Prediction and diagnosis of colorectal anastomotic leakage: A systematic review of literature

Table 1 Clinical methods

Author	Type ofstudy	Loe	n (CAL/non-CAL)	Colorectal/rectum	Stapled/handsewn anastomosis	Study subject/tool		Se	Sp	PPV	NPV	ROC	Main outcome
Dekker et al[22]	Pro	3b	10/121	Colorectal	?	Leakage score		-	-	-	-	0.95	OR = 1.74 for leakage score predictive of CAL
den Dulk et al[23]	Pro	2b	21/223	Colorectal	Both	Leakage score		-	-	-	-	-	Delay of treatment reduced from 4 d to 1.5 d
Sutton et al[18]	Pro	3b	22/398	Colorectal	?	Clinical symptoms		0.33	0.97	0.59	0.93		Over 40% of patients with cardiac event has CAL
Haase et al[19]	Pro	4	3/40	Colorectal	?	Clinical symptoms		-	-	-	-	-	No difference in heart rate variability between CAL and non-CAL
Ghariani et al[17]	Retro	3b	23/314	Colon	?	Clinical symptoms		-	-	-	-	-	Respiratory, neurological disorders and bloating precipitate CAL
Bellows et al[16]	Retro	3b	25/311	Colorectal	?	Clinical symptoms	Respiratory symptoms	0.52	0.84	0.22	0.95	-	Respiratory, neurological disorders and abdominal pain and distension precipitate CAL
							Neurology symptoms	0.24	0.97	0.4	0.94	-
							Abdominal pain and distension	0.52	0.83	0.21	0.95	-
Nesbakken et al[20]	Pro	3b	5/56	Rectum	?	Clinical symptoms	Daily assessment by surgeon	0.50	0.89	0.5	0.89	-	50% of CAL is silent
Tang et al[21]	Pro	3b	10/195	Rectum	Both	Digital rectal examination		0.98	-	-	-	-	As valuable as WSCE before stoma closure
Pettigrew et al[13]	Pro	3b	28/113	Colorectal and general	?	Risk prediction by surgeon		0.38	0.91	0.56	0.82		Highest predictive value for postop surg assessment
Makela et al[14]	Retro	3b	44/88	Rectum	Both	Risk prediction by surgeon		-	-	-	-	-	In 86% of pts with > 3 risk factors CAL occurs
Karliczek et al[15]	Pro	3b	26/191	Colorectal	?	Risk prediction by surgeon	High anastomosis	0.38	0.46	-	-	-	Low predictive value for prediction of CAL by surgeon
							Low anastomosis	0.62	0.52	-	-	-

Pro: Prospective; Retro: Retrospective; Loe: Level of evidence; CAL: Colorectal anastomotic leakage; Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; ROC: Receiver-operating characteristic curve; WSCE: Water soluble contrast enema.

