Cryotherapy following total knee replacement

Ashwin Aggarwal; Sam Adie; Ian A Harris; Justine Naylor

doi:10.1002/14651858.CD007911.pub3

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Figure 1

PRISMA study flow diagram

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Funnel plot of comparison: 1 Any cold versus any control, outcome: 1.6 COMBINED Blood loss.

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Figure 4

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.6 COMBINED Blood loss.

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Figure 5

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.9 Pain at POD 2 VAS.

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Figure 6

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.13 Transfusion rate.

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Figure 7

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.16 Range of motion ‐ degrees of flexion at discharge.

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Figure 8

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.18 Function at POD 8‐14.

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Figure 9

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.21 Adverse events.

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Figure 10

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.22 Withdrawals due to adverse events.

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Figure 11

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.27 COMBINED Analgesic use.

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Figure 12

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.28 change in swelling at mid‐patella.

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Figure 13

Forest plot of comparison: 1 Any cold versus any control, outcome: 1.31 Length of hospital stay ‐ days.

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Analysis 1.1

Comparison 1: Any cold therapy versus any control, Outcome 1: Blood loss ‐ total body mL

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Analysis 1.2

Comparison 1: Any cold therapy versus any control, Outcome 2: Blood loss ‐ wound drainage mL/24 hours

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Analysis 1.3

Comparison 1: Any cold therapy versus any control, Outcome 3: Blood loss ‐ wound drainage mL/48 hours

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Analysis 1.4

Comparison 1: Any cold therapy versus any control, Outcome 4: Blood loss ‐ total wound drainage mL

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Analysis 1.5

Comparison 1: Any cold therapy versus any control, Outcome 5: Blood loss ‐ haemoglobin drop mmol/L/24 hours

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Analysis 1.6

Comparison 1: Any cold therapy versus any control, Outcome 6: COMBINED Blood loss

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Analysis 1.7

Comparison 1: Any cold therapy versus any control, Outcome 7: COMBINED Blood loss ‐ cement and no cement

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Analysis 1.8

Comparison 1: Any cold therapy versus any control, Outcome 8: Pain at post‐operative day 1 ‐ visual analogue scale (VAS)

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Analysis 1.9

Comparison 1: Any cold therapy versus any control, Outcome 9: Pain at post‐operative day 2 ‐ visual analogue scale (VAS)

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Analysis 1.10

Comparison 1: Any cold therapy versus any control, Outcome 10: Pain at post‐operative day 3 ‐ visual analogue scale (VAS)

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Analysis 1.11

Comparison 1: Any cold therapy versus any control, Outcome 11: Pain at 6 weeks ‐ visual analogue scale (VAS)

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Analysis 1.12

Comparison 1: Any cold therapy versus any control, Outcome 12: Pain at 12 weeks ‐ visual analogue scale (VAS)

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Analysis 1.13

Comparison 1: Any cold therapy versus any control, Outcome 13: Transfusion rate

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Analysis 1.14

Comparison 1: Any cold therapy versus any control, Outcome 14: Range of motion ‐ degrees of knee flexion post‐operative days 1 to 6

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Analysis 1.15

Comparison 1: Any cold therapy versus any control, Outcome 15: Range of motion ‐ degrees of knee flexion post‐operative days 7 to 14

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Analysis 1.16

Comparison 1: Any cold therapy versus any control, Outcome 16: Range of motion ‐ degrees of flexion at discharge

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Analysis 1.17

Comparison 1: Any cold therapy versus any control, Outcome 17: Range of motion ‐ degrees of flexion at 3 months

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Analysis 1.18

Comparison 1: Any cold therapy versus any control, Outcome 18: Function ‐ post‐operative days 8 to 14

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Analysis 1.19

Comparison 1: Any cold therapy versus any control, Outcome 19: Function ‐ 6 weeks

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Analysis 1.20

Comparison 1: Any cold therapy versus any control, Outcome 20: Function ‐ 3 months

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Analysis 1.21

Comparison 1: Any cold therapy versus any control, Outcome 21: Total adverse events

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Analysis 1.22

Comparison 1: Any cold therapy versus any control, Outcome 22: Withdrawals due to adverse events

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Analysis 1.23

Comparison 1: Any cold therapy versus any control, Outcome 23: Analgesic use mg/kg/24 hours

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Analysis 1.24

Comparison 1: Any cold therapy versus any control, Outcome 24: Analgesic use mg/kg/48 hours of morphine equivalent

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Analysis 1.25

Comparison 1: Any cold therapy versus any control, Outcome 25: Analgesic use mg/kg/72 hours

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Analysis 1.26

Comparison 1: Any cold therapy versus any control, Outcome 26: Analgesia use total mg/kg

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Analysis 1.27

Comparison 1: Any cold therapy versus any control, Outcome 27: COMBINED Analgesic use

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Analysis 1.28

Comparison 1: Any cold therapy versus any control, Outcome 28: Change in swelling at mid‐patella in mm ‐ post‐operative days 2 to 6

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Analysis 1.29

Comparison 1: Any cold therapy versus any control, Outcome 29: Change in swelling at mid‐patella in mm ‐ 6 weeks

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Analysis 1.30

Comparison 1: Any cold therapy versus any control, Outcome 30: Change in swelling at 12 weeks

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Analysis 1.31

Comparison 1: Any cold therapy versus any control, Outcome 31: Length of hospital stay ‐ days

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Analysis 1.32

Comparison 1: Any cold therapy versus any control, Outcome 32: Quality of life ‐ 3 months

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Analysis 1.33

Comparison 1: Any cold therapy versus any control, Outcome 33: Activity level ‐ post‐operative days 1 to 7

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Analysis 1.34

Comparison 1: Any cold therapy versus any control, Outcome 34: Activity level ‐ 6 weeks

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Analysis 2.1

Comparison 2: Any cold therapy versus any control (Sensitivity analyses excluding studies with bilateral TKRs), Outcome 1: COMBINED Blood loss

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Analysis 2.2

Comparison 2: Any cold therapy versus any control (Sensitivity analyses excluding studies with bilateral TKRs), Outcome 2: Transfusion rate

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Analysis 2.3

Comparison 2: Any cold therapy versus any control (Sensitivity analyses excluding studies with bilateral TKRs), Outcome 3: Adverse events total

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Summary of findings 1. Any cold therapy compared with no cold therapy following total knee replacement

Outcomes	*Illustrative comparative risks (95% CI)**		Difference	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Any cold therapy compared with no cold therapy following total knee replacement
Patient or population: people undergoing total knee replacement Settings: post‐operative, either in hospital or in the community Intervention: any cold therapy with or without other treatment for pain or swelling (compression, regional nerve block or continuous passive motion) Comparison: no treatment; or the other treatment alone
	Assumed risk	Corresponding risk
	No cold therapy	Any cold therapy
Blood loss Time point: mean 48 hours, range 1 to 13 days. Higher blood loss indicates a worse outcome.	The mean blood loss from the control group in Smith 2002 was 824.7 mL.	The mean blood loss in the intervention groups was 560.7 mL.	264 mL less (7 to 516 mL less)	‐	956 (12 studies)	⊕⊕⊝⊝ Low^a,b	Cryotherapy may improve blood loss after TKR. This may or may not be clinically significant.^c The SMD was 0.72 standard deviations lower in the cryotherapy group (1.41 to 0.02 lower).^d
Pain at post‐operative day 2 Scale from 0 (best) to 10 (worst). Follow‐up: 2 days	The mean pain at post‐operative day 2 in the control group in Smith 2002 was 4.8 points.	The mean pain at post‐operative day 2 in the intervention groups was 3.16 points.	1.64 points lower (2.28 to 1.00 lower)	‐	530 (6 studies)	⊕⊕⊝⊝ Low^a	Cryotherapy may improve pain two days after TKR. This may or may not be clinically significant.^e
Transfusion rate Follow‐up: 0 to 13 days	370 per 1000	788 per 1000 (15 to 1000)	418 more per 1000 (355 fewer to 40,146 more)	RR 2.13 (0.04 to 109.63)	91 (2 studies)	⊕⊝⊝⊝ Very low^a,b,f	We are uncertain whether cryotherapy improves transfusion rate after TKR.
Range of motion at discharge Scale from 0 (worst) to 125 (best). Follow‐up: mean 9 days	The range of motion at discharge in the control group in Kullenberg 2006 was 62.9 degrees.	The mean range of motion at discharge in the intervention groups was 71.24 points.	8.34 degrees higher (3.57 higher to 13.12 higher)	‐	174 (3 studies)	⊕⊕⊝⊝ Low^a,g	Cryotherapy may improve range of motion at discharge after TKR. This may or may not be clinically significant.^h
Function Standardised scale with positive score indicating a better outcome. Scale from 0 (worst) to 100 (best). Follow‐up: 2 weeks	The function score in the control group in Thijs 2019 was 75.4.	The mean function score in the intervention group was 88.58 points.	13.18 points better (0.55 worse to 27.08 better)	‐	296 (4 studies)	⊕⊝⊝⊝ Very low^a,b	We are uncertain whether cryotherapy improves function after TKR. The SMD was 0.72 standard deviations higher in the cryotherapy group (0.03 lower to 1.48 higher).ⁱ
Total adverse events Adverse events included discomfort, local skin reactions, superficial infections, cold‐induced injuries and thrombolytic events. Follow‐up: 0 to 30 days	21 per 1000	27 per 1000 (11 to 66)	6 more per 1000 (10 fewer to 45 more)	RR 1.30 (0.53 to 3.20)	1199 (16 studies)	⊕⊝⊝⊝ Very low^a,f,g	We are uncertain whether cryotherapy improves total adverse events after TKR.
Withdrawals due to adverse events Follow‐up: 0 to 30 days	2 per 1000	4 per 1000 (1 to 26)	2 more per 1000 (1 fewer to 25 more)	RR 2.71 (0.42 to 17.38)	1347 (19 studies)	⊕⊝⊝⊝ Very low^a,f,g	We are uncertain whether cryotherapy improves withdrawals due to adverse events after TKR.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TKR: total knee replacement; RR: risk ratio; SMD: standardised mean difference
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded for high risk of bias (two levels if a subjective outcome): selection, performance, detection, reporting or other bias ^bDowngraded for inconsistency: significant unexplained heterogeneity (96% for blood loss, 87% for transfusion rate, 89% for function) ^cThe clinically significant value for blood loss is 300 mL. ^dWe converted the SMD to a clinically meaningful measure using Smith 2002 (SD 366 mL). ^eThe clinically significant value for pain is 1.5 points on a visual analogue scale. ^fDowngraded for imprecision: wide 95% CI for intervention ^gDowngraded for indirectness: limitations in outcome measurement (diversity in definition and timing of measurement) ^hThe clinically significant value for range of motion is 7 degrees. ⁱWe converted the SMD to a clinically meaningful measure using Thijs 2019 (SD 18.3).

Summary of findings 1. Any cold therapy compared with no cold therapy following total knee replacement

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Comparison 1. Any cold therapy versus any control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Blood loss ‐ total body mL Show forest plot	2	140	Mean Difference (IV, Random, 95% CI)	‐637.06 [‐753.61, ‐520.50]

1.1.1 Cold Compression vs. Compression	2	140	Mean Difference (IV, Random, 95% CI)	‐637.06 [‐753.61, ‐520.50]
1.2 Blood loss ‐ wound drainage mL/24 hours Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.2.1 Cold Compression vs. Compression	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.3 Blood loss ‐ wound drainage mL/48 hours Show forest plot	4	273	Mean Difference (IV, Random, 95% CI)	‐142.14 [‐300.85, 16.57]

1.3.1 Cold vs. Compression	1	84	Mean Difference (IV, Random, 95% CI)	75.30 [‐107.23, 257.83]
1.3.2 Cold Compression vs. Nothing	2	129	Mean Difference (IV, Random, 95% CI)	‐187.45 [‐321.12, ‐53.78]
1.3.3 Cold Compression vs. Compression	1	60	Mean Difference (IV, Random, 95% CI)	‐480.00 [‐949.99, ‐10.01]
1.4 Blood loss ‐ total wound drainage mL Show forest plot	2	66	Mean Difference (IV, Random, 95% CI)	‐96.04 [‐256.86, 64.77]

1.4.1 Cold Compression vs. Compression	1	36	Mean Difference (IV, Random, 95% CI)	‐188.00 [‐458.89, 82.89]
1.4.2 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Mean Difference (IV, Random, 95% CI)	‐46.00 [‐245.84, 153.84]
1.5 Blood loss ‐ haemoglobin drop mmol/L/24 hours Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.5.1 Cold Compression vs. Nothing	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.6 COMBINED Blood loss Show forest plot	12	956	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.41, ‐0.02]

1.6.1 Cold vs. Compression	1	84	Std. Mean Difference (IV, Random, 95% CI)	0.17 [‐0.26, 0.60]
1.6.2 Cold Compression vs. Nothing	3	212	Std. Mean Difference (IV, Random, 95% CI)	‐0.29 [‐0.73, 0.16]
1.6.3 Cold Compression vs. Compression	7	630	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐2.18, ‐0.03]
1.6.4 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.88, 0.56]
1.7 COMBINED Blood loss ‐ cement and no cement Show forest plot	10	662	Std. Mean Difference (IV, Random, 95% CI)	‐0.55 [‐0.99, ‐0.11]

1.7.1 Cement	5	295	Std. Mean Difference (IV, Random, 95% CI)	‐0.34 [‐0.92, 0.23]
1.7.2 No Cement	5	367	Std. Mean Difference (IV, Random, 95% CI)	‐0.82 [‐1.53, ‐0.10]
1.8 Pain at post‐operative day 1 ‐ visual analogue scale (VAS) Show forest plot	9	735	Mean Difference (IV, Random, 95% CI)	‐0.78 [‐1.78, 0.22]

1.8.1 Cold versus compression	1	84	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.72, 0.92]
1.8.2 Cold compression versus nothing	4	389	Mean Difference (IV, Random, 95% CI)	‐1.66 [‐2.59, ‐0.73]
1.8.3 Cold compression versus compression	3	204	Mean Difference (IV, Random, 95% CI)	0.12 [‐0.66, 0.89]
1.8.4 Cold plus analgesia versus analgesia	1	58	Mean Difference (IV, Random, 95% CI)	Not estimable
1.9 Pain at post‐operative day 2 ‐ visual analogue scale (VAS) Show forest plot	6	530	Mean Difference (IV, Random, 95% CI)	‐1.64 [‐2.28, ‐1.00]

1.9.1 Cold versus compression	1	84	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐1.33, 0.33]
1.9.2 Cold compression versus nothing	3	306	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐1.73, ‐1.42]
1.9.3 Cold compression versus compression	2	140	Mean Difference (IV, Random, 95% CI)	‐2.36 [‐4.41, ‐0.31]
1.10 Pain at post‐operative day 3 ‐ visual analogue scale (VAS) Show forest plot	9	789	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.45, ‐0.15]

1.10.1 Cold versus compression	2	100	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐2.38, 1.89]
1.10.2 Cold compression versus nothing	2	185	Mean Difference (IV, Random, 95% CI)	‐0.98 [‐2.06, 0.10]
1.10.3 Cold compression versus compression	5	504	Mean Difference (IV, Random, 95% CI)	‐1.13 [‐1.68, ‐0.57]
1.11 Pain at 6 weeks ‐ visual analogue scale (VAS) Show forest plot	5	522	Mean Difference (IV, Random, 95% CI)	‐0.55 [‐1.01, ‐0.09]

1.11.1 Cold versus nothing	1	67	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.52, 0.38]
1.11.2 Cold versus compression	1	16	Mean Difference (IV, Random, 95% CI)	0.40 [‐1.17, 1.97]
1.11.3 Cold compression versus nothing	1	100	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐1.80, ‐0.80]
1.11.4 Cold compression versus compression	1	58	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.18, 0.38]
1.11.5 Cold and continuous passive motion (CMP) versus CPM	1	281	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐0.89, ‐0.41]
1.12 Pain at 12 weeks ‐ visual analogue scale (VAS) Show forest plot	2	341	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.94, 0.08]

1.12.1 Cold compression versus compression	1	60	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.95, 1.15]
1.12.2 Cold and continuous passive motion (CMP) versus CPM	1	281	Mean Difference (IV, Random, 95% CI)	‐0.56 [‐0.82, ‐0.30]
1.13 Transfusion rate Show forest plot	2	91	Risk Ratio (IV, Random, 95% CI)	2.13 [0.04, 109.63]

1.13.1 Cold compression versus nothing	1	31	Risk Ratio (IV, Random, 95% CI)	20.19 [1.28, 319.17]
1.13.2 Cold compression versus compression	1	60	Risk Ratio (IV, Random, 95% CI)	0.35 [0.16, 0.77]
1.14 Range of motion ‐ degrees of knee flexion post‐operative days 1 to 6 Show forest plot	8	478	Mean Difference (IV, Random, 95% CI)	5.57 [0.16, 10.97]

1.14.1 Cold versus compression	2	100	Mean Difference (IV, Random, 95% CI)	5.55 [‐11.26, 22.36]
1.14.2 Cold compression versus nothing	3	212	Mean Difference (IV, Random, 95% CI)	7.49 [‐2.51, 17.48]
1.14.3 Cold compression versus compression	2	136	Mean Difference (IV, Random, 95% CI)	4.49 [‐8.74, 17.71]
1.14.4 Cold versus ultrasound	1	30	Mean Difference (IV, Random, 95% CI)	3.20 [‐1.74, 8.14]
1.15 Range of motion ‐ degrees of knee flexion post‐operative days 7 to 14 Show forest plot	3	170	Mean Difference (IV, Random, 95% CI)	8.56 [‐0.77, 17.89]

1.15.1 Cold compression versus compression	2	140	Mean Difference (IV, Random, 95% CI)	12.89 [8.48, 17.30]
1.15.2 Cold versus ultrasound	1	30	Mean Difference (IV, Random, 95% CI)	0.70 [‐2.31, 3.71]
1.16 Range of motion ‐ degrees of flexion at discharge Show forest plot	3	174	Mean Difference (IV, Random, 95% CI)	8.34 [3.57, 13.12]

1.16.1 Cold versus nothing	2	91	Mean Difference (IV, Random, 95% CI)	5.91 [0.05, 11.78]
1.16.2 Cold compression versus nothing	1	83	Mean Difference (IV, Random, 95% CI)	12.20 [4.75, 19.65]
1.17 Range of motion ‐ degrees of flexion at 3 months Show forest plot	3	128	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐6.61, 2.61]

1.17.1 Cold compression versus nothing	1	31	Mean Difference (IV, Random, 95% CI)	Not estimable
1.17.2 Cold and continuous passive motion (CPM) versus CPM	1	30	Mean Difference (IV, Random, 95% CI)	Not estimable
1.17.3 Cold versus nothing	1	67	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐6.61, 2.61]
1.18 Function ‐ post‐operative days 8 to 14 Show forest plot	4	296	Std. Mean Difference (IV, Random, 95% CI)	0.72 [‐0.03, 1.48]

1.18.1 Cold compression versus nothing	2	206	Std. Mean Difference (IV, Random, 95% CI)	0.98 [0.28, 1.68]
1.18.2 Cold compression versus compression	1	60	Std. Mean Difference (IV, Random, 95% CI)	‐0.34 [‐0.85, 0.17]
1.18.3 Cold versus ultrasound	1	30	Std. Mean Difference (IV, Random, 95% CI)	1.33 [0.52, 2.13]
1.19 Function ‐ 6 weeks Show forest plot	2	160	Std. Mean Difference (IV, Random, 95% CI)	0.21 [‐0.10, 0.53]

1.19.1 Cold Compression vs. Nothing	1	100	Std. Mean Difference (IV, Random, 95% CI)	0.32 [‐0.07, 0.72]
1.19.2 Cold Compression vs. Compression	1	60	Std. Mean Difference (IV, Random, 95% CI)	0.03 [‐0.47, 0.54]
1.20 Function ‐ 3 months Show forest plot	2	127	Std. Mean Difference (IV, Random, 95% CI)	0.21 [‐0.14, 0.56]

1.20.1 Cold vs. Nothing	1	67	Std. Mean Difference (IV, Random, 95% CI)	0.08 [‐0.40, 0.56]
1.20.2 Cold Compression vs. Compression	1	60	Std. Mean Difference (IV, Random, 95% CI)	0.37 [‐0.14, 0.88]
1.21 Total adverse events Show forest plot	16	1199	Risk Ratio (IV, Random, 95% CI)	1.30 [0.53, 3.20]

