Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Barriga, 2008

Type of study:

(quasi-)RCT

Setting and country:

Tertiary medical center-University hospital; Memphis, TN, USA

Funding and conflicts of interest:

Funding not reported; “None of the authors have anything to disclose.”

Patients undergoing elective esophago- gastroduodenoscopy

Inclusion criteria:

• Age > 18 years
• able to give written informed consent for elective diagnostic outpatient endoscopy

Exclusion criteria:

• Histories of substance abuse
• previous sedation difficulty,
• head and neck problems
• ASA classification III or higher
• had therapeutic interventions such as dilation and variceal banding
• unable to follow up (either via clinic visit or phone call).
• Inpatients

N total at baseline:

Intervention: 37

Control: 34

Important prognostic factors²:

Age, mean (range):

I: 49y (29-72)

C: 50y (20-74)

Sex:

I:  11/34 (32%) M

C: 13/37 (35%) M

ASA classification

I:

ASA-I: 14/36 (38.9%)

ASA-II: 22/36 (61.1%)

C:

ASA-I: 11/35 (31.4%)

ASA-II: 24/35 (68.6%)

Groups comparable at baseline; control group slightly more ASA-II status.

Fentanyl + midazolam

All patients were placed on supplemental oxygen per nasal cannula at a

rate of 2 L/min.

All patients had their oropharynx sprayed with a topical anesthetic (Cetacaine) twice, before intubation.

Before intubation, both groups of patients received (IV) a first dose of 1 mg of IV midazolam.

After 2 to 3 minutes, patients were re-evaluated, after which in the M/F group, after the initial dose of midazolam, patients received 50 µg of fentanyl IV, followed by either drug in fixed increments, 1 mg of midazolam or 50 µg of fentanyl, to achieve adequate sedation.

In the M/F group, the mean dose of midazolam was

2.5 mg and the mean dose on fentanyl was 78.5 µg.

Midazolam alone

All patients were placed on supplemental oxygen per nasal cannula at a

rate of 2 L/min.

All patients had their oropharynx sprayed with a topical anesthetic (Cetacaine) twice, before intubation.

Before intubation, both groups of patients received (IV) a first dose of 1 mg of IV midazolam.

After 2 to 3 minutes, patients were re-evaluated, after which patients in group M could receive as many doses of additional medication, in fixed 1 mg increments, as considered necessary to achieve the desired degree of conscious sedation.

In the M group, the mean dose of midazolam used was 3.5 mg.

Length of follow-up:

During procedure, directly after the procedure (examiner satisfaction) 72 hours (short telephone interview; patient satisfaction)

Loss-to-follow-up:

I: 2/37 (5.4%)

C: 4/34 (11.8%)

Reasons: addition of a different drug to

sedate the patient, and the inability to complete the examination due to lack of cooperation from the patient; not further specified

Sedation level

Not reported

Recovery time

Not reported

Patient satisfaction

Patient’s tolerance during the procedure, as asked during telephone follow-up (four options: excellent, good, fair, and poor)

Excellent tolerance per patient:

I: 33/35

C:27/29

p=1.0

How much they remembered of the procedure, as asked during telephone follow-up  (nothing, some, good part of it, or all of the procedure).

No or minimal recollection

I: 29/35

C: 26/29

P=0.49

How much they remember of the procedure, as asked during telephone follow-up (nothing, some, good part of it, or all of the procedure)

No or only some memory

of the procedure

I: 29/35 patients (82.8%)

C: 26/29 patients (89.6%)

P=0.49

If they felt any discomfort, , as asked during telephone follow-up  (none, mild, moderate, or severe pain)

No or mild discomfort

I: 32/35 (91.4%)

C:  27/29 (93%)

P=1

Provider satisfaction

Provider was questioned after procedure regarding the patient’s tolerance (excellent, good, fair, and poor) during the procedure

Excellent:

I: 29/37 (82%)

C: 19/34 (63.3%)

P=0.074

Adverse events

No complications existed and no drugs were needed to counteract the effect of sedation.

Respiratory depression

Not reported seperately

Apnea

Not reported seperately

Definitions:

-

Remarks:

• This was a quasi-RCT
• Number of patients and results (e.g. age in table 1, repeated slightly different) show some inconsistencies

Authors conclusion:

In summary, following an intention to treat analysis, this

study showed that based on endoscopist perspectives, the use of IV midazolam plus fentanyl achieves better sedation than a single drug. From the patient’s perspective no significant difference was founded. Further studies with blinding of the endoscopist in a larger cohort of patients are needed to confirm our findings.

Çinar, 2009

Type of study:

RCT

Setting and country:

September 2008 and March 2009;

Turkey

Funding and conflicts of interest:

Not reported

Patients undergoing routine colonoscopy

Inclusion criteria:

• admitted for routine colonoscopy

Exclusion criteria:

• re-examinations

N total at baseline: 74

After randomization, two patients had to be excluded due to failure in cecum intubation.

N

Intervention: 40

Control: 34

Important prognostic factors²:

For example

age ± SD:

I: 49.9, SD 15.8

C: 58.9, SD 13.7

Sex, male:

I: 14/40 (35%)

C: 17/34 (50%)

Baseline oxygen saturation (%)

I: 96.7, SD 1.10

C: 96.6, SD 1.12

p=0.778

Baseline heart rate (beat per min)

I: 71, SD 7.1

C: 71, SD 8.05

P=0.902

Baseline systolic pressure (mmHg)

I: 15.4 118, SD 15.06

C: 115, SD

P=0.332

History of coronary artery disease: I: 3,

C: 2; P=0.782

.. systemic hypertension: I: 4, C: 7; P=0.202

.. diabetes mellitus

I: 7, C: 6; P=0.987

Groups comparable at baseline.

Midazolam + meperidine

Oral sodium

phosphate solution was used in all patients

during preparation for colonoscopy.

Sedation for colonoscopy was performed in both

groups according to the routine practice in the

study center, with a total i.v. technique containing

midazolam.

Both groups received

an average dose of 2 mg midazolam (range: 2-5 mg).

In the midazolam/ meperidine group, a bolus of 25 mg meperidine was added.

In case of insufficient

sedation, midazolam dose was incremented up to a

maximum of 5 mg with additional bolus doses. In

case of insufficient analgesia, meperidine dose was increased up to a maximum of 75 mg. In case of oxygen saturation decreasing below 90%, oxygen supplement

was provided via nasal cannula (2 L/min).

In addition to the medication(s), all patients received continuous i.v. saline infusion (100 ml/h).

Midazolam alone

Oral sodium

phosphate solution was used in all patients

during preparation for colonoscopy.

Sedation for colonoscopy was performed in both

groups according to the routine practice in the

study center, with a total i.v. technique containing

midazolam.

Both groups received

an average dose of 2 mg midazolam (range: 2-5 mg).

In case of insufficient

sedation, midazolam dose was incremented up to a

maximum of 5 mg with additional bolus doses. In

case of insufficient analgesia, meperidine dose was increased up to a maximum of 75 mg. In case of oxygen saturation decreasing below 90%, oxygen supplement

was provided via nasal cannula (2 L/min).

In addition to the medication(s), all patients received continuous i.v. saline infusion (100 ml/h).

Length of follow-up:

4-6 hours post-procedure

Loss-to-follow-up:

Intervention: 0

Control: 0

Incomplete outcome data:

Not specified

Sedation level

Not reported

Recovery time, min, defined as the mean value for the time until the patient was fully

alert after colonoscopy

I: mean 28.2 min, SD 5.3

C: mean 28.3 min, SD 5.4

p=0.605

Patient satisfaction

Not reported

Provider satisfaction

Not reported

Adverse events

Respiratory depression

“A serious decline in oxygen saturation (initial O2

saturation vs lowest O2 saturation during the procedure) was seen in only 1 patient in the midazolam/

meperidine group (nasal oxygen supplement with 2 L/min via nasal cannula was provided); however, no potentially harmful drop in the oxygen saturation lower than 90% was observed.”

I: 0/40

C: 0/34

Apnea

Not reported

Also reported:

Degree of pain (VAS scale 0-10 rated by endoscopist and endoscopy nurse), procedure time, other adverse events

Definitions:

-

Remarks:

-pain is described as a variable for ‘patient satisfaction’. Pain scores were provided by endoscopist and endoscopy nurse. Therefore, not used in this summary as measure for either patient of provider satisfaction.

Authors conclusion:

Patient safety, outcomes, and satisfaction are similar in colonoscopy procedures performed under sedation protocols using either midazolam and meperidine or

midazolam alone. Although endoscopists favor the use of both medications together, adding meperidine to midazolam before the colonoscopy does not seem to have additive beneficial effect

for the patients.

Garip, 2007

Type of study:

RCT

Setting and country:

Turkey; setting not described

Funding and conflicts of interest:

Not reported

Inclusion criteria:

• listed for extraction of impacted mandibular third molars
• age 17 – 37 y
• ASA grade I and II

Exclusion criteria:

• systemic disease,
• inability to use the handset
• history of drug addiction or current use of opioids
• allergy to experimental drugs

N total at baseline:

Intervention: 20

Control: 20

Important prognostic factors²:

For example

age (SD):

I: 23y (SD 4)

C: 26y (SD 6)

Sex:

I: 9/20, 45 % M

C: 8/20, 40 % M

ASA grades I/II

I: 19/1

C: 18/2

Groups comparable at baseline.

Midazolam + reminfetanil

An intravenous cannula was inserted into a vein in the dorsal side of the hand, and a continuous, free flow infusion of 0.9% sodium chloride was started.

After the injection of the

initial dose of 0.03 mg/kg midazolam (Dormicum; Roche, Switzerland), the patients in both groups were given the demand button for the analgesia pump and were allowed to

press it until they felt adequately sedated.

Pumps were programmed to deliver bolus volumes of 2 ml.

The bolus dose of the combination of midazolam–remifentanil was set to deliver 0.5 mg/ml

midazolam and 12.5 µg/ml remifentanil (UltivaTM) with each successful attempt, and the lockout interval was also set at 5 min. The maximum dose was set at 12 mg of midazolam

and 300µg/h of remifentanil.

After the intravenous sedation, local anaesthetic (2 ml of 40 mg/ml articaine hydrochloride with 0.012 mg/ml adrenaline hydrochloride; Ultracain® D-S Forte, Aventis)

was given.

Midazolam alone

An intravenous cannula was inserted into a vein in the dorsal side of the hand, and a continuous, free flow infusion of 0.9% sodium chloride was started.

After the injection of the

initial dose of 0.03 mg/kg midazolam (Dormicum; Roche, Switzerland), the patients in both groups were given the demand button for the analgesia pump and were allowed to

press it until they felt adequately sedated.

Pumps were programmed to deliver bolus volumes of 2 ml.

The bolus dose of midazolam was set at 0.5 mg/ml with each successful attempt, and the lockout interval was set at 5 min. The maximum dose was set at 12 mg of midazolam/

h.

After the intravenous sedation, local anaesthetic (2 ml of 40 mg/ml articaine hydrochloride with 0.012 mg/ml adrenaline hydrochloride; Ultracain® D-S Forte, Aventis)

was given.

Length of follow-up:

24 hours postoperative

Loss-to-follow-up:

I: 0

C: 0

Incomplete outcome data:

not specified

Sedation level

Not reported

Time for adequate sedation (Ramsey II), min (SD)

I: 2 (0.2)

C: 2 (0.2)

Recovery time, minutes, mean (SD)

Time in recovery room

I: 23 (14)

C: 20 (7)

Length of stay in hospital

I: 75 (23)

C: 64 (12)

Patient satisfaction*; Immediately after procedure

I: Excellent: 19/20

Good: 1/20

C: Excellent: 19/20

Good: 1/20

After 24h

I: Excellent: 15/20

Good: 3/20

Poor: 2/20

C: Excellent: 19/20

Good: 1/20

Provider satisfaction**

I: Excellent: 11/20

Good: 7/20

Satisfactory: 1/20

Unacceptable: 1/20

C: Excellent: 9/20

Good: 11/20

Satisfactory: 0/20

Unacceptable: 0/20

Adverse events

Respiratory depression

Saturation < 95%:

I:  10/20

These desaturations were reversed by a verbal command to take a deep breath in all but one patient, who required the triple airway manoeuvre and supplementary oxygen.

C: 0/20 (also not < 97%)

***

Apnoea

Not reported

Also reported:

Sedative dosages, number of demands by patient, systolic and diastolic blood pressure and heart rate during procedure, amnesia, duration of procedure, time in operating theatre, description of other adverse events (dreams, itch, venous thrombosis)

Definitions/additional info:

*Patient satisfaction: asked immediately after the operation + 24-h postoperative: if they were happy with the sedation they had received, if they would like to have the same sedation again, and about their overall satisfaction with the procedure (score 1-5; unacceptable, poor, satisfactory, good, and

excellent)

**Provider satisfaction: At the end of the operation, the surgeon evaluated the

degree of sedation and the operating conditions during the procedure similarly by assigning a score from 1 to 5.

*** There were no significant differences between the groups for SpO2 during sedation except at 30 min when that in the two-drug group (95.9 (1.59)) was

significantly lower than that in the single-drug group (97.4

(1.6), p < 0.05; Fig. 3). – not included in summary as no absolute data was provided

Remarks:

-

Authors conclusion:

Our results indicate that the combination of remifentanil with midazolam at the doses

given leads to significant respiratory depression, but this may not be of clinical concern because these desaturations were reversed by giving verbal commands to the patient to take a deep breath. Only one patient presented a clinical problem

with a reduction in oxygen saturation that had to be resolved by applying the triple airway manoeuvre and supplementary oxygen at 3 l/min.

+

Patient-controlled analgesia with midazolam or midazolam and remifentanil is safe and reliable during extraction of third molars.

Khan, 2019

Type of study:

RCT

Setting and country:

Recruitment March to December of 2012; St. Joseph’s

Healthcare Hamilton; Canada

Funding and conflicts of interest:

Funding not specified but University department named in acknowledge-ments. “Special thanks to … the Division of Gastro-enterology at McMaster University

for funding support.”

Potential conflicts of interest not described.

Inclusion criteria:

• age 18 to 65 years
• scheduled for outpatient upper endoscopy

Exclusion criteria:

• mental incompetency,
• pregnancy,
• weight <55 kg,
• emergent procedures,
• known hyper-sensitivity or allergy to fentanyl or midazolam
• chronic use of benzodiazepines or opioids,
• patients known a priori to require therapeutic interventions

in conjunction with their EGD

• major cardio-respiratory comorbidities, sleep apnea, liver cirrhosis, renal failure

N total at baseline: 139 randomized, 137 analysed

Intervention: 68

Control: 69

Important prognostic factors²:

Mean age:

I: 44.9y

C: 45.7y

Sex, male

I: 46% M

C: 35% M

ASA 1 - I: 62, C: 56

ASA 2 - I: 5, C: 12

ASA 3 - I:  1, C: 0

Groups comparable at baseline? More males in intervention group, more ASA-I in intervention group, more ASA-II in control group.

Midazolam + fentanyl

After an initial 2 mg dose of intravenous Midazolam, patients were immediately given a 100 mcg dose of intravenous fentanyl

Additional Midazolam was titrated as needed in

1 mg increments for deeper sedation at the discretion of the endoscopist, but no further fentanyl could be given.

Topical xylocaine could be administered in the oropharynx at the discretion

of the endoscopist (occurred in 48/68; 71%).

Midazolam

After an initial 2 mg dose of intravenous Midazolam, patients were immediately given a 100 mcg dose of

an identical syringe of placebo.

Additional Midazolam was titrated as needed in

1 mg increments for deeper sedation at the discretion of the endoscopist.

Topical xylocaine could be administered in the oropharynx at the discretion

of the endoscopist (occurred in 54/69; 78%).

Length of follow-up:

During procedure, immediately after procedure and 48 hours after procedure (question willingsness to repeat procedure)

Loss-to-follow-up:

Two patients withdrew after being randomized: one refused to participate after she consented, and the other’s procedure was cancelled by the endoscopist

No lost to follow-up reported.

Incomplete outcome data:

Not specified;

Outcome ‘willingness to repeat procedure’ available for 60 and 56 patients respectively.

Sedation level

Not reported

Recovery time

Time to discharge after procedure, minutes

I: 35.6

C: 37.2

P=0.54

Patient satisfaction

5-point visual Likert-scale; 1 extremely satisfied, 5 extremely dissatisfied.

I: 1.3
C: 1.5

P=0.4

Willingness to repeat procedure if necessary; telephone question in sub-group.

I: 60/60

C: 56/56

Provider satisfaction

5-point visual Likert-scale; 1 extremely satisfied, 5 extremely dissatisfied.

Endoschopist

I: 1.4

C: 2.5

P<0.001

Nurse

I: 1.4

C: 2.5

P<0.001

Adverse events

Respiratory depression;

Transient drops in oxygen saturation <90%

I:  3/68 (4.4%)

C: 0/69 (0.0%)

Apnea

Not reported

Also reported:

retching that persisted after intubation, time of procedure, dosage midazolam, frequency of vomiting and nausea.

Definitions:

-

Remarks:

-baseline characteristics (sex, ASA status) not balanced between treatment groups

-sample size just under power calculation

Authors conclusion:

Endoscopists and nurses found adding fentanyl significantly improved sedation, led to a shorter procedure time, and allowed for less midazolam to be used per case. It did not affect the patient experience of sedation and was safe. Fentanyl use for routine outpatient upper endoscopy

should be considered as a safe option to improve procedural sedation.

Lee, 2011

Type of study:

RCT

In this study, a separate control group is compared with a midazolam (M) and a midazolam+ remifentanil (M+R) group.

We included this study using the M+R group as intervention group and M group as control group. The original control group results of the publication are not included in this summary.

Setting and country:

Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, School of Medicine, Hallym University; Korea

Funding and conflicts of interest:

Funding not reported; dr J H Lee takes responsibility for the integrity of the content of the paper.

Competing interests: None declared”

Patient undergoing middle-ear surgery

Inclusion criteria:

• undergoing middle-ear surgery under local anaesthesia

Exclusion criteria:

• age < 20 or > 60 years;
• chest or heart problems;
• pregnancy;
• history of chronic sedative use;
• history of alcohol or drug abuse
• known or suspected psychiatric disturbance.
• requiring surgery lasting > 3 hours (due to severe middle-ear and/or mastoid pathology).

N total at baseline: 40

Intervention: 21

Control: 19

Important prognostic factors²:

age ± SD:

I: 44.6 ±10.6

C: 44.3± 9.2

Sex, male:

I: 4/21 (19.0%)

C: 6/19 (31.6%)

Groups comparable at baseline? More males in the control group.

midazolam + remifentanil

no premedication was given

midazolam plus remifentanil (midazolam as 0.04 mg/kg loading dose then 0.04 mg/kg/hour continuous dose, plus remifentanil as 0.5 μg/kg loading dose then 0.05 μg/kg/minute continuous dose).

midazolam alone

no premedication was given

midazolam (0.04 mg/kg loading dose then 0.04 mg/kg/hour continuous dose) + intravenous

saline, in the same volume as the remifentanil in the

midazolam–remifentanil group.

Length of follow-up:

24 hours

Loss-to-follow-up &

Incomplete outcome data:

Not specified; results describe 19 vs. 21 patients; implying no loss-to-follow-up.

Sedation level

Peri-operative sedation levels;  

By patient report*:

- announced but not reported

By investigator report**

I: range 2-4

C: range 2-4

No absolute data reported: “However, a

statistically significant difference was still observed

between the mean alertness and sedation scores of the

midazolam and midazolam–remifentanil groups”

Recovery time

Not reported

Patient satisfaction

Patients’ satisfaction with sedation***;

I: 4.47 (n=5)

C: 3.57 (n=5)

Memory of operation; reported remembering

their operation

I: 7/21 (33.3%)

C: 8/19 (42.1%)

Provider satisfaction

Not reported

Adverse events

Respiratory depression; breathing rate <10 breaths/ minute

-announced but not reported

Oxygen desaturation (<94 per cent)

I:  2/21 (9.5%)

C: 1/19 (5.3%)

Desaturated patients recovered to normal oxygen saturation levels after physical stimulation, such as gentle shaking.

****

Apnea

Not reported

Also reported: anaesthetic time, surgical time, pain during local anaesthetic injection and during operation, anxiety,

hypotension (i.e. systolic blood

pressure<90 mmHg), bradycardia (heart rate<60

beats/minute), postoperative nausea, vomiting and dizziness.

Definitions:

* Patients graded their intra-operative sedation level (patients’ memory) using a VAS, where 0=asleep and 5=alert

**Investigators graded the patients’ intra-operative

sedation status using the observer’s assessment of

alertness and sedation scale (OAAS scale), where 1=fully alert and 5=deep sleep.

*** patient satisfaction: assessed using the following scale: 5= extremely satisfied, 4= satisfied, 3=undecided, 2=dissatisfied and 1=extremely dissatisfied.

****

“In the MR group, the mean

oxygen saturation was significantly reduced during

the period from 1 minute after midazolam injection to

25 minutes after local anaesthetic injection, compared with midazolam group; however, the mean oxygen saturation in the midazolam–remifentanil group was greater than 97 per cent during all monitored periods (Figure 2).” – no absolute data provided

Remarks:

-lacking details on study design

-inconsistencies in paper; no protocol available

-number of patients per outcome unclear or small

Authors conclusion:

Patients undergoing middle-ear surgery under local anaesthesia alone frequently report pain, anxiety and adverse events. However, the majority of our patients who were sedated with midazolam satisfactorily overcame pain, anxiety and adverse events. Results were better still when midazolam was accompanied by remifentanil.

Özel, 2008

Type of study:

RCT

Setting and country:

Department of Gastroentorology, Gülhane Military Medical Academy, Haydarpafla Training Hospital, Istanbul; Turkey

Funding and conflicts of interest:

Not reported

Patients undergoing upper gastro-intestinal endoscopy

Inclusion criteria:

• scheduled for routine UGE
• otherwise healthy (not further specified)

Exclusion criteria:

• hypertension,
• known ischemic heart diseases and malignancies

N total at baseline:

Intervention: 30

Control: 30

Important prognostic factors²:

age ± SD:

I: 53.13 ± 21.16

C: 46.60 ± 18.17

Sex:

I: 18/30 (60.0%)

C: 10/30 (33.3%)

Groups comparable at baseline? More males in intervention group.

Midazolam  + meperidine

Patients were given a bolus dose of meperidine 0.3 mg/kg IV followed 1 min later by midazolam 0.05

mg/kg IV (0.5 mg dosages at 30-sec intervals until

total dose was achieved) (Group II)

Midazolam

Patients were given a

bolus dose of saline solution (0.5 ml) followed 1 min later by midazolam 0.05 mg/kg IV (0.5 mg dosages at 30-sec intervals until total dose was achieved) (Group I)

Length of follow-up:

Unclear, probably intra-procedural en post-procedural assessments.

Loss-to-follow-up &

Incomplete outcome data:

Not reported; data presented as if available for all 30 vs. 30 patients.

Sedation level

Overall score for conditions at intubation (also called patient compliance in publication)*

Poor:

I: 2/30 (6.7%)

C: 6/30 (20%)

Good:

I: 6/30 (20%)

C: 13/30 (43.3%)

Excellent:

I: 22/30 (73.3%)

C: 11/30 (36.7%)

Recovery time

not reported

Patient satisfaction

not reported

Provider satisfaction

not reported

Adverse events

Respiratory depression

not reported as dichotomous variables; not compared between groups, no absolute values reported

Apnea

not reported

Also reported: Hemodynamic parameters (HR SAP MAP DAP SpO2) at baseline, after medication, minute 1, 3, 5 and 7)

Definitions:

*the endoscopists assessed ease of pharyngoesophageal

intubation, patient response to intubation, level of

consciousness, and physical resistance against the

procedure. These criteria were used to score overall

conditions at intubation as Excellent (No gagging during hypopharynx-oesophagus transit, very good patient compliance, patient is asleep or near asleep, no physical resistance against endoscope);

Good (Patient gags but not so severe, patient is partially uncomfortable, almost awake, partial resistance against endoscope) or

Poor (Severe gagging during hypopharynx-esophagus transit, patient is not compliant, totally awake, significant resistance against endoscope).

Remarks:

-outcomes not clear defined, inconsistencies between methods and results section;

-follow-up period not specified

Authors conclusion:

In conclusion, our findings revealed that sedation

with midazolam increases HR more than sedation with meperidine plus midazolam, whereas SAP, DAP and SpO2 decrease with both sedation methods without any significant clinical finding (i.e.

critically low BP or SpO2), and that there is no difference

between the groups with respect to these changes. However, patient compliance was significantly better when midazolam was used in combination with meperidine. Our results lead us to believe

that use of combined sedation with midazolam

and meperidine in selected patients will provide a safe sedation and a better patient compliance during UGE.

Prabhudev, 2017

Type of study:

RCT

This study compared 3 groups: Group 1 – placebo, Group 2 – midazolam, and Group 3 – fentanyl-midazolam.

For the current summary, we used the results of group 2 as control group and group 3 as intervention group.

Setting and country:

October 2013 to July 2015; India

Funding and conflicts of interest:

“Financial support and sponsorship: Nil; Conflicts of interest

There are no conflicts of interest.”

Patients undergoing flexible bronchoscopy

Inclusion criteria:

• age 18–70 years
• advised flexible bronchoscopy for diagnostic workup

Exclusion criteria:

• oxygen saturation (SpO ) <95% on room air;
• hemodynamic instability;
• renal failure, hepatic insufficiency;
• chronic obstructive pulmonary disease with FEVI <50%;
• platelet count <50,000/mm;
• body weight was >85 kg;
• depression of consciousness or cognitive impairment rendering them unable to answer questionnaires;
• history of hypersensitivity or contraindications to the drugs

N total at baseline:

Intervention: 48

Control: 48

Important prognostic factors²:

Age, median (IQR):

I: 52 (42.25-62.75)

C: 50.5 (39.25-59.25)

Sex, male:

I: 31/48 (64.6%)

C:33/48 (68.8%)

Groups comparable at baseline.

Midazolam + fentanyl

Two ml of 2% lignocaine jelly was administered into one of the patent nostrils of the patient.

Initially, 0.5 ml of the drug from syringe A (fentanyl; 1 ml (50 μg)) was administered. Then, after 5 min, 2.5 ml of the drug from syringe B (midazolam 0.035 mg/kg diluted in normal saline to a volume of 5 ml)

was administered.

After an additional waiting period of 2 min, the bronchoscope was passed through the patent nostril and then the throat. Two ml of 2% lignocaine spray was sprayed at the throat and additional 2 ml at vocal cords, by spray-as-you-go technique.

Patients were administered another 0.5 ml study drug

from syringe A (1 ml (50 μg) of fentanyl)) and 2.5 ml from syringe B (midazolam 0.035 mg/kg diluted in normal saline to a volume of 5 ml), before crossing the vocal cords.

After waiting for a minute, the bronchoscope was advanced below the vocal cords and stationed at the level of carina, where 1 ml 2% lignocaine was sprayed.

The bronchoscope was advanced beyond carina where 1 ml of 2% lignocaine was sprayed into each main bronchus. Once the coughing subsided, the bronchoscope was advanced into either

bronchi to evaluate the bronchial tree, and the sampling procedure for which the patient was scheduled was

completed.

Additional 2% lignocaine was sprayed if the patient had recurrence of cough.

If the Ramsay Sedation Scale (RSS) was 1 at any time after the lignocaine application was completed, the rescue medication in the form of Injection Midazolam 0.5 mg IV (open-label syringe) was administered in a stepwise manner, with a 2-min gap between doses.

Midazolam

Two ml of 2% lignocaine jelly was administered into one of the patent nostrils of the patient.

Initially, 0.5 ml of the drug from syringe A (1 ml of normal saline) was administered. Then, after 5 min, 2.5 ml of the drug from syringe B (midazolam 0.035 mg/kg diluted in normal saline to a volume of 5 ml)

was administered.

After an additional waiting period of 2 min, the bronchoscope was passed through the patent nostril and then the throat. Two ml of 2% lignocaine spray was sprayed at the throat and additional 2 ml at vocal cords, by spray-as-you-go technique.

Patients were administered another 0.5 ml study drug

from syringe A (1 ml of normal saline) and 2.5 ml from syringe B (midazolam 0.035 mg/kg diluted in normal saline to a volume of 5 ml), before crossing the vocal cords.

After waiting for a minute, the bronchoscope was advanced below the vocal cords and stationed at the level of carina, where 1 ml 2% lignocaine was sprayed.

The bronchoscope was advanced beyond carina where 1 ml of 2% lignocaine was sprayed into each main bronchus. Once the coughing subsided, the bronchoscope was advanced into either

bronchi to evaluate the bronchial tree, and the sampling procedure for which the patient was scheduled was

completed.

Additional 2% lignocaine was sprayed if the patient had recurrence of cough.

If the Ramsay Sedation Scale (RSS) was 1 at any time after the lignocaine application was completed, the rescue medication in the form of Injection Midazolam 0.5 mg IV (open-label syringe) was administered in a stepwise manner, with a 2-min gap between doses.

Length of follow-up:

4 hours after procedure

Loss-to-follow-up:

Intervention: 0

Control: 0

Incomplete outcome data:

No incomplete or missing data reported

Sedation level

Ramsay sedation score* during bronchoscopy; median (IQR)

I: 2 (2 – 2)

C: 2 (1.25 - 2)

Recovery time

Not reported

Patient satisfaction

Patient's tolerance of the procedure and their satisfaction level (assessed with questionnaire) – composite, median (IQR); 19 items with 1-4 points per item (1=poor, 4=very good.)

I: 62 (58.5, 66)

C: 59 (57, 61.5)

P=0.002

Provider satisfaction

Physician-reported feasibility of the procedure; 6 items with 1-5 points per item (1=worse score, 5 = best score)

median, interquartile range

I: 26 (25, 29)

C: 25 (21, 27)

P=0.008

Adverse events

Respiratory depression

“One patient in fentanyl-midazolam group developed

significant oxygen desaturation (84%–86%). The procedure was prematurely stopped at the 10th min, and

the episode was successfully managed, without any adverse consequences, by administering 60% oxygen

and salbutamol nebulization.”

Respiratory rate, mean±SD

Baseline

I: 21.96±3.65

C: 22.79±3.34

5 min after start procedure

I: 22.96±3.69

C: 23.79±4.93

10 min postprocedure

I: 23.08±3.11

C: 23.00±3.91

P=0.238

Oxygen saturation level (%), mean±SD

Baseline

I: 99.79±0.82

C: 99.63±1.06

5 min after start procedure

I: 99.46±1.35

C: 99.48±1.21

10 min postprocedure

I: 99.04±2.37

C: 98.90±2.35

P=

Apnea

Not reported

Also reported:

Lidocaine dosage, total number of rescue medication,

completeness of the procedure, complications if any (hypotension), and total duration of procedure; vital parameters baseline, 5 min after start procedure and 10-min after completion of procedure; heart rate, SPB, DBP)

Definitions:

*Ramsay sedation score:

1-Patient is anxious and agitated or restless, or both

2-Patient is co-operative, oriented, and tranquil

3-Patient responds to commands only

4-Patient exhibits brisk response to light glabellar tap or loud auditory stimulus

5-Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus

6-Patient exhibits no response

Remarks:

-

Authors conclusion:

Conscious sedation with fentanyl-midazolam combination can result in better patient and operator

satisfaction when compared with midazolam alone, with manageable adverse event profile.

Toman, 2016

Type of study:

(quasi)-RCT

This study compared sedation using midazolam (group M), midazolam and alfentanil (group MA) and propofol (group P). For this literature analysis, group MA was included as the intervention group and group M was the control group.

Setting and country:

Turkey

Funding and conflicts of interest:

“Funding: No specific funding was received for this study; Transparency declaration: Competing interests: None to declare.”

Patients undergoing transesophageal echocardiography

Inclusion criteria:

• Planned transesophageal echocardiography

Exclusion criteria:

• severe cardio-pulmonary dise­ase,
• obesity,
• suspected or confirmed pregnancy,
• history of allergic reaction to study medicati­ons
• not able to communicate

N total at baseline:

Intervention: 30

Control: 30

Important prognostic factors²:

age ± SD:

I: 44.3±16.9

C: 42.8±15.2

Sex:

I: 12/30 (40%)

C: 13/30 (43%)

Groups comparable at baseline.

Midazolam + alfentanil

Topical oropharyngeal

anesthesia was provided by 10% lidocaine spray

(Xylocaine pump spray, AstraZeneca Ilaç San.

ve Tic. Ltd. Sti. Istanbul, Turkey).

Group MA patients were given 1 mg midazolam and 5 μg/kg alfentanil (rapifen,

Johnson & Johnson Sıhhi Malzeme San. ve Tic.

Ltd. Sti. Turkey) for sedation as an intravenous bolus dose.

According to the hemodynamics and

sedation degree of patients, dose titration was

completed with an additional dose of 0.5 mg midazolam as necessary or a total maximum dose

of 5 mg at 5 minute intervals, and an additional

dose of 2,5 μg/kg alfentanil as required or a total

maximum dose of 1000 μg at 5 minute intervals.

Midazolam

Topical oropharyngeal

anesthesia was provided by 10% lidocaine spray

(Xylocaine pump spray, AstraZeneca Ilaç San.

ve Tic. Ltd. Sti. Istanbul, Turkey).

Group M patients were given 2.5 mg midazolam

(dormicum, Roche Ilaç Sanayi A.S. Turkey) for

sedation as an intravenous bolus dose.

If necessary additional 1 mg or a total maximum dose

of 8 mg at 5 minute intervals was administered

intravenously.

Length of follow-up:

Up to discharge from hospital

Loss-to-follow-up &

Incomplete outcome data:

Not described; as all outcomes are peri-procedural, no lost-to-follow-up could be expected

Sedation level

Ramsey sedation score, evaluated every 5 minutes and at end of procedure

No absolute data provided*

Recovery time, minutes, mean±SD

I: 14±7

C: 18±7

Modified Aldrete score, assesses patient activity, respiration, blood pressure, consciousness, and color

No absolute data provided;

“When the TEE probe was removed the MAS in

Group M was found to be statistically higher compared to Group P (p<0.05). In the 5th and 10th minute in the recovery unit, the MAS values

of Group P were found to be high compared to Group M and Group MA (p<0.05). The patients in Group P were all discharged before the 10th

minute. The patients in Group MA were discharged before the 20th minute while the patients in Group M were discharged by the 30th minute on average (Figure 2).”

Patient satisfaction

Not reported

Provider satisfaction

Not reported

Adverse events

Respiratory depression

- Required nasal mask

due to SpO2 dropping below 93%

I: 1/30 (3.3%)

C: 4/30 (13.3%)

Apnea

I: 0/30 (0%)

C: 0/30 (0%)

Also reported:

Sedatives consumption (midazolam, alfentanil); numbers (%) patients requiring additional medication; total duration hospital stay

Definitions/additional info:

* “There was no statistically significant difference

in terms of basal RSS values of the cases when compared between the groups (p>0.05). On insertion of the TEE probe, RSS values remained the same in Group M, fell in Group MA and increased clearly in Group P and this was statistically significant (p<0.05). Comparing Group M with Group MA and Group P separately in the 5th minute of the procedure, there was a statistical fall in RSS observed (p<0.05). In the 10th and 15th minutes of the procedure the RSS in Group MA was found to be much higher than in Group M (p<0.05). In the 20th and 25th minutes and when the TEE probe was removed the RSS in all 3 groups was not found to be statistically significant when compared

among themselves (p>0.05) (Figure 1).”

Remarks:

-quasi-randomized trial

Authors conclusion:

During the TEE intervention, the use of propofol, contrary to requirements for additional dose and observation of

apnea, appears to be advantageous due to providing more rapid and effective sedation depth without a need of expensive antagonist agents, and allowing early discharge of patients. Additionally, it seems that the use of midazolam combined with alfentanil, is more advantageous comparing to midazolam alone.

Wang, 2011

Type of study:

RCT

This study compared sedation using midazolam (group N), midazolam and fentanyl (group F) and  midazolam and propofol (group P). For this literature analysis, group F was included as the intervention group and group N was the control group.

Setting and country:

January 2003 to May 2003; Central South University, Changsha, China.

Funding and conflicts of interest:

Not reported

Patients undergoing colonoscopy

Inclusion criteria:

• Receiving outpatient diagnostic colonoscopy

Exclusion criteria:

• Age < 18 or > 75y
• previous history of colonoscopy
• previous colonic resection,
• severe hepato-renal or cardio-pulmonary compromise,
• known hyper-sensitivity to midazolam, propofol, or fentanyl.

N total at baseline:

Intervention: 160

Control: 160

Important prognostic factors²:

age ± SD:

I: 48.2±2.3

C: 50±3.4

Sex:

I: 91/160 (56.9%)

C: 92/160 (57.5%)

Groups comparable at baseline.

Midazolam + fentanyl

The dose of intravenously administered midazolam

was adjusted according to the age of the patient as

follows:

• 20–40 years: received a dose of 0.04 mg/kg but no more than 2.0 mg;
• 41–60 years: 0.03 mg/kg but no more than 1.5 mg;
• 61–75 years: 0.02 mg/kg but no more than 1.0 mg.

Patients receiving fentanyl treatment (group F) subsequently received a single dose (50–100 mg) of intravenously administered fentanyl (Yichang Humanwell Pharmaceutical

Co., Ltd., Yichang, China).

The dose of fentanyl was

also adjusted according to the age of patient as follows:

• 20–40 years: a dose of 100 mg;
• 41–60 years: 75 mg;
• 61–75 years: 50 mg.

Midazolam

The dose of intravenously administered midazolam

was adjusted according to the age of the patient as

follows:

patients of 20–40 years received a dose of 0.04 mg/kg but no more than 2.0 mg;

those of 41–60 years

received 0.03 mg/kg but no more than 1.5 mg;

those of 61–75 years received 0.02 mg/kg but no more than 1.0 mg.

Control patients (group N)

received no medication other than midazolam throughout the procedure.

Length of follow-up:

“Monitoring was maintained in the recovery unit (usually for 30 min), until the patients were discharged when their memory, calculation, and orientation

had returned to normal.”

Loss-to-follow-up &

Incomplete outcome data:

Not specified

Sedation level

Level of sedation; evaluated by endoscopist; score 1 to

10 (0, not sedated with poor cooperation; 10, superficial

sleep but arousable).

- no absolute data provided

“Combining midazolam with either fentanyl or propofol

resulted in acceptable sedative and analgesic effects

compared to midazolam alone (P<0.001)”

Recovery time

Not reported

Patient satisfaction

Not reported

Provider satisfaction

Not reported

Adverse events

Respiratory depression

No absolute data provided

“The frequencies of clinically significant changes in pulse rate and SpO2 were comparable among the three groups (P>0.05).”

+

“while the two latter modalities were similar in the frequency of serious adverse events (defined as: (a) blood pressure >190/100 mmHg, <90/60 mmHg, or a >20-mmHg change in systolic blood pressure (SBP) and >15 mmHg in diastolic blood pressure (DBP); (b) a change in pulse rate >20 beats per minute (bpm); or (c) SpO2<90%.) (Fig. 2).”

Apnea

Not reported

Also reported:

Amnesia rate analgesia score, pulse rate, blood pressure,

Definitions:

-

Remarks:

-

Authors conclusion:

The combination of midazolam with either

fentanyl or propofol allowed patients to undergo colonoscopy under comparable sedative and analgesic conditions.

The combination with fentanyl had a significantly lower effect on pulse rate and blood pressure. The combination with propofol produced superior amnestic effects.

Also reported: level of analgesia (VAS presence of absence of pain), level of sedation (VAS by endoscopist; 0, not sedated with poor cooperation; 10, superficial

sleep but arousable); amnesia profile (no amnesia or amnesia); discharge scoring (mental status + pain + ability to ambulate; 3 x 2 points; 6 points is threshold for discharge)

Yalcin Cok, 2008

Type of study:

RCT

Setting and country:

hospital; Turkey

Funding and conflicts of interest:

Not reported

Patients undergoing cataract surgery

Inclusion criteria:

• Age ≥ 18 years
• ASA status I-III

Exclusion criteria:

• ASA status IV,
• allergy to study drugs
• history of drug abuse
• disorders preventing use of regional anesthesia or sedation

N total at baseline:

Intervention: 100

Control: 101

Important prognostic factors²:

age ± SD:

I: 68.9 ± 11.3

C:67.2 ± 12.7

Sex:

I: 37/100 (37%) M

C: 46/101 (45.6%) M

Groups comparable at baseline? Slightly more males in control group (46% vs. 37%)

Midazolam + fentanyl

Patients received midazolam 1 mg and fentanyl 25 μg intravenously .

Retrobulbar nerve block was performed by the

same ophthalmic surgeon who was unaware of

group allocation with 4 ml lidocaine 2% via the

percutaneous route with a 25 G, 38 mm Atkinson

needle (John Weiss & Son Limited, Milton Keynes,

England), at inferotemporal site. No patient received an additional facial nerve block.

Heart rate (HR), systolic (SAP) and diastolic

(DAP) arterial pressure values were recorded

3 minutes after the sedation as baseline and after

retrobulbar injection to assess the effect of sedatives during the block.

After sedation and retrobulbar block, all

patients were transferred to the operating room

where recording of all parameters was continued. In the operating room, patients received supplemental oxygen 5 L min-1 insufflated by a tray under the drapes.

Midazolam

Patients received midazolam 1 mg

intravenously

Retrobulbar nerve block was performed by the

same ophthalmic surgeon who was unaware of

group allocation with 4 ml lidocaine 2% via the

percutaneous route with a 25 G, 38 mm Atkinson

needle (John Weiss & Son Limited, Milton Keynes,

England), at inferotemporal site. No patient received an additional facial nerve block.

Heart rate (HR), systolic (SAP) and diastolic

(DAP) arterial pressure values were recorded

3 minutes after the sedation as baseline and after

retrobulbar injection to assess the effect of sedatives during the block.

After sedation and retrobulbar block, all

patients were transferred to the operating room

where recording of all parameters was continued. In the operating room, patients received supplemental oxygen 5 L min-1 insufflated by a tray under the drapes.

Length of follow-up:

1 day; day of surgery

Loss-to-follow-up:

Intervention: 0%

Control:  0%

Incomplete outcome data:

Not specified

Sedation level

Observer’s Assessment of

Alertness/Sedation (OAA/S) scale

After sedation

I: 17.1

C: 18.1

After additional retrobulbar block

I: 16.5

C: 17.6

Recovery time

Not reported

Patient satisfaction

asked to verbally rate their level of satisfaction* after the operation

I: 0/2/1/2/95

C: 0/0/0/11/89

Provider satisfaction

Surgeon asked to verbally rate their level of satisfaction after the operation

I:  0/0/0/1/99

C: 0/0/0/3/97

Adverse events

Respiratory depression

I: 0/100

C: 0/101

Apnea

Not reported

Also reported: pain after block and surgery, recall of retrobulbar block, adverse events (bradycardia,

tachycardia, hypertension or hypotension, nausea and vomiting)

Definitions:

* level of satisfaction at 5 degree scale; very bad, bad, moderate, good and very good.

Remarks:

-

Authors conclusion:

In conclusion, the addition of fentanyl to midazolam during regional anesthesia for cataract surgery did not result in a significant difference in

sedation, pain relief, satisfaction or adverse events.

Therefore the authors suggest that sedation with

midazolam alone may be sufficient to provide optimal block conditions for this procedure.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

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

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure^g

LOW

Some concerns

HIGH

Barriga, 2008

Definitely no

Reason: no random allocation (“Patients were assigned by alternating enrollment to the group who would receive midazolam only (group M) or to the combination group of midazolam plus fentanyl (group M/F).”)

Definitely no

Reason: no concealed allocation

Probably no

Reason: endoscopists were not blinded; no further details about patients, outcome assessors and data analyst provided.

Probably no

Reason: 5 and 12% of patients were not included in the analysis due to different reasons, not further specified per treatment group.

Probably yes

Reason: no protocol available; outcomes in the method section are reported in the results

Probably yes

Reason: no further problems reported

HIGH risk of bias (patient satisfaction, provider satisfaction, adverse events)

Reason: quasi-randomized, no adequate allocation concealment, no blinding

Çinar, 2009

No information

Reason: no details on randomization

No information

Reason: no details on concealment of allocation

No information

Reason: no details on blinding; trial not described as single or double blinded.

Probably yes

Reason: no lost to follow up reported; 2 patients excluded after randomization due to medical condition

No information

Reason: no protocol; results briefly described

No information

Reason: funding and possible conflicts of interest not reported

Some concerns (recovery time, adverse events)

Reason: no information about randomization, allocation concealment, blinding, prespecified outcomes, funding and potential conflicts of interest

Garip, 2007

No information

Reason: no details on randomization

Probably yes

Reason: “The patients were randomly divided into the two groups using sealed envelopes.”

Probably no

Reason: “Both the

patient and the surgeon were unaware of which patient was

in which group.”

No information about data analyst and roles in assessing outcomes.

Probably yes

Reason: no lost to follow up reported

No information

Reason: no protocol; results briefly described

No information

Reason: funding and possible conflicts of interest not reported

Some concerns (recovery time, patient and provider satisfaction, adverse events)

Reason: no information about randomization, blinding details, prespecified outcomes, funding and potential conflicts of interest

Khan, 2019

Probably yes

Reason: A computer-generated, two-group randomization table was prepared

by the inpatient pharmacy.

Probably yes

Reason: “…the research team was only informed of the contents of the syringes after study completion.”

Definitely yes

Reason: “Identical syringes of Fentanyl

or placebo (saline solution) were assembled by the pharmacy,

and allocation was concealed to any of the patients, research

or clinical staff.  …. blinding was

preserved throughout the study, and the research team was only informed of the contents of the syringes after study completion.“

Probably yes

Reason: 2 patients withdrew after being randomized; other patients completed study

Probably no

Reason:

Primary and secondary outcomes differ from protocol; not all outcomes announced in protocol (NCT 01514695).

Unclear whether bias in results could be expected.

No information

Reason: funding and possible conflicts of interest not reported or not reported in detail.

Some concerns (recovery time, patient satisfaction, provided satisfaction, adverse events)

Reason: some inconsistencies with protocol, no details on funding and potential conflicts of interest.

Lee, 2011

No information

Reason: “The 40 patients were allocated randomly (by opening

a sealed, numbered envelope containing the study group designation)”

Probably yes

Reason: “The 40 patients were allocated randomly (by opening

a sealed, numbered envelope containing the study group designation)”

No information

Reason: only information is about assessment of 1 variable; “Twenty-four hours after surgery, patients were again assessed, by a different anaesthetist to the one involved in their operation.”

Probably no

Reason: for the outcome patient satisfaction (VAS scale), the outcome is reported for only 5 patients in each group. It is unclear whether other patient data is missing or whether patients were lost-to-follow-up in the mean time.

For other scores it is not always indicated in how many patients the results were assessed.

Probably no

Reason: no protocol available; outcomes inconsistent between methods and results section

No information

Reason: no details about funding; statement that no conflicts of interest were declared

HIGH risk (sedation level, patient satisfaction, adverse events)

Reason: no information about randomization, blinding or handling missing data, inconsistencies between method and results section, no protocol available, no details on funding.

Özel, 2008

Definitely yes

Reason: “previously

labeled and numbered syringes according to a

computer-generated random numbers table.”

Definitely yes

Reason: “previously

labeled and numbered syringes according to a

computer-generated random numbers table. Patents were taken into the endoscopy unit with their previously prepared syringes. Different nurses

prepared the syringes and performed the injections to provide double blindness.”

Probably yes

Reason: syringes not recognizable; nurses that prepared the syringes did not perform injections; endoscopist blinded; outcome assessor blinded.

Blinding of data analyst not reported

Probably yes

Reason: no lost to follow up reported; all data presented as available for 30 vs. 30.

Probably no

Reason: no protocol available; outcomes inconsistent between methods and results section

No information

Reason: funding and possible conflicts of interest not reported

Some concerns (sedation level)

Reason: inconsistencies in publication, outcomes not clearly defined; unclear how and by whom assessment was performed.

Prabhudev, 2017

Probably yes

Reason:

“Randomization was done by block randomization (chit method).

Probably yes

Reason:

“Sealed opaque-envelope method was used for allocation

concealment.”

Definitely yes

Reason: separate roles are clearly described; syringes prepared by independent observer with no further role in study; syringes similar in appearance.

Blinding of data analyst not reported.

Definitely yes

Reason: no lost to follow up

Probably yes

Reason: no protocol available; relevant outcomes seem to be reported

Probably yes

Reason: funding and possible conflicts of interest reported (none).

LOW risk (sedation level, patient satisfaction, provider satisfaction, adverse events)

Reason: no clues for possible risk of bias

Toman, 2016

Definitely no

Reason: quasi-randomized; “Patients undergoing TEE were randomized in sequence and divided into three groups containing 30 patients each:”

Definitely no

Reason: no concealed allocation, randomized in sequence

No information

Reason: no details on blinding; trial not described as single or double blinded.

Probably yes

Reason: ‘The study was completed with 90 patients..’, suggesting no lost-to-follow-up

Probably no

Reason: no protocol; results briefly described without providing absolute numbers

No information

Reason: funding and possible conflicts of interest not reported

HIGH risk of bias (all outcomes)

Reason: quasi-randomized; no information about blinding; no protocol, results described but no absolute data provided; no details on funding and potential conflicts of interest.

Wang, 2011

Probably yes

Reason:  patients were

randomly assigned to three treatment arms using a computer generated

list (n=160 for each group).”

No information

No information

Probably yes

Reason: not specified but no lost to follow up

Probably no

Reason: no protocol; results briefly described without providing absolute numbers; outcome announced but not reported

No information

Reason: funding and possible conflicts of interest not reported

Some concerns (all outcomes)

Reason: no information about allocation concealment and blinding; no protocol; results described but no absolute data provided; no details on funding and potential conflicts of interest.

Yalcin Cok, 2008

Probably yes

Reason: “Randomisation was

established according to computer-generated random numbers list.”

No information

Probably no

Reason: no information about outcome assessor, patient, data analyst blinding.

“Drugs were administered by an anesthesia technician who was not involved in the study.“

Probably yes

Reason: not specified but no lost to follow up

Probably no

Reason: no protocol; results briefly described without providing absolute numbers;

No information

Reason: funding and possible conflicts of interest not reported

Some concerns (all outcomes)

Reason: no information about allocation concealment and blinding; no protocol; results described but no absolute data provided; no details on funding and potential conflicts of interest.