR analges* OR opioid* OR opiate* OR morphine* OR alfentanil OR alphadolone OR alphaxalone OR benoxinate OR benzocaine OR "benzyl alcohol" OR bumecain OR bupivacaine OR butamben OR carbizocaine OR carticaine OR chloralose OR chloroprocaine OR cyclopropane OR desflurane OR diazepam OR dibucaine OR diphenhydramine OR dyclonine OR emla OR enflurane OR entonox OR etidocaine OR etomidate OR ether OR fentanyl OR halothane OR heptacaine OR innovar OR isoflurane OR ketamine OR levobupivacaine OR lidocaine OR lignocaine)

Databases=PREVIEWS Timespan=All Years

Study title                                                                                               

Screener             

OSC

KK

First study author                            

Source (e.g. journal, abstract)        

Publication year     

Inclusion criteria

Yes            

No              

Unknown  

Study design    

RCT, CCT?

Participants      

Tumour surgery in adults and/or    

children?

Intervention      

General anaesthesia (GA)

vs regional anaesthesia (RA) or

vs combination (GA + RA)?

or

opioid anaesthesia

vs opioid‐free anaesthesia?

Outcome           

Mortality and/or

tumour recurrence?

Reason for exclusion                                                                                                             

First study author

Year

Study title:

Initials of review author:

Source (Journal, Abstract…):

Study design:

RCT

CCT

Participants

Group 1

(control)

Group 2

(intervention)

N per group

Age (mean)

Paediatric patients (n)

Male/female (n)

Type of cancer, site

Type of cancer, histology

TNM clinical

TNM pathological

Stage (0–IV)

Type(s) of surgery

Resection of the primary tumour (yes/no)

Preceding chemotherapy (n)

Preceding radiation (n)

Following chemotherapy (n)

Following radiation (n)

Additional information/notes:  

Intervention

Type of intervention (RA or combination GA + RA)

Type of RA (block technique) (name all that apply)

Single shot or catheter technique?

Local anaesthetic (LA) used for RA

Dose of LA (% mL) (mean) used for RA

Time RA administered (preop/postop)

Duration of RA (for catheter techniques) (mean per group)

Control group GA?

Type of GA (TIVA, BAL)

If BAL: type of volatile anaesthetic used

Amount of opioid used perioperatively per group (mean)

Continuous IV lidocaine infusion used perioperatively?

If yes: give duration and dosage

Any opioids administered intrathecally, epidurally or peripherally?

If yes: give route of administration, dose and time

Outcome: overall survival

Group 1

(control)

Group 2

(intervention)

total

Randomization ratio

Participants randomly assigned (n)

Participants analysed (n)

Observed events (n)

Log‐rank expected events (n)

Hazard ratio, CI, level (e.g. 95%)

Log‐rank variance

Log‐rank observed—expected events

Hazard ratio (+CI/level or standard error or variance)

from adjusted or unadjusted Cox

Test statistics, 2‐sided P value, test used

(e.g. log‐rank, Mantel‐Haenszel, Cox)

Advantage for intervention or control?

Actuarial or Kaplan‐Meier curves reported?

Number at risk reported

Follow‐up:

Minimum

Maximum

Median

Time period of recruitment

Interval censoring method

Outcome: progression‐free survival

Group 1

(control)

Group 2

(intervention)

total

Randomization ratio

Participants randomly assigned (n)

Participants analysed (n)

Observed events (n)

Log‐rank expected events (n)

Hazard ratio, CI, level (e.g. 95%)

Log‐rank variance

Log‐rank observed—expected events

Hazard ratio (+CI/level or standard error or variance)

from adjusted or unadjusted Cox

Test statistics, 2‐sided P value, test used

(e.g. log‐rank, Mantel‐Haensel, Cox)

Advantage for intervention or control?

Actuarial or Kaplan‐Meier curves reported?