Table 2 Laboratory tests

Author	Type of study	Loe	n (CAL/non-CAL)	Colorectal/rectum	Stapled/handsewn anastomosis	Study subject/tool	Cut-off value	Se	Sp	PPV	NPV	ROC	Main outcome	OnsetCAL(POD)
Slotwinksi et al[29]	Pro	3b	2/16	Colorectal	?	sTNF-R1, IL-1RA/-6/-8/-10, CRP	-	-	-	-	-	-	TNF higher at POD 1 in CAL	?
Iversen et al[30]	Pro	3b	17/341	Colorectal	Both	s-Fibrin, TAT-complex, PT-f1/-2	-	-	-	-	-	-	PT-f1/-2, TAT-complex, s-Fibrin higher at POD 1/2 in CAL	7
Woeste et al[25]	Retro	3b	26/342	Colorectal	Both	CRP	-	-	-	-	-	-	CRP higher from POD 3 to POD 7 in CAL	8,7
Warschkow et al[24]	Meta	3a	?/1832	Colorectal	Both	CRP	135 mg/L at POD 4	0.680	0.830	0.560	0.89	-	CRP < 135 mg/L at POD 4 discharge is safe	?
Kornerin et al[24]	Retro	3b3	18/231	Colorectal	Both	CRP	190 mg/L at POD 3	0.820	0.730	-	-	0.820	Persisting elevation of CRP is indicative for CAL	8
Mackayin et al[24]	Pro	3b3	5/160	Colorectal	?	CRP	145 mg/L at POD 4	0.850	0.860	0.610	0.96	-	CRP > 145 mg/L at POD 4 is highly predictive for CAL	?
Ortegain et al[24]	Pro	3b3	21/133	Colorectal	Both	CRP	125 mg/L at POD 4	0.820	0.960	-	-	-	CRP > 125 mg/L at POD 4 discharge is not safe	6
Welschin et al[24]	Pro	3b3	22/961	Rectum	Staples	CRP	140 mg/L at POD 3	0.802	0.812	0.862	-	-	Persisting elevation of CRP is indicative for CAL	8
Warschkowin et al[24]	Retro	3b3	89/1115	Colorectal	?	CRP	143 mg/L at POD 4	0.750	0.710	0.190	0.97	-	Use CRP as screening at POD 4	9
Platt et al[26]	Pro	3b	26/454	Colorectal	Both	CRP	190 mg/L at POD 3	0.772	0.802	-	-	0.892	CRP at POD 3 is useful for predicting CAL	6-8
Matthiessen et al[27]	Pro	3b	9/33	Rectum	?	CRP	-	-	-	-	-	-	CRP higher from POD 2 in CAL	8
Almeida et al[28]	Retro	3b	24/149	Colorectal	?	CRP	140 mg/L at POD 3	0.780	0.860	-	-	-	CRP sign higher from POD 2 in CAL	7

¹Selected groups;

²All complications;

³Included in meta-analysis. Pro: Prospective; Retro: Retrospective; Meta: Meta-analysis; Loe: Level of evidence; CAL: Colorectal anastomotic leakage; TNF: Tumour necrosis factor; IL: Interleukin; CRP: C-reactive protein; TAT: Thrombin-antithrombin complexes; PT: Prothrombin; POD: Postoperative day; Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; ROC: Receiver-operating characteristic curve.

Table 3 Drain fluid analysis

Aauthor	Type ofstudy	Loe	n (CAL /non-CAL)	Colorectal/rectum	Stapled/handsewn anastomosis	Study subject/tool	Main outcome	Onset CAL (POD)
Bertram et al[36]	Pro	4	3/28	Colorectal	?	Cytokines	No correlation between IL-6, TNF-alpha and CAL	5.3
Herwig et al[34]	Pro	3b	12/24	Colorectal	?	Cytokines	IL-6 and TNF-alpha elevated from POD 1 in CAL	5.8
Yamamoto et al[35]	Pro	3b	7/90	Colorectal	Stapled	Cytokines	IL-1beta, IL-6, TNF-alpha elevated from POD 3 in CAL	5-8
Ugras et al[32]	Pro	3b	4/34	Colorectal	Both	Cytokines	IL-6, IL-10, TNF-alpha elevated from POD 1 in CAL	6
Fouda et al[31]	Pro	3b	8/56	Rectum	Both	Cytokines	IL-6, IL-10 elevated from POD 1 in CAL, TNF-alpha elevated from POD 2 in CAL	6
Mattiessen et al[33]	Pro	3b	7/23	Rectum	?	Microdialysis, cytokines	L/P-ratio elevated at POD 5/6 in CAL; IL-6, IL-10, TNF-alpha elevated from POD 1 in CAL	Early CAL: 6 Late CAL: 20
Ellebaek et al[37]	Pro	3b	4/50	Colorectal	?	Microdialysis	Mean L/P-ratio higher in CAL,	Early CAL: 5-10 Late CAL: 20
Tsujinaka et al[38]	Pro	3b	21/196	Rectum	Both	Drainproduction	15/21 Patients with CAL had changes in drain content	7
Eckmann et al[39]	Retro	3b	30/306	Rectum	Stapled	Drainproduction	80% of leakages were indicated by drain, 40% of which prior to clinical symptoms	?
Millan et al[40]	Pro	3b	6/90	Colorectal	Stapled	Intramucosal pH	Intramucosal pH < 7.28 on POD1 increases risk of CAL 22 fold	?
Junger et al[41]	Pro	3b	3/22	Colorectal	Both, biodegradable ring	LPS	Excretion of LPS and LPS concentration is higher at POD 3 in CAL	6,7
Miller et al[42]	Pro	2b	2/42	Rectum	Stapled	Lysozym activity	No correlation between lysozyme activity and CAL	?

