Effect of Intra-Operative Hypothermia on Post-Operative Morbidity in Patients with Colorectal Cancer

Abstract

Background:

Current guidelines recommend maintaining intra-operative normothermia to avoid surgical site infections (SSI) after colorectal cancer surgery. The aim of this study was to assess whether compliance with normothermia as part of temperature management measures is an effective strategy to reduce post-operative SSI and complications.

Patients and Methods:

This was a cohort study of patients undergoing surgery for primary colorectal cancer in 2011–2017 in a large teaching hospital in which temperature management using the Bair Hugger™ system (3M™ Center, St. Paul, MN) was standard care. Data from the prospective Dutch Surgical Audit (DCRA) database were complemented by highly granular intra-operative central body temperature data. A multivariable logistic regression model was used.

Results:

A total of 1,015 patients undergoing surgery for primary colorectal cancer were included. Temperature outcomes for the entire study cohort were as follows: mean temperature was 36.3°C (standard deviation [SD] ±0.5°C), median temperature nadir was 35.8°C (interquartile range [IQR] 35.6°C–36.1°C), median percentage of time at nadir was 2.0% (IQR 0.8%–10.7%), and median percentage of time less than 36.0°C was 1.0% (IQR 0.0%–33.3%). Thirty-day SSI rate was 10% (n = 101). Logistic regression models adjusting for gender, diabetes mellitus, body mass index (BMI), rectal cancer, duration of surgery, open surgery, emergency surgery, and period of surgery showed no association between any of the four temperature outcomes and SSI. Multivariable analysis also failed to show an association between intra-operative hypothermia and 30-day complications, mortality, or re-admission.

Conclusions:

In a hospital in which temperature management is standard care, intra-operative hypothermia and SSI rates in patients undergoing colorectal cancer surgery were low. Compliance with normothermia appears to be an effective strategy to reduce SSI.

In 2009, the World Health Organization (WHO) published Guidelines for Safe Surgery: Safe Surgery Saves Lives [1]. One of several recommendations in these guidelines was the maintenance of normothermia during surgery aimed at reducing the incidence of post-operative surgical site infections (SSI). The WHO did not provide a clear definition of normothermia. The Agency for Healthcare Research and Quality (AHRQ) has a similar recommendation of maintaining intra-operative normothermia to prevent SSI [2]. The AHRQ defined normothermia as a temperature higher than 36°C, measured just before time of incision, before leaving the operating room, and upon arrival at the recovery unit. Three randomized controlled trials (RCTs) were at the basis of these recommendations and showed increased incidence of SSIs, mortality, and extended hospital stay after hypothermia [3 –5]. These RCTs were conducted in general and colorectal surgery populations.

Other studies have demonstrated that intra-operative hypothermia is associated with hypertension because of vasoconstriction [6], increased risk of blood transfusions [7,8], and longer duration of neuromuscular blockade resulting from medication [9]. Hypothermia also contributes to the experience of discomfort of the patient. For patients to return to post-operative normothermia, an increased metabolism is required with increased oxygen use. In addition, there is peri-operative risk of arrhythmias, acidosis, and coagulopathy [10]. This has led to a variety of methods to reduce hypothermia [11].

Many hospitals have implemented temperature management measures such as warmed intravenous fluids and forced-air warming devices. However, several studies conducted in hospitals that already have implemented temperature management measures have reported high rates of intra-operative hypothermia in orthopedic, gynecologic, and colorectal surgery [12 –15].

Core body temperature can vary greatly during the procedure and therefore it is important to measure this variable continuously. However, most of the previously mentioned studies have used nadir temperature, maximum temperature, temperature at the end of the procedure, or post-operative temperature [12 –14]. This approach does not encapsulate the true nature of the continuous physiologic core body temperature variable.

Post-operative complications are common in patients undergoing colorectal cancer (CRC) surgery [16]. Because resources are increasingly limited in healthcare, it is important to assess whether current temperature management measures are sufficient in preventing hypothermia and related adverse post-operative outcomes. The current study aimed to assess whether compliance with normothermia as part of temperature management measures is an effective strategy to reduce SSI.

Patients and Methods

Study design and data collection

This retrospective cohort study was conducted in a large teaching hospital in which temperature managament using the Bair Hugger™ system (3M™ Center, St. Paul, MN) was standard care. Intra-operative core body temperature data were obtained from an anesthesia information management system (AIMS) used during surgery and post-operative stay in the recovery unit. Intra-operative core body temperature was measured continuously using a nasal temperature probe located in the nasopharynx at one-minute intervals. A panel comprising a staff anesthesiologist and surgