Surg Endosc (200l) 15:463--466 DOt: l 0.1007/s004640000348

Surg!cal End_oscopy Ultrasound and Interventional Techniques 9 Springer-Verlag New York lnc, 2001

Prospective evaluation of the systemic immune response following abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy E. Malik, ~ O. Buchweitz, t M. Miiller-Steinhardt, 2 P. Kressin, 1 A. Meyhrfer-Malik, ~ K. Diedrich 1

1Departmentof Obstetricsand Gynecology,Medical Universityof Luebeck,RatzeburgerAllee 160, D-23538 Ltibeck,Germany 2 Departmentof Immunology,Medical Universityof Luebeck,RatzeburgerAltee 160. D-23538 Ltibeek,Germany Received: 10 March 2000/Acceptedin final form: 9 August 2000/Online publication: 13 March 2001

Abstract

Background: Alterations in serum levels ot cytokine interleukin-6 (IL-6) and acute-phase protein C-reactive protein (CRP) correlate directly with extent of tissue damage and inflammatory reaction. We therefore prospectively compared the postoperative levels of IL-6 and CRP following abdominal (AH), vaginal (VH), and laparoscopically assisted vaginal hysterectomy (LAVH). Methods: A total of 29 patients were included in the study (10 VH, 10 LAVH, 9 AH). Nine blood samples were taken from each patient at various time points before, during, and after surgery. CRP and IL-6 were measured under standardized conditions using ELISA and turbidometry. Results: Preoperative levels of IL-6 and CRP were low in all three patient groups. There was a significant increase in the IL-6 level in patients undergoing AH at the time of peritoneal closure that reached a maximum 2 h postoperatively and remained significantly elevated for 12 h postoperatively when compared to the IL-6 levels of patients undergoing VH or LAVH (p < 0.05). The levels of the IL-6 time courses differed significantly among the three operative procedures (p = 0.013). In contrast, the levels of the CRP time courses did not differ significantly (p = 0.066); however, CRP expression was elevated 36 h postoperatively in patients undergoing AH, as compared with those undergoing VH. Conclusion: Elevated IL-6 levels subsequent to AH may reflect significantly greater tissue damage in these patients than in patients who undergo VH or LAVH. LAVH should therefore be considered in cases that cannot be managed by the vaginal route alone. Key words: Laparoscopically assisted vaginal hysterectomy - - Hysterectomy - - Surgical stress - - Cytokine - IL-6

Operative procedures cause metabolic and inflammatory changes that correlate with the extent of tissue damage [2, 3]. Their subjective impact on the human organism can be judged by assessing the intensity and duration of postoperative pain and time taken until activity returns to normal. One objective method of judging the extent of the trauma is the measurement of markers of the acute-phase reaction [20]. IL-6, IL-1, and tumour necrosis factor a are the major mediators of the acute-phase reaction. IL-6 primarily regulates the hepatic component of the acute-phase response and produces acute-phase proteins such as CRP, fibrinogen, o~-lantitrypsin, and haptoglobin [2, 5]. IL-6 is a 20-30 KD protein comprising 212 amino acids [5]. IL-6 is secreted by monocytes, T and B lymphocytes, keratinocytes, endothelial cells, and fibroblasts. It interacts with different growth factors and precursor ceils of hematopoesis [20]. The expression of IL-6 is a sensitive and early marker of tissue damage and correlates with the extent of surgical trauma [2, 15, 20]. Numerous trials have demonstrated the impact of minimally invasive surger3, vs traditional open surgery on the acute-phase reaction. Laparoscopic cholecystectomy, for example, leads to a significantly lower IL-6 expression than an open procedure [i, 12, 18, 20]. A linear correlation between IL-6 and CRP levels has been demonstrated [12]. Hysterectomy is one of the most common procedures worldwide. In the United States alone, -600,000 hysterectomies are performed annually [4]. Since the first documented procedure in 1989, laparoscopicalty assisted vaginal hysterectomy (LAVH) [16] has become a popular alternative to abdominal hysterectomy (AH) (in cases apparently difficult to manage via the vaginal route alone). This study was initiated to compare AH, vaginal hysterectomy (VH), and LAVH in terms of their impact on the acute-phase reaction. Mean outcome variztbles were serum levels of IL-6 and CRP. Patients and methods

Correspondence m: E. Malik

Between 1998 and 1999, 29 patients were included in the study (9 AH, 10 VH, 10 LAVH). All patients signed a written informedconsent form. The study was approved by the locat ethics committee,

464 Table 1. Patient characteristics

Treatment

n

Age (yr)

VH LAVH AH

10 10 9

50• 50• 56-+t3

Height (cm)

Weight (kg)

Uterus size (cm)

Operating time (min)

Hb difference (mg/dl)

166• 165-+6 169•

68-+10 75• 74-10

11 xT.Sxr.2 12.5 x 8.5 x 5.1 12xl0x6

86-+37 109• lll•

1.3• 1.7_+1 1.9•

VH, vaginal hysterectomy; LAVH, laparoscopically assisted vaginal hysterectomy; AH, abdominal hysterectomy All data given as mean • SD Uterine size according to the pathologist's report (length x width • depth in cm) Mean blood loss given as drop in hemoglobin level measured preoperatively and on the I st postoperative day

Blood samples of 8 ml were taken from each patient. The first sample was taken on the day of admission, the second during initiation of anesthesia, the third after opening the peritoneum or placement of the trocar, the fourth 30 rain afterward. Blood samples five through nine were taken on peritoneal closure and 2, 12, 24, and 36 h postoperatively. Twenty-five women presented with uterine fibroids, while four had relapsing bleeding anomalies. Treatment was determined by the performing consultant. At our hospital, the vaginal approach is most favored for simple hysterectomies. LAVH is favored for nulliparous patients, immobile uterus, previous pelvic surgery, or suspected adhesions. The abdominal route was chosen on the insistence of the patient or according to the preference of the performing surgeon. Patiem selection therefore followed subjective criteria. LAVH was performed according to the LAVH ~ previously described by Reich et al. [16]. AH and VH proceeded in the standard fashion described by Hirsch et al. [6]. A standardized anesthesia protocol was followed throughout all procedures, including a 0. t-4).2 mg ",dfentanilebolus, 0.07 mg/kg vecuronium bromide, and 2 mg/kg propofol for anesthesia, and 0.6-1.0 vol% isoflurane to maintain anesthesia. Postoperative pain management was based exclusively on intramuscular injections of piritramide and documented on a time scale. 1L-6 was measured in the university's Institute of Immunology using an ELISA ,assay (Bender MedSystems, Boehringer, Ingelheim, Germany). The assay detects IL-6 concentrations as low as 1.4 pg/ml and has an intraassay and interassay variation coefficient of 3.4% and 5.2%, respectively. CRP levels were measured by means of turbidometry (Boehringer). Measurements were blinded without the investigator knowing the surgical procedure. Postoperative pain duration and need for analgesics (in c~g piritramide) were documented on a standardized chart. Additional outcome variables were operative time and estimated blood loss as determined by preoperative and postoperative hemoglobin concentration. Statistical analysis was performed using an analysis of variance (ANOVA) with repeated measurements. Extreme outliers were identified by a Q-Q plot and excluded from the analysis. Post-hoc tests were done with a t-test (Bonferroni correction). Results were considered significant with p < 0.05. In order to indicate the effect of variables such as operating time, an analysis of variance with repeated measurements and one covariable was performed.

Results The patient's m e a n age, height, weight, and postoperative size of the uterus (length x width x depth in cm) according to the pathology report are given in Table 1. The patient ~ o u p undergoing V H had the shortest m e a n operating time (86 rain), followed by L A V H (109 min) and finally A H (111 rain). Due to these differences, we investigated the operative time as a possible covariable of the IL-6 and C R P expression. W e d e m o n s t r a t e d that these differences in operative times are not significant and do not interfere with the time courses. T h e fall in the h e m o g l o b i n concentration did not differ significantly a m o n g the three groups.

Figure 1 shows the IL-6 concentrations at the different time points in the three patient groups. The A N O V A testing of within-subjects effects s h o w e d significant differences in the expression o f II-6 with respect to the time course and the parallelism within each group. Testing of between-subjects effects s h o w e d significant differences in the height of the expression of I1-6 between the three groups (p < 0.013). The preoperative levels of IL-6 were comparably l o w There was a significant increase in the IL-6 level in patients undergoing A H at the time of peritoneal closure. In all three groups, this increase reached a m a x i m u m 2 h postoperatively. In the group undergoing AH, it was significantly higher than the IL-6 levels of patients undergoing V H or L A V H (113.4 pg/ml vs 42.4 pg/ml and 46.5 pg/ml). The IL-6 level in the A H group r e m a i n e d significantly elevated for 12 h postoperatively. The concentration then fell and was c o m p a r a b l e in all three groups 24 h after surgery. The post-hoc tests yielded significant differences at the time of opening of the peritoneum and 2 and 12 h after surgery a m o n g the patient groups. Figure 2 shows the C R P concentrations at the various time points in the three patient groups. Preoperative and intmoperative levels of C R P were comparably low. At 12 h after surger?', there was a linear rise of the CRP concentration that reached a peak after 36 hs. The post-hoc tests yielded significant differences between A H and V H 36 hs after surgery. However, the levels of the time courses did not differ significantly (p = 0.06). Pain duration after A H was 0.8 to 1.5 days longer than that following V H and L A V H (Fig. 3). Analgesic requirem e n t s were higher in the A H group (Fig. 3). However, these differences were not statistically significant.

Discussion There are three different routes for hysterectomy: AH, VH, and L A V H . N u m e r o u s studies have c o m p a r e d the subjective parameters of surgical trauma, such as pain duration a n d intensity, postoperative" analgesic requirements, and time token to return to normal activity [10, 11, 14, 17]. According to these subjective criteria, the surgical trauma provoked by A H is significantly greater than that experie n c e d with V H or L A V H . This is the first prospective study to c o m p a r e the surgical trauma of the three different techniques in terms of an

465

150150-

9 VH 9 LAVH .... AH

.

100-

-, ~ 100

VH t.AVH AH

i.,,

rl n,,, ~c

50-

50-

0

o 2

1

3

4

5

6

7

8

9

1'0

Measurement point

6-

2

"

i

;

i

i

i

i

4

s

6

7

;

;

;0

Measurement point

~VH

5-

[--q LAVH ~1

ODuration of pain in days

2

2

AH

Piritramide in dg

3 Fig. 1. Pre-, intra-, and postoperative 1L-6 concentrations in I0 cases of vaginal hysterectomy (VH. n = 10), laparoscopieally assisted vaginal hysterectomy (LAVH, n = 10), and abdominal hysterectomy (AII, n = 9). Measurement points: 1 = admission, 2 = during anesthesia, 3 = opening of the peritoneum, 4 = 30 rain after opening of the peritoneum, 5 = closure of the peritoneum, 6 = 2 h after surgery, 7 = 12 h after surgery, 8 = 24 h after surgery', 9 = 36 h after surgery. All data are given as mean + SEM. Levels of the time courses between the patient groups are different (p = 0.0t3). *AH vs VII and LAVH p < 0.05.

of the peritoneum, 4 = 30 min after opening of the peritoneum, 5 = closure of the peritoneum, 6 = 2 h alter surgery, 7 = 12 h after surgery, 8 = 24 h after surgery, 9 = 36 h after surgery. All data are given as mean _+SEM. Levels of the time courses between the patient groups are different (p = 0.013). ~AH vs VII and LAVH p < 0.05.

Fig. 2. Pre-, intra-, and postoperative CRP concentrations in l0 cases of vaginal hysterectomy (VH, n = 10), laparoscopicalty assisted vaginal hysterectomy (LAVH, n = 10), and abdominal hysterectomy (AH, n = 9). Measurement points: t = admission, 2 = daring anesthesia, 3 = opening

Fig. 3. Duration of pain (in days) and need for analgesics (in dg piritramide) after vaginal hysterectomy (VH, n = 10), laparoscopically assisted vaginal hysterectomy (LAVH. n = 10), and abdominal hysterectomy (AH, n = 9). Measurement points: 1 = admission, 2 = during anesthesia, 3 = opening of the peritoneum. 4 = 30 rain after opening of the peritoneum, 5 = closure of the peritoneum. 6 = 2 h after surgery, 7 = 12 h after surgery, 8 = 24 h after surgery, 9 = 36 h after surgery. All data are given as mean • SEM. *AH vs VH p < 0.05.