Pro: Prospective; Retro: Retrospective; Loe: Level of evidence; CAL: Colorectal anastomotic leakage; LPS: Lipopolysaccharides; IL: Interleukin; TNF: Tumour necrosis factor; POD: Postoperative day.

Table 4 Intra-operative techniques

Author	Type of study	Loe	n (CAL/non-CAL	Colorectal/rectum	Stapled/handsewn anastomosis	Test	Testper-formed	Test +	Intra-operative correction	CAL test+	Test -	CAL test-	Test not per-formed	CALtest not per-formed	Mainoutcome
Beard et al[43]	Pro	1b	13/145	Colorectal	Both	ALT	73	18	18	3	55	0	70	10	ALT and preoperative repair reduce risk of AL
Davies et al[44]	Pro	3b	4/33	Rectum	?	ALT	33	6	6	1	27	3	-	-	LT helpful to reduce leakage rate
Dixon et al[45]	Retro	3b	2/202	Rectum	Both	ALT	119	5	5	0	114	0	-	-	Leaks were avoided
Gilbert et al[46]	Retro	3b	1/21	Colorectal	Handsewn	ALT	21	5	5	1	16	0	-	-	ALT facilitates IOR
Lazorthes et al[47]	Pro	3b	3/82	Colorectal	Stapled, doughnut complete 68	ALT	68	0	0	0	68	3	-	-	High NPV for ALT
					Stapled, doughnut incomplete 14		14	4	4	0	10	0	-	-
Ricciardi et al[48]	Retro	3b	48/998	Colorectal	Both	ALT	825	65	65	5	760	29	173	14	ALT for leftsided anastomosis
Schmidt et al[49]	Pro	3b	68/933	Rectum	Both	ALT	260	47	42	5	213	22	36	4	Risk of AL is unrelated to ALT
Wheeler et al[50]	Pro	4	7/102	Colorectal	?	ALT	99	21	21	2	85	2	-	-	LT facilitates IOR
Yalin et al[51]	Po	3b	1/23	Colo-rectal	Stapled	ALT	21	5	5	1	16	0	-	-	LT facilitates IOR
Griffith et al[54]	Pro	4	2/60	Colorectal	Stapled	ALT	60	11	11	0	49	2	-	-	ALT facilitates IOR
Sakanoue et al[55]	Pro	3b	4/70	Rectum	?	ALT	35	2	2	0	33	0	35	4	Useful for intraoperative decision making
Smith et al[53]	Pro	4	7/229	Colon	Both	ALT	229	16	16	0	213	7	-	-	After IOR no CAL occurred
Lanthaler et al[56]	Pro	3b	6/122	Colorectal	Stapled	IOE	73	5	5	0	68	4	49	2	ALT prevents early leak
Li et al[57]	Pro	3b	2/244	Rectum	Stapled	IOE	107	11	11	0	96	0	137, 30 IOC1	2/137, 1/30	Routine IOE and selective IOE equal results
Shamiyeh et al[58]	Pro	3b	7/253	Rectum	Stapled	IOE	85	2	2	0	83	1	253	4	Routine IOE does not reduce CAL
Ishihara et al[52]	Pro	4	1/73	Rectum	Stapled	IOE and ALT	73	4	4	0	69	1	-	-	ALT recommended
Ambrosetti et al[59]	Pro	4	2/200	Colorectal	Both	Doppler ultra-sound									Doppler facilitates IOR
Vignali et al[60]	Pro	3b	8/55	Colorectal	Stapled	Laser doppler	-	-	-	-	-	-	-	-	Reduction in microperfusion increases risk of CAL
Kudszus et al[61]	Retro	3b	22/402	Colorectal	Both	LFA	201	28	28	8	-	-	201	15	LFA reduces reoperation rate for AL, most prominent in handsewn
Hirano et al[62]	Pro	4	1/20	Colorectal	?	Near infrared spectro-scopy									StO2 < 60% in CAL
Novell et al[64]	Pro	3b	275	Colorectal	Both	Obser-vation of marginal artery bleeding									Pulsatile flow: lower incidence CAL
Sheridan et al[65]	Pro	3b	5/50	Colon	?	Tissue pO2 measurement									Reduced anastomotic pO2 predictive CAL
Karliczek et al[63]	Pro	3b	14/77	Colorectal	?	Visible light spectro-scopy									pO2 could predict CAL

¹Indicated by the surgeon. Pro: Prospective; Retro: Retrospective; Exp: Experimental (model); Loe: Level of evidence; CAL: Colorectal anastomotic leakage; ALT: Air or methylene blue leak test; IOC: Intra-operative endoscopy; LFA: Laser fluorescence angiography; IOR: Intra-operative repair; NPV: Negative predictive value.

Table 5 Radiology

Author	Type of study	Loe	n (CAL/non-CAL)	Colorectal/rectum	Stapled/handsewn anastomosis	Study tool	Se	Sp	PPV	NPV	Main outcome
Eckmann et al[77]	Retro	3b	30/306	Rectum	Stapled	CT	-	-	-	-	29 of 30 CAL detected by CT
Power et al[78]	Retro	3b	17/50	Colorectal	?	CT	0.30	0.90	0.58	0.74	Peri-anastomotic located fluid containing air found in CAL
Gouya et al[75]	Retro	3b	10/195	Rectum	?	CT	-	-	1.00	1.00	CT has role in predicting CAL
DuBrow et al[68]	Retro	3b	35/75	Rectum	?	CT	-	-	-	-	30% of pts with CAL have presacral abnormalities
Nicksa et al[73]	Retro	4	36 CAL	Rectum	?	CT	0.12	-	-	-	Low percentage true positives
Doeksen et al[67]	Retro	3b	68/429	Colorectal	?	CT	0.54	0.78	0.68	0.66	Interobserver variability 10%
Nesbakken et al[20]	Pro	3b	5/56	Rectum	?	CT	0.57	1.00	-	-	94% accuracy of CT for detection of CAL
Severini et al[74]	Retro	3b	12/175	Rectum	?	WSCE	-	-	-	-	2 CAL out of 78 positive WSCE, low predictive value
Hoffmann et al[70]	Retro	3b	5/51	Colorectal	Both	WSCE	0.20	0.85	0.13	0.91	WSCE not recommended for routine use
Markham et al[72]	Retro	3b	1/136	Rectum	Handsewn	WSCE	1.00	0.57	0.02	1.00	WSCE no contribution to surgical management
Kalady et al[71]	Retro	3b	8/211	Rectum	?	WSCE	0.88	1.00	1.00	0.99	WSCE does not provide additional information
Akyol et al[66]	Pro	3b	12/233	Colorectal	Both	WSCE	0.52	0.87	0.30	0.94	WSCE provides little useful clinical information
Haynes et al[69]	Retro	3b	14/117	Colorectal	Both	WSCE	0.71	0.86	0.42	0.96	WSCE not recommended for routine use
Gouya et al[75]	Retro	3b	10/195	Rectum	?	WSCE	-	-	1.00	0,98	WSCE is recommended for routine use
Nicksa et al[73]	Retro	4	36 CAL	Rectum	?	WSCE	0.88	-	-	-	WSCE superior to CT
Doeksen et al[67]	Retro	3b	68/429	Colorectal	?	WSCE	0.68	0.94	0.91	0.76	Interobserver variability 13%
Nesbakken et al[20]	Pro	3b	5/56	Rectum	?	WSCE	0.60	1.00	-	-	93% accuracy of WSCE for detection of CAL
Williams et al[76]	Retro	4	10/31	Rectum	Stapled	X-ray	0.90	1.00	1.00	0.95	Staple line dehiscence in 9/10 patients with CAL
Tang et al[79]	Pro	4	2/64	Colorectal	?	X-ray	-	-	-	-	Increase free air after POD 5 higher chance CAL

Pro: Prospective; Retro: Retrospective; Meta: Meta-analysis; Leo: Level of evidence; CAL: Colorectal anastomotic leakage; CT: Computer tomography; WSCE: Water-soluble contrast enema; Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; POD: Postoperative day.