1.21.1 Cold vs. Nothing	2	112	Risk Ratio (IV, Random, 95% CI)	0.11 [0.01, 1.86]
1.21.2 Cold vs. Compression	2	100	Risk Ratio (IV, Random, 95% CI)	2.00 [0.22, 17.89]
1.21.3 Cold Compression vs. Nothing	4	357	Risk Ratio (IV, Random, 95% CI)	4.39 [0.93, 20.72]
1.21.4 Cold Compression vs. Compression	7	600	Risk Ratio (IV, Random, 95% CI)	0.82 [0.26, 2.60]
1.21.5 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Risk Ratio (IV, Random, 95% CI)	Not estimable
1.22 Withdrawals due to adverse events Show forest plot	19	1347	Risk Ratio (IV, Random, 95% CI)	2.71 [0.42, 17.38]

1.22.1 Cold vs. Nothing	3	179	Risk Ratio (IV, Random, 95% CI)	Not estimable
1.22.2 Cold vs. Compression	2	100	Risk Ratio (IV, Random, 95% CI)	Not estimable
1.22.3 Cold Compression vs. Nothing	5	388	Risk Ratio (IV, Random, 95% CI)	2.71 [0.42, 17.38]
1.22.4 Cold Compression vs. Compression	8	650	Risk Ratio (IV, Random, 95% CI)	Not estimable
1.22.5 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Risk Ratio (IV, Random, 95% CI)	Not estimable
1.23 Analgesic use mg/kg/24 hours Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.23.1 Cold compression versus nothing	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.24 Analgesic use mg/kg/48 hours of morphine equivalent Show forest plot	4	255	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.18, 0.10]

1.24.1 Cold versus compression	1	84	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.03, 0.23]
1.24.2 Cold compression versus nothing	1	31	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.30, 0.02]
1.24.3 Cold compression versus compression	2	140	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.27, 0.14]
1.25 Analgesic use mg/kg/72 hours Show forest plot	1	88	Mean Difference (IV, Random, 95% CI)	0.19 [‐0.10, 0.48]

1.25.1 Cold versus nothing	1	88	Mean Difference (IV, Random, 95% CI)	0.19 [‐0.10, 0.48]
1.26 Analgesia use total mg/kg Show forest plot	2	90	Mean Difference (IV, Random, 95% CI)	‐213.80 [‐604.00, 176.39]

1.26.1 Cold Compression vs. Compression	1	60	Mean Difference (IV, Random, 95% CI)	‐450.00 [‐781.16, ‐118.84]
1.26.2 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Mean Difference (IV, Random, 95% CI)	‐46.00 [‐105.42, 13.42]
1.27 COMBINED Analgesic use Show forest plot	8	516	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.39, 0.14]

1.27.1 Cold vs. Nothing	1	88	Std. Mean Difference (IV, Random, 95% CI)	0.27 [‐0.17, 0.71]
1.27.2 Cold vs. Compression	1	84	Std. Mean Difference (IV, Random, 95% CI)	0.34 [‐0.10, 0.77]
1.27.3 Cold Compression vs. Nothing	2	114	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.71, 0.19]
1.27.4 Cold Compression vs. Compression	3	200	Std. Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.77, 0.15]
1.27.5 Cold and Continuous Passive Motion vs. Continuous Passive Motion	1	30	Std. Mean Difference (IV, Random, 95% CI)	‐0.54 [‐1.27, 0.19]
1.28 Change in swelling at mid‐patella in mm ‐ post‐operative days 2 to 6 Show forest plot	7	403	Mean Difference (IV, Random, 95% CI)	‐7.32 [‐11.79, ‐2.84]

1.28.1 Cold versus compression	2	100	Mean Difference (IV, Random, 95% CI)	‐5.36 [‐18.02, 7.31]
1.28.2 Cold compression versus nothing	2	137	Mean Difference (IV, Random, 95% CI)	‐4.76 [‐5.84, ‐3.69]
1.28.3 Cold compression versus compression	3	166	Mean Difference (IV, Random, 95% CI)	‐10.83 [‐21.53, ‐0.12]
1.29 Change in swelling at mid‐patella in mm ‐ 6 weeks Show forest plot	5	283	Mean Difference (IV, Random, 95% CI)	‐1.89 [‐13.66, 9.88]

