Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Hsu, 2019

PS., study characteristics and results are extracted from the SR (unless stated otherwise*)

SR and meta-analysis of 10 RCTs, of which 2 were relevant for the current analysis

Literature search up to September 2018

A: Ghai, 2010

B: Gulhas, 2003

Study design: RCT

Setting and Country: Single centre, Taiwan

A: India

B: Turkey

Source of funding and conflicts of interest:

Funding: not reported

CI: the authors declare no conflict of interest

Inclusion criteria SR: 1) published human RCTs 2) comparing clonidine with a placebo or an active comparator, regardless of the route or the dose of administration, 3) Clonidine had to be given before surgery. We also included studies where clonidine was given immediately after induction before surgery, which was considered as premedication in our study. 4) pediatric patients aged younger than 18 years 5) who were scheduled for an ophthalmic surgical procedure under anesthesia; 6) Data were accepted if the study included at least 70% of ophthalmology patients.

Exclusion criteria SR: Cohort studies, case series, and case reports

Surgery: ophthalmic surgery

2 of 10 studies included

A: Aged 1‐6 y, ASA I‐II, cataract surgery

B: Aged 3-12y, ASA I, strabismus surgery, history of PONV or motion sickness

Important patient characteristics at baseline:

N, mean age (SD)

A:

A1: 40 patients, 3.4 (1.5) yrs

A2: 43 patients, 2.9 (1.5) yrs

A3: 41 patients, 3.0 (1.4) yrs

B:

A1: 40 patients, 7 yrs

A2: 40 patients, 7 yrs

Sex (% Male):

A:

A1: 61.5%

A2: 65.9%

A3: 60%

B:

A1: 45%

A2: 35%

Weight (kg)

A:

A1: 12.5 (2.0)

A2: 12.2 (1.9)

A3: 13.0 (2.1)

B:

A1: 24

A2: 23

Groups comparable at baseline? Baseline characteristics of age, sex, or weight were similar among groups in each study

Clonidine, timing

A:

A1: C, IV 1 μg/kg, after induction

A2: C, IV 2 μg/kg, after induction

B:

A1: C, oral 4 μg/kg, 60 min

Placebo, timing

A: A3: Placebo, after induction

B: A2: Placebo, 60 min

End-point of follow-up:

A: 90 min

B: 48 hours

For how many participants were no complete outcome data available?

(intervention/control)

A:

A1: 1

A2: 0

A3: 2

B:

A1: 0

A2: 0

Postoperative pain

(measured by pain scores)

Postoperative pain PACU

Effect measure: mean difference (SD) [n]

A:

A1: 1.33 (1.53) [39]

A2: 0.66 (1.5) [41]

A3: 1.5 (1.9) [40]

Postoperative agitation*

Pain/discomfort score, PDS (every 15 minutes for 90 minutes long)

PDS ≥3 at any time point for items 3 to 5 agitation.

PDS >6: severe agitation.

PDS ≥3

A:

A1: 2 (5.1%) [39]

A2: 0 [41]

A3: 11 (27.5%) [40]

PDS >6, requiring rescue medication

A:

A1: 1 (2.6%) [39]

A2: 0 [41]

A3: 5(12.5%) [40]

PDS scores per 15 minutes provided in box plots.

“The PDS for items 3 to 5 were significantly

different among the three groups until 60 minutes

postoperatively (P <0.001, Kruskal-Wallis) (Figure

1). Pairwise comparison revealed significantly lower

scores for items 3 to 5 of the PDS in group C2

compared to groups C1 and NS until 60 minutes

postoperatively (P <0.05, Mann-Whitney). Group

C1 had significantly lower scores of these three items

at 15 minutes compared to NS (P=0.03, Mann- Whitney), while these scores were comparable

between group C1 and NS at all subsequent time

intervals postoperatively (P >0.05, Mann-Whitney).

PDS for all items were significantly different among

the three groups for 45 minutes postoperatively

(P <0.001, Kruskal-Wallis) (Figure 2). Pair-wise

comparison revealed significantly low PDS scores

in group C2 compared to groups C1 and NS for

45 minutes postoperatively (P <0.05, Mann_Whitney). Group C1 had significantly lower PDS

scores at 15 minutes compared to NS (P=0.018,

Mann-Whitney), while PDS scores were comparable between groups C1 and NS at all subsequent time

intervals postoperatively (P >0.05, Mann-Whitney).”

Postoperative opioid consumption*

B: “None

of the children needed supplemental suppositories for postoperative pain.”

Complications

Sedation score before surgery

SMD: 0.14 [-1.37, 1.64]

Other complications*

A: data in line diagrams. Hemodynamic and respiratory parameters were comparable between the clonidine and placebo groups. à None of the children developed hypotension, bradycardia or respiratory depression during the intraoperative or postoperative periods.

Length of stay*

In min, mean ± SD (95%CI)

A:

A1: 48.4±14.0 (43.9-53.07)

A2: 79.5±12.8 (75.4-83.5)

A3: 73.13±20.4 (66.6-79.6)

B:

A1: 23±6

A2: 22±5

Study objective: To assess whether clonidine premedication may safely decrease postoperative vomiting and postoperative pain in pediatric patients who received an ophthalmic surgery.

Risk of bias (high, some concerns or low):

A: Low

B: Low

Outcomes:

A:

• The primary outcome of our study was the incidence of postoperative agitation.
• Time to discharge,
• incidence of cardiovascular and respiratory depression,
• nausea and vomiting were studied as secondary outcome measures.

B:

• Complete response was defined as no retching, no vomiting, and no need for rescue antiemetic medication.
• Episodes of vomiting or retching were logged separately.
• In circumstances where two or more episodes of emetic symptoms occurred, i.v. metoclopramide 0.2mgkga1 was administered as a rescue antiemetic. In each group, the number of symptom episodes were totalled for the time intervals 0–6, 6–24, 24–48, and 0–48 h.

Lambert, 2015

PS., study characteristics and results are extracted from the SR (unless stated otherwise*)

SR and meta-analysis of RCTs

Literature search: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 12, 2012), Ovid MEDLINE (1966 to 21 December 2012) and Ovid EMBASE (1982 to 21 December 2012), as well as reference lists of other relevant articles and online trial registers.

A: Hackmann, 2003

B: Nishina, 2000

Study design: RCT

Source of funding and conflicts of interest:

[commercial / non-commercial / industrial co-authorship]

Inclusion criteria SR: We included all randomized (or quasi-randomized), controlled trials comparing clonidine premedication to placebo, a higher dose of clonidine, or another agent when used for surgical or other invasive procedures in children under the age of 18 years and where pain or a surrogate (principally the need for supplementary analgesia) was reported.

Exclusion criteria SR:

Surgery: pediatric surgery

2 of 11 studies included (7 wrong comparison; 2 < 2000)

A: Healthy adolescent patients scheduled for orthognathic surgery

B: ASA I children from 2-12 years old, undergoing ophthalmological surgery. One hundred and twenty five children were allocated to 5 groups of 25

Important patient characteristics at baseline:

N, mean age (years)*

A:

I: 19, 14 ± 1.4
C: 20, 14 ± 0.9

B:

I: 50, 7
C: 50, 7

Weight (kg)*:

A:

I: 58 ± 9.6

C: 55 ± 10.8

B: -

Groups comparable at baseline?

No

Clonidine

A: clonidine 5 μg/kg orally at bedtime the night before surgery and 90 min prior to induction (rounded to nearest 50 μg)

B: 4 µg/kg orally, 105 min before estimated time of induction

placebo or no treatment

A: identical-looking placebo at the same times

B: diclofenac (2 mg/kg rectally) or flurbiprofen (1mg/kg intravenously), given immediately post-induction**

End-point of follow-up*:

A: not reported (PACU)

B: 24 hours

For how many participants were no complete outcome data available?

(intervention/control)

A: Forty-six (46) consecutive patients considered eligible; excluded 7 as below, leaving 19 for the clonidine group and 20 for the placebo group.

B: One hundred and twenty five children were allocated to 5 groups of 25.

Postoperative pain 0-12 hours

Objective Pain Scale (OPS). Pain scores reported were the maximum score for each child over the 12 hours following surgery, mean (SD) [n]

B:

I: 2.8 (1.8) [50]

C: 4.8 (1.8) [50]

Opioid consumption

Morphine in PACU (mg) in mean (range)

A:

I: 1.6 (0–4)

C: 1.3 (0–6)

Codeine in PACU (mg) in mean ± SD

A:

I: 109 ±  58

C: 78 ±  54

Number requiring analgesia

Additional analgesia at any time postoperatively (acetaminophen (200±400 mg) or diclofenac (12.5 or 25 mg))

B:

I: 5/50

C: 29/50

Complications

Hypotension time (min)

A:

I: 174 ±  42

C: 184 ±  39

Preoperative sedation*

To assess the anxiolytic effect of the premedication, patients were asked to indicate their emotional state on a visual analog scale (VAS; 10-cm length; range from 0 = completely calm to 10 = worst possible anxiety)

VAS – admission (mean ±  SD)

A:

