Acute Cytokine Response During Breast Cancer Surgery: Potential Role of Dexamethasone and Lidocaine and Relationship with Postoperative Pain and Complications – Analysis of Three Pooled Pilot Randomized Controlled Trials

Figures & data

Figure 1 Consolidated Standards of Reporting Trials (CONSORT) flow chart of the three consecutive randomized controlled trials.

Table 1 Patients’ Perioperative Characteristics in the Three Consecutive Randomized Controlled Trials

	RCT 1: No Dexamethasone		RCT 2: Dexamethasone 4 mg		RCT 3: Dexamethasone 8 mg
	Placebo, n=8	Lidocaine, n=8	Placebo, n=8	Lidocaine, n=8	Placebo, n=8	Lidocaine, n=8
Age (yr)	55 (13) [34–73]	59 (11) [42–75]	61 (12) [43–75]	55 (8) [43–68]	55 (8) [47–67]	61 (11) [47–80]
BMI (kg m^−2)	26 (5) [20–34]	28 (6) [20–36]	25 (5) [20–33]	23 (4) [19–31]	25 (4) [21–35]	24 (4) [20–32]
ASA physical status (n)
1	2	4	3	6	5	5
2	6	4	5	2	3	3
Tumour classification (n)
Carcinoma in situ	2	2	2	1	1	1
T1	4	5	5	4	6	5
T2	2	1	1	3	1	2
Node classification (n)
N0	7	8	7	6	5	7
N1	1	0	1	2	3	1
Surgery duration (min)	109 (42) [39–152]	87 (35) [35–156]	76 (18) [58–110]	92 (36) [24–133]	65 (19) [39–92]	68 (24) [36–109]
Sufentanil (μg kg^−1 hr^−1)	0.32 (0.09) [0.20–0.45]	0.25 (0.13) [0.13–0.54]	0.29 (0.09) [0.17–0.43]	0.26 (0.15) [0.12–0.60]	0.31 (0.09) [0.17–0.44]	0.29 (0.16) [0.11–0.52]
NRS
At t0	0.9 (1.1) [0–3]	0.1 (0.4) [0–1]	0.3 (0.5) [0–1]	0.8 (1.4) [0–4]	0 (0) [0–0]	0.4 (1.1) [0–3]
At t1	1.6 (2.1) [0–5]	1.5 (1.5) [0–4]	1.3 (1.8) [0–5]	1.4 (1.5) [0–4]	1.5 (2.1) [0–6]	0.3 (0.7) [0–2]
At t2	2.4 (1.2) [0–7]	1.8 (1.5) [0–4]	1.9 (1.1) [0–4]	2.1 (1.7) [0–4]	2.6 (0.9) [2–4]	2.4 (1.2) [0–4]
Diclofenac (n)
0 mg	1	0	1	0	0	1
75 mg	6	6	7	7	8	7
125 mg	1	2	0	1	0	0
Piritramide (mg)	9.7 (6.0) [0–20]	8.1 (5.8) [0–20]	8.8 (4.8) [5–20]	8.4 (6.3) [0–20]	9.4 (3.7) [5–17.5]	10.0 (4.4) [5–20]
Clonidine (n)
0 μg	6	5	7	7	8	8
75 μg	1	2	1	1	0	0
150 μg	1	1	0	0	0	0
30-Day complications (N)
CDC I	2	2	5	4	3	0
CDC II	0	1	0	1	0	2
CDC IIIb	1	0	0	0	0	1

Notes: Data are mean (SD) [minimum–maximum], number of patients (n) or number of complications (N). At t0 = baseline, t1 = direct postoperative, and t2 = 4 hours after surgery.

Abbreviations: RCT, randomized controlled trial; BMI, body mass index; ASA, American Society of Anesthesiologists; T, tumor staging; NRS, Numeric Rating Scale; CDC, Clavien Dindo Classification.

Figure 2 Difference (Δ) between interleukin (IL)-6, IL-10 plasma levels and ratio IL-6/IL-10 at baseline (t0) and those 4 hours after surgery (t2) in six groups (n=8 per group). Each symbol represents one patient. A symbol above or below the zero line represents an increase or decrease, respectively, from t0 to t2. Error bars are the 25th–75th percentiles around the medians. (A) Observations for ΔIL-6 and (B) for ΔIL-10 per group. (C) Observations for the ratio ΔIL-6/IL-10 per group and linear regression of the pooled observations on the duration of surgery. The full regression line is accompanied with dotted lines showing its 95% confidence limits. There is one missing value in the group dexamethasone 8 mg with placebo for ΔIL-10 and ΔIL-6/IL-10. Plac, placebo; Dexa, dexamethasone; Lido, lidocaine.

Figure 3 Difference (Δ) between interleukin (IL)-1β, IL-1Ra plasma levels and ratio IL-1β/IL-1Ra at baseline (t0) and those 4 hours after surgery (t2) in six groups (n=8 per group). Each symbol represents one patient. A symbol above or below the zero line represents an increase or decrease, respectively, from t0 to t2. Error bars are the 25th–75th percentiles around the medians. (A) Observations for ΔIL-1β and (B) for ΔIL-1Ra per group. (C) Observations for the ratio ΔIL-1β/IL-1Ra per group and linear regression of the pooled observations on the duration of surgery. The full regression line is accompanied with dotted lines showing its 95% confidence limits. Plac, placebo; Dexa, dexamethasone; Lido, lidocaine.

Table 2 The Effects (Column “b”) of Lidocaine, Dexamethasone 4 mg, Dexamethasone 8 mg and Surgery Duration on the Levels of Interleukins and Their Ratios After Surgery

	ΔIL-6			ΔIL-10			ΔIL-6/IL-10
	b	(95% CI)	P	b	(95% CI)	P	b	(95% CI)	P
Intercept	2.03	(−14.14–18.19)	0.802	− 4.74	(−11.41–1.94)	0.160	2.03	(−0.07–4.12)	0.057
Lidocaine	3.02	(−5.30–11.34)	0.468	2.61	(−0.86–6.08)	0.137	−0.12	(−1.21–0.97)	0.824
Dexamethasone 4 mg	−3.54	(−13.91–6.82)	0.494	4.37	(0.10–8.65)	0.045	−2.60	(−3.93–−1.26)	<0.001
Dexamethasone 8 mg	−8.04	(−19.15–3.07)	0.152	12.70	(8.06–17.34)	<0.001	−3.59	(−5.04–−2.13)	<0.001
Surgery time (min)	0.162	(0.020–0.303)	0.026	0.053	(−0.005–0.111)	0.074	0.019	(0.001–0.037)	0.040
		R^2 = 0.227			R^2 = 0.449			R^2 = 0.526
	ΔIL-1β			ΔIL-1Ra			ΔIL-1β/IL-1Ra
	b	(95% CI)	P	b	(95% CI)	P	b	(95% CI)*	P
Intercept	0.83	(0.03–1.64)	0.043	124	(−1210–1458)	0.852	0.88	(−0.20–1.97)	0.108
Lidocaine	−0.08	(−0.50–0.34)	0.699	367	(−319–1053)	0.287	−0.11	(−0.67–0.45)	0.701
Dexamethasone 4 mg	−0.49	(−1.01–0.03)	0.062	−338	(−1193–517)	0.430	−0.07	(−0.76–0.63)	0.843
Dexamethasone 8 mg	−0.39	(−0.94–0.17)	0.167	268	(−649–1184)	0.559	−0.21	(−0.96–0.53)	0.571
Surgery time (min)	−0.004	(−0.011–0.003)	0.229	0.420	(−11.23–12.07)	0.942	−0.012	(−0.021–−0.002)	0.016
		R^2 = 0.097			R^2 = 0.070			R^2 = 0.134

Notes: Results are intercept and partial regression coefficients (b) with their 95% CI obtained from multiple regression analysis. *Results for IL-1β/IL-1Ra are to be multiplied by 10⁻³. ∆, difference between the levels of IL and their ratios at baseline and those at 4 hours after surgery. R², coefficient of determination.

Abbreviations: IL, interleukin; CI, confidence interval.

Table 3 Relationships Between Cytokine Levels, Pain Scores and Postoperative Complications

		Odds Ratio (95% CI)	P
NRS	t2	1.464 (0.941–2.278)†	0.091
	t2	2.028 (1.134–3.628)‡	0.017
IL-6	t0	1.359 (0.918–2.010)	0.125
	t2	1.036 (0.992–1.082)	0.113
IL-10	t0	0.690 (0.207–2.301)	0.546
	t2	1.053 (0.963–1.151)	0.255
IL-6/IL-10	t0	2.918 (0.848–10.047)	0.089
	t2	1.196 (0.917–1.559)	0.186
IL-1β	t0	0.321 (0.007–14.874)	0.561
	t2	0.802 (0.228–2.822)	0.731
IL-1Ra	t0	1.003 (0.999–1.007)	0.136
	t2	1.000 (0.999–1.001)	0.940
IL-1β/IL-1Ra*	t0	0.521 (0.167–1.623)	0.261
	t2	1.251 (0.601–2.605)	0.549

Notes: Odds ratios with 95% confidence intervals (CI) obtained from univariate binary logistic regressions estimating the association between pain scores or cytokine levels on one hand and the occurrence of a 30-day complication on the other. For pain scores, which were obtained with Numeric Rating Scale (NRS) at 4 hours after operation (t2) the dependent variable was the occurrence of any complication according to the CDC^† or only a potentially immune-related complication^‡ (PIRC). For cytokine levels and two of their ratios at baseline (t0) and t2, the dependent variable was the occurrence of a PIRC. NRS was associated with PIRC in these univariate analyses. *Results for IL-1β/IL-1Ra are to be multiplied by 10⁻³.