o b j e c t i v e p a r a m e t e r s u c h as the a c u t e - p h a s e reaction. L a b i b et al. [8] have c o m p a r e d A H to L A V H , d e m o n s t r a t i n g that 24 a n d 36 hs after A H the IL-6 c o n c e n t r a t i o n was signific a n t l y h i g h e r than it w a s after L A V H . T h e r e w a s a linear c o r r e l a t i o n b e t w e e n IL-6 and C R P levels. In our study, levels o f IL-6 and C R P were significantly h i g h e r f o l l o w i n g A H than after V H and L A V H . T h e r e was no d i f f e r e n c e in the a c u t e - p h a s e reaction p r o v o k e d b y V H or L A V H . IL-6 rose 12 h prior to the increase in C R P . T h e levels o f the C R P time c o u r s e s d i d not differ significantly a m o n g the patient g r o u p s ; h o w e v e r , a pair-wise c o m p a r i s o n s h o w e d an e l e v a t e d C R P e x p r e s s i o n 36 h p o s t o p e r a t i v e l y in patients u n d e r g o i n g A H , as c o m p a r e d with VH. M i n i m i z a t i o n o f a p o s s i b l e s e l e c t i o n bias is an i m p o r t a n t issue in o b s e r v e r studies. Table 1 s h o w s that there were no s i g n i f i c a n t d i f f e r e n c e s a m o n g the three patient g r o u p s . E v e n the o p e r a t i o n time h a d n o i m p a c t on IL-6 and C R P e x p r e s sion. H o w e v e r , o p e r a t i o n time, s u r g e o n , indication, a n d c h o i c e o f o p e r a t i v e p r o c e d u r e can be i m p o r t a n t c o v a r i a b l e s . T h e last three factors c a n n o t be e l i m i n a t e d c o m p l e t e l y . This a s p e c t is r e f l e c t e d in the d i f f e r i n g rates o f vaginal app r o a c h e s r e p o r t e d in p u b l i c a t i o n s c o n c e r n i n g h y s t e r e c t o -

m i e s , w h i c h range f r o m 81% [7] to 12% [19]. E x p e r t s in the vaginal a p p r o a c h argue that it is not n e c e s s a r y to a p p l y additional l a p a r o s c o p i c t e c h n i q u e s in this setting. T h e r e f o r e , the indications for t a p a r o s c o p i c a l l y assisted vaginal h y s t e r e c t o m i e s vary significantly in the literature [9, 10, 13]. E v e n if o b j e c t i v e criteria lbr the c h o i c e o f the o p e r a t i v e p r o c e d u r e existed, a certain selection bias could not be e x c l u d e d c o m p l e t e l y . A single s u r g e o n w o u l d have to p e r f o r m all o f the operations, a n d e v e n then the s u r g e o n ' s e x p e r i e n c e with the various o p e r a t i v e a p p r o a c h e s m i g h t differ. L a b i b et al. [8] m e a s u r e d IL-6 a n d C R P levels o n l y twice, at 24 and 36 hs after surgery. C l o s e r m o n i t o r i n g o f the s e r u m p a r a m e t e r s a l l o w e d us to d o c u m e n t the p r o g r e s s o f the a c u t e - p h a s e reaction. In c o n t r a s t to our findings, L a bib et at. [8] did not find any elevation in the IL-6 level after L A V H . H o w e v e r , our results correlate with the f i n d i n g s in n u m e r o u s trials o f l a p a r o s c o p i c vs o p e n c h o l e c y s t e c t o m y s h o w i n g a significantly greater increase o f the IL-6 and C R P levels w h e n o p e n surgery was p e r f o r m e d - - a f i n d i n g that is c o n s i s t e n t with the greater tissue trauma f o l l o w i n g t a p a r o t o m y [1, 12, 15, 20]. O u r results regarding p o s t o p e r a tive pain and a n a l g e s i c r e q u i r e m e n t s f o l l o w i n g the t h r e e

466 d i f f e r e n t surgical p r o c e d u r e s are c o m p a r a b l e to p r e v i o u s l y p u b l i s h e d data [6, 10, 11, 14, 17]; h o w e v e r , the n u m b e r o f patients in our series is too smaJl to a c h i e v e significant results. O u r s t u d y s h o w s that V H s h o u l d b e the first c h o i c e w h e n s t a n d a r d h y s t e r e c t o m y is p e r f o r m e d . In b e n i g n dise a s e s o f the uterus that are a p p a r e n t l y difficult to m a n a g e via the vaginal route alone, L A V H should replace traditional o p e n h y s t e r e c t o m y .