I: 40 ± 24
C: 40 ±  30

VAS – morning (mean ±  SD)

A:

I: 44 ±  21
C: 42 ±  30

VAS – operating room (mean ±  SD)

A:

I: 44 ±  17
C: 37 ±  30

Sedation score

(four-point scale: 1, awake and talkative; 2, awake but uncommunicative; 3, drowsy, quiet, and easily arousable; and 4, asleep, not easily arousable)

bv anesthesiologist (mean, range)

A:

I: 2.3 (1–3)
C: 1.3 (1–3)

bv nurse (mean, range)

A:

I: 2.5 (1–3)
C: 1.3 (1–3)

Study objective: To evaluate the evidence for the effectiveness of clonidine, when given as a premedication, in reducing postoperative pain in children less than 18 years of age. We also sought evidence of any clinically significant side effects.

** 5 arms: 1) Oral placebo followed by rectal diclofenac 2 mg/kg 2) Oral placebo followed by intravenous flurbiprofen 1 mg/kg 3) Oral clonidine 4 μg/kg alone 4) Oral clonidine 4 μg/kg followed by rectal diclofenac 2 mg/kg 5) Oral clonidine 4 μg/kg followed by intravenous flurbiprofen 1 mg/kg à For the purposes of comparison, we have pooled the diclofenac/placebo and flurbiprofen/placebo groups together, and compared these to the pooled diclofenac/clonidine and flurbiprofen/clonidine groups

Risk of bias (high, some concerns or low):

A: Low

B: unclear (selection bias, reporting bias), low

Outcomes:

A:

• Morphine or codeine given in PACU

•PACU length of stay

•Hemodynamic values before surgery and at induction

•Preoperative sedation

• Temperature

• Time to arrival in PACU

• Time to eye opening

• Time to movement to command

•Extubation

Primary outcome of this study was controlled hypotension perioperatively, but also reported on analgesic requirements postoperatively; note that fentanyl was given intraoperatively to control BP (different amounts to each group)

B:

• Pain by modified Objective Pain Scale (OPS) (blood pressure component removed to avoid confounding by clonidine's antihypertensive effect; presented as overall highest OPS score

• Number of children requiring rescue analgesia (diclofenac suppository) in the first 12 hours after surgery

• Number of children pain-free in the first 12 hours after surgery

• Postoperative nausea and vomiting

• Time to extubation

• Time to eye opening

• Time to obeying commands

• Postoperative recovery score (Aldrete) on return to ward

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Clonidine

Placebo

Freeman, 2002

Type of study: RCT

Setting and country: single centre, USA

Funding and conflicts of interest: not reported

Inclusion criteria: children undergoing tonsillectomy and adenoidectomy; aged 3-10 years

Exclusion criteria: known allergy or sensitivity to clonidine.

Surgery:

tonsillectomy and adenoidectomy

N total at baseline:

I: 19
C: 20

Important prognostic factors²:

age ± SD (months):

I: 76 ± 26

C: 77 ± 24

Weight (kg):

I: 23 ± 9

C: 28 ± 14

Groups comparable at baseline? Yes, The groups did not differ significantly with respect to age, weight or surgical time

Clonidine; i.m.

injection of 2 lgÆkg)1 of clonidine (0.5 ml in the left

deltoid muscle).

Saline; i.m. injection of 0.5 ml normal saline (in the left deltoid muscle)

Length of follow-up:

POD1

Loss-to-follow-up:

There were 40 patients enrolled in the study (but only 39 were included in the final analysis; one patient was removed due to break of protocol; this resulted in 19 in group C and 20 in group S)

Postoperative pain

PACU

assessed and treated by a nurse (trained in pain evaluation) blinded to group assignment, using a six-point objective pain scale

Results not reported.

POD1

Parents rated their children’s pain at rest and with movement, with 0 corresponding to ‘no pain’ and 10 corresponding to ‘the worst pain imaginable’.

Results reported in box plots in median and IQR

POD1-rest

I: 5 (1-7)
C: 5 (2-8)

POD1-movement

I: 4 (3-6)
C: 5 (2-6)

Aldrete scores

No significant differences in Aldrette scores on arrival to, or discharge from, PACU were present.

Data not reported

Postoperative opioid consumption

Fentanyl in PACU (µg*kg)-1

I: 0.7 ± 06
C: 0.8 ± 0.6

POD1

The number of doses of acetaminophen/codeine and the occurrence of emesis episodes were recorded by parents.

I: 3.4 ± 1.5

C: 3.6 ± 2.0

Neither postoperative requirements for fentanyl, nor number of acetaminophen/codeine doses required postoperatively for the first 24 h differed between the saline and clonidine groups.