1.29.1 Cold versus compression	1	16	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐28.34, 24.34]
1.29.2 Cold compression versus nothing	2	131	Mean Difference (IV, Random, 95% CI)	1.32 [‐12.11, 14.75]
1.29.3 Cold compression versus compression	2	136	Mean Difference (IV, Random, 95% CI)	‐3.80 [‐26.68, 19.09]
1.30 Change in swelling at 12 weeks Show forest plot	2	98	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.63, 0.33]

1.30.1 Cold versus nothing	1	67	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.63, 0.33]
1.30.2 Cold compression versus nothing	1	31	Std. Mean Difference (IV, Random, 95% CI)	Not estimable
1.31 Length of hospital stay ‐ days Show forest plot	6	297	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐1.80, 0.72]

1.31.1 Cold versus nothing	1	24	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐3.65, 0.65]
1.31.2 Cold versus compression	2	100	Mean Difference (IV, Random, 95% CI)	‐1.16 [‐3.17, 0.84]
1.31.3 Cold compression versus nothing	1	83	Mean Difference (IV, Random, 95% CI)	‐1.40 [‐2.16, ‐0.64]
1.31.4 Cold compression versus compression	1	60	Mean Difference (IV, Random, 95% CI)	2.00 [0.93, 3.07]
1.31.5 Cold and continuous passive motion (CPM) versus CPM	1	30	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.72, 1.32]
1.32 Quality of life ‐ 3 months Show forest plot	2	127	Std. Mean Difference (IV, Random, 95% CI)	0.14 [‐0.21, 0.49]

1.32.1 Cold versus nothing	1	67	Std. Mean Difference (IV, Random, 95% CI)	0.02 [‐0.46, 0.50]
1.32.2 Cold compression versus compression	1	60	Std. Mean Difference (IV, Random, 95% CI)	0.28 [‐0.23, 0.79]
1.33 Activity level ‐ post‐operative days 1 to 7 Show forest plot	1	16	Mean Difference (IV, Random, 95% CI)	‐12.50 [‐53.39, 28.39]

1.33.1 Cold versus compression	1	16	Mean Difference (IV, Random, 95% CI)	‐12.50 [‐53.39, 28.39]
1.34 Activity level ‐ 6 weeks Show forest plot	2	116	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐16.00, 11.40]

1.34.1 Cold versus compression	1	16	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐16.00, 11.40]
1.34.2 Cold compression versus nothing	1	100	Mean Difference (IV, Random, 95% CI)	Not estimable

Comparison 1. Any cold therapy versus any control

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Comparison 2. Any cold therapy versus any control (Sensitivity analyses excluding studies with bilateral TKRs)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 COMBINED Blood loss Show forest plot	10	849	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.67, ‐0.03]

2.1.1 Cold versus compression	1	84	Std. Mean Difference (IV, Random, 95% CI)	0.17 [‐0.26, 0.60]
2.1.2 Cold compression versus nothing	2	181	Std. Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.70, 0.35]
2.1.3 Cold compression versus compression	6	554	Std. Mean Difference (IV, Random, 95% CI)	‐1.48 [‐2.72, ‐0.23]
2.1.4 Cold and continuous passive motion (CPM) versus CPM	1	30	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.88, 0.56]
2.2 Transfusion rate Show forest plot	1	60	Risk Ratio (IV, Random, 95% CI)	0.35 [0.16, 0.77]

2.2.1 Cold compression versus compression	1	60	Risk Ratio (IV, Random, 95% CI)	0.35 [0.16, 0.77]
2.3 Adverse events total Show forest plot	12	833	Risk Ratio (IV, Random, 95% CI)	1.13 [0.44, 2.89]

2.3.1 Cold versus nothing	2	112	Risk Ratio (IV, Random, 95% CI)	0.11 [0.01, 1.86]
2.3.2 Cold versus compression	1	84	Risk Ratio (IV, Random, 95% CI)	Not estimable
2.3.3 Cold compression versus nothing	3	283	Risk Ratio (IV, Random, 95% CI)	3.63 [0.77, 17.11]
2.3.4 Cold compression versus compression	5	324	Risk Ratio (IV, Random, 95% CI)	0.82 [0.26, 2.60]
2.3.5 Cold and continuous passive motion (CPM) versus CPM	1	30	Risk Ratio (IV, Random, 95% CI)	Not estimable

Comparison 2. Any cold therapy versus any control (Sensitivity analyses excluding studies with bilateral TKRs)

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