References 1. Cho JM, LaPorta AJ, Clark JR, Schofield MJ, Hammond SL, Mallory PL (1994) Response of serum cytokines in patients undergoing taparoscopic cholecystectomy Surg Endosc 8:1380--1384 2. Cmickshank AIr1, Fraser WD, Burns HJG, Shenkin A (1990) Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 79:16t-t65 3. Dominioni L, Diogni R, Cividini F (i980) Determination of C-reactive protein: an alpha-l-antitrypsin for quantitative assessment of surgical trauma. Eur Surg Res 12 (Suppl): 133 4. Graves EJ, Kozak LJ (1992) National hospital discharge survey: annual summary, 1990. Vital Health Star 13:1-51 5 Hirano T (1998) Interleukin-6. In: Thomson A (editor) The cytokine handbook, 3rd ed. Academic Press, New York, pp 145-156 6. Hirsch HA, Kaeser O, Ikle FA (!.995) Atlas der gyn~ikologischen Operation. 5th ed. Georg Thietue Verlag, Stuttgart-New York, pp 240-261 7. Kovac SR (1986) ]ntra,nyometrial coring as an adjunct to vaginal hysterectomy. Obstet Gynecol 67:131-136 8. Labib M, Palfrey S, Paniagua E, Callender R (1.997) The postoperative inflammatory response to injury following laparoseopic assisted vaginal hysterectomy versus abdominal hysterectomy. Ann Clin Biochem 34 (Pt 5): 543-545

9. Liu CY (1992) Laparoseopic hysterectomy: report of 215 cases. Gyneco! Endosc 2:73-77 10. Malik E, Schmidt M, Scheidel P (1997) Complications after 106 laparoscopic hysterectomies. Zentralbl Gynakol 119:61 l--615 11. Marana R, Busacea M, Zupi E, Gareea N, Paparella P, Catalano GF (1999) Laparoscopically assismd vaginal hysterectomy versus total abdomincd hysterectomy: a prospective, randomized, multicenter study. Am J Obstet Gynecol 180:270-275 12. Maruszynski M, Pojda Z (1994) Interleukin-6 (It-6) levels in the monitoring of surgical trauma. Surg Endosc 8:1216-1220 13. Nezhat F, Nezhat CH, Admon D, Gordon S, Nezhat C (1995) Complications and results of 361 hysterectomies performed at laparoscopy. J Am Coil Surg 180:307-316 14. Nwosu CR, Gupta JK (1999) Abdominal, laparoscopic, and vaginal hysterectomy with bilateral salpingo-oophorectomy: a feasibility study for further evaluation in randomized trials. Surg Endosc t3:148-150 15. Ohzato H, Yoshizaki K, Nishimoto N, Ogata A, Tagoh H, Monden M, Gotoh M, Kishimoto T, Moil T (1992) interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery t I 1:201-209 16. Reich H, DeCaprio J, McGlynn F (1989) Laparoscopic hysterectomy. J Gynecol Surg 5:213-216 17, Spellacy WN (1999) A muhicenter randomized comparison of laparoscopically assisted vaginal hysterectomy and abdominal hysterectomy in abdominal hysterectomy candidates. Obstet Gynecot 93: 16016l 18. Suzuki M, Oka M, Tangoku A (1994) Interleukin-6 and granulocytic elastase leveIs following taparoscopic chotecystectomy. Surg Endosc 8:447 (Abstract) 19. Vessey MP, Villard-Mackintosh L, McPherson K, Coulter A, Yeates D (1992) The epidemiology of hysterectomy findings in a large cohort study. Br J Obstet Gynecol 99:402-407 20. Vittimberga FJ, Foley DP, Meyers WC, Callery MP (1998) Laparoseopic surgery and the systemic immune response. Ann Surg 227: 326-334