Number at risk reported

Follow‐up:

Minimum

Maximum

Median

Time period of recruitment

Interval censoring method

Outcome: time to tumour progression

Group 1

(control)

Group 2

(intervention)

total

Randomization ratio

Participants randomly assigned (n)

Participants analysed (n)

Observed events (n)

Log‐rank expected events (n)

Hazard ratio, CI, level (e.g. 95%)

Log‐rank variance

Log‐rank observed—expected events

Hazard ratio (+CI/level or standard error or variance)

from adjusted or unadjusted Cox

Test statistics, 2‐sided P value, test used

(e.g. log‐rank, Mantel‐Haensel, Cox)

Advantage for intervention or control?

Actuarial or Kaplan‐Meier curves reported?

Number at risk reported

Follow‐up (months):

Minimum

Maximum

Median

Time period of recruitment

Interval censoring method

Adverse events reported (in‐hospital)

Group 1

(control)

Group 2

(intervention)

PONV

Postoperative respiratory complications

(i.e. pneumonia, respiratory insufficiency, aspiration, pulmonary embolism)

Postoperative cardiovascular events (i.e. myocardial ischaemia, myocardial infarction, heart failure, cardiac arrest)

Trial characteristics

Single‐centre/multi‐centre

Country/Countries

How was participant eligibility defined?

Was the outcome of interest (tumour recurrence) defined as a primary or secondary outcome in the original protocol?

If 'NO':

When was the decision made to assess tumour recurrence?

Was there a formal study protocol amendment?

If 'YES': When? What was the amendment?

How was tumour recurrence assessed?

‐ Follow‐up visits were part of the original study design and were used to assess tumour recurrence

‐ Assessment of tumour recurrence was extracted from cancer registry

‐ Assessment of tumour recurrence was extracted from hospital records

Additional information/notes:

Methodological quality:

Adequate (random)

Inadequate (e.g. alternate)

Unclear

Allocation of intervention

Describe method: 

Concealment of allocation

Describe method: 

Blinding

Yes

No

Unclear

Caregiver

Participant

Outcome assessor

Intention‐to‐treat

All participants entering trial

15% or fewer excluded

More than 15% excluded

Not analysed as

intention‐to‐treat

Unclear

Withdrawals described?

Additional notes: 

Domain

Description

Review authors’ judgement

Sequence generation

Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups

Was the allocation sequence adequately generated?

Allocation concealment

Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment

Was allocation adequately concealed?

Blinding of participants, personnel and outcome assessorsAssessments should be made for each main outcome (or class of outcomes) 

Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information regarding whether the intended blinding was effective

Was knowledge of the allocated intervention adequately prevented during the study?

Incomplete outcome dataAssessments should be made for each main outcome (or class of outcomes) 

Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomly assigned participants), reasons for attrition/exclusions when reported and any re‐inclusions in analyses performed by the review authors

Were incomplete outcome data adequately addressed?

Selective outcome reporting

State how the possibility of selective outcome reporting was examined by the review authors, and describe what was found

Are reports of the study free of suggestion of selective outcome reporting?

Other sources of bias

State any important concerns about bias not addressed in the other domains in the tool

If particular questions/entries were prespecified in the review protocol, responses should be provided for each question/entry

Was the study apparently free of other problems that could put it at high risk of bias?

SEQUENCE GENERATION

Was the allocation sequence adequately generated? [Short form: Adequate sequence generation?] 

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

Investigators describe a random component in the sequence generation process such as:

·         Referring to a random number table;

·         Using a computer random number generator;

·         Coin tossing;

·         Shuffling of cards or envelopes;

·         Throwing of dice;

·         Drawing of lots;

·         Minimization*.

 *Minimization may be implemented without a random element, and this is considered to be equivalent to being random.

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

Investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example:

·         Sequence generated by odd or even date of birth;

·         Sequence generated by some rule based on date (or day) of admission;

·         Sequence generated by some rule based on hospital or clinic record number.

Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorization of participants, for example:

·         Allocation by judgement of the clinician;

·         Allocation by preference of the participant;

·         Allocation based on the results of a laboratory test or a series of tests;

·         Allocation by availability of the intervention.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

Insufficient information about the sequence generation process to permit judgement of ‘Yes’ or ‘No’

ALLOCATION CONCEALMENT 

Was allocation adequately concealed? [Short form: Allocation concealment?]

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation:

·         Central allocation (including telephone, web‐based and pharmacy‐controlled, randomization);

·         Sequentially numbered drug containers of identical appearance;

·         Sequentially numbered, opaque, sealed envelopes.

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on:

·         Use of an open random allocation schedule (e.g. a list of random numbers);

·         Assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or were not sequentially numbered);

·         Alternation or rotation;

·         Date of birth;

·         Case record number;

·         Any other explicitly unconcealed procedure.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

Insufficient information to permit judgement of ‘Yes’ or ‘No.’ This is usually the case if the method of concealment is not described or is not described in sufficient detail to allow a definitive judgement—for example, if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed

BLINDING OF PARTICIPANTS, PERSONNEL AND OUTCOME ASSESSORS

Was knowledge of the allocated interventions adequately prevented during the study? [Short form: Blinding?]

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

Any one of the following:

·         No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding;

·         Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken;

·         Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others is unlikely to introduce bias.

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

Any one of the following:

·         No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding;

·         Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken;

·         Either participants or some key study personnel were not blinded, and the non‐blinding of others is likely to introduce bias.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

Any one of the following:

·         Insufficient information to permit judgement of ‘Yes’ or ‘No’;

·         The study did not address this outcome.

INCOMPLETE OUTCOME DATA 

Were incomplete outcome data adequately addressed? [Short form: Incomplete outcome data addressed?]

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

Any one of the following:

·         No missing outcome data;

·         Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);

·         Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;

·         For dichotomous outcome data, the proportion of missing outcomes compared with the observed event risk not enough to have a clinically relevant impact on the intervention effect estimate;

·         For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size;

·         Missing data have been imputed using appropriate methods.

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

Any one of the following:

·         Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups;

·         For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate;

·         For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;

·         ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization;

·         Potentially inappropriate application of simple imputation.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

Any one of the following:

·         Insufficient reporting of attrition/exclusions to permit judgement of ‘Yes’ or ‘No’ (e.g. number randomly assigned not stated, no reasons for missing data provided);

·         The study did not address this outcome.

SELECTIVE OUTCOME REPORTING 

Are reports of the study free of suggestion of selective outcome reporting? [Short form: Free of selective reporting?]

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

Any of the following:

·         The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way;

·         The study protocol is not available, but it is clear that published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon).

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

Any one of the following:

·         Not all of the study’s prespecified primary outcomes have been reported;

·         One or more primary outcomes are reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified;

·         One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect);

·         One or more outcomes of interest in the review are reported incompletely, so that they cannot be entered into a meta‐analysis;

·         The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

Insufficient information to permit judgement of ‘Yes’ or ‘No.’ It is likely that most studies will fall into this category

OTHER POTENTIAL THREATS TO VALIDITY 

Was the study apparently free of other problems that could put it at risk of bias? [Short form: Free of other bias?]

Criteria for a judgement of ‘YES’ (i.e. low risk of bias)

The study appears to be free of other sources of bias

Criteria for a judgement of ‘NO’ (i.e. high risk of bias)

There is at least one important risk of bias. For example, the study:

·         Had a potential source of bias related to the specific study design used; or

·         Stopped early because of some data‐dependent process (including a formal‐stopping rule); or

·         Had extreme baseline imbalance; or

·         Has been claimed to have been fraudulent; or

·         Had some other problem.

Criteria for a judgement of ‘UNCLEAR’ (uncertain risk of bias)

There may be a risk of bias, but there is either:

·         Insufficient information to assess whether an important risk of bias exists; or

·         Insufficient rationale or evidence that an identified problem will introduce bias.