Data not reported.

Complications

There was no significant decrease in blood pressure in the clonidine group compared with the saline group.

No significant differences in sedation were noted at the time of PACU discharge.

Data not reported

Length of stay / Time to discharge

Five patients (four in group S, one in group C) were admitted for i.v. hydration because they were unable to tolerate oral intake due to nausea; the remaining 34 children were discharged home on the day of the operation.

PACU discharge time also did not differ between the two groups (a stay of 5–6 h was mandatory by hospital policy). Data not reported

Study objective: to determine whether intramuscular (I.M.) clonidine would decrease pain in paediatric patients undergoing T&A.

Helali, 2013

Type of study:

RCT

Setting and country: single centre, Bangladesh

Funding and conflicts of interest: not reported

Inclusion criteria: Children of ASA physical status I, between 3months -3 years of age, undergoing chiloplasty and palatoplasty surgery

Exclusion criteria:

Not reported

Surgery: chiloplasty and palatoplasty surgery

N total at baseline:

I: 30

C: 30

Important prognostic factors²:

For example

age ± SD (months:

I: 16.5±11.8

C: 18.66±10.29

Weight (kg)

I: 9.73±2.72
C: 10.51±2.96

Groups comparable at baseline? Yes, there was no significant difference observed between the groups.

clonidine (4 µg/kg) in juice or milk, 60 minutes before the estimated time of induction of anesthesia.

Placebo (juice or milk)

Length of follow-up:

12 hours

Loss-to-follow-up:

Not reported/none; outcomes available for all 60 included patients.

Incomplete outcome data:

Not reported/none; outcomes available for all 60 included patients.

Postoperative pain

rated by an independent observer using the objective pain scale (OPS)* for post operative pain assessment in children.

Highest Objective Pain Score (OPS) (median and range)

I: 3.4 (0-8)
C: 4.5 (3-8)

Postoperative opioid consumption**

(diclofenac suppository)
Overall number of patients (n and%) required postoperative analgesic “Rescue” therapy

I: 02 (6.66%)
C: 25 (83.33%)

Complications
No children in the clonidine group experienced severe hypotension, bradycardia, respiratory depression according to our arbitrary extreme definitions and none of these children received any post operative pharmacological treatment for these complications. No children were suffered from mild hypotension and only 3 children developed mild bradycardia in the clonidine group. However, these differences in post operative vital signs among the two groups were of little clinical significance.

Study objective: to compare the post operative pain between patients receiving clonidine and the patients of control group (without clonidine).

* The parameters used in this scale are systolic blood pressure, crying, movement, agitation and complains of pain. The minimum score is 0 and the maximum score is 10. However, the maximum score is 8 in cases if the child is too young to complain. In this study we took the highest score as 8 because of the age group of the children is 3months to 3 years who could not verbalize the pain. Pain free denotes those children who scored 0 (no pain) over the specified time period. In this study, pain assessment was made post-operatively immediately after awakening in the operating room and 0.5,1,2,3,4,5,6,8 and 12 hours thereafter by a single independent observer.

**Children with OPS score of 4 or greater received a diclofenac suppository (12.5 mg) as a rescue analgesic.

Hsu, 2019

Yes

Yes

Yes/ unclear; not for each excluded study separately but exclusion reasons with numbers are provided.

Yes

Not applicable; SR of RCTs

Yes

• Ghai, 2010: Low
• Gulhas, 2003: Low

Yes/ unclear; heterogeneity

No

No, only for SR

Lambert, 20

Yes

Yes

Yes

Yes

Not applicable, SR of RCTs

Yes

• Hackmann, 2003: Low
• Nishina, 2000: unclear (selection bias, reporting bias), low

Yes/unclear; heterogeneity

Yes

No, only for SR

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

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?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

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?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Freeman, 2002

Probably yes;

Reason: Randomization by a computer generated list

Probably no;

Reason: not reported.

Probably no;

Reason: control group is placebo, patients blinded; outcome assessors blinded (blinding of health care providers, data collectors and analysts not reported)

Definitely yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely no;

Reason: postoperative pain in PACU as assessed by a blinded nurse; and postoperative opioid consumption for fentanyl; and complications not reported.

Definitely yes;

Reason: No other problems noted

Some concerns

Helali, 2013

Probably no;

Reason: only stated that patients were selected randomly

Probably no;

Reason: not reported.

Probably no;

Reason: control group is placebo, patients blinded; independent observer (blinding of health care providers, data collectors and analysts not reported)

Probably yes

Reason: not reported, but all selected patients had outcome data.

Definitely yes

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems noted.

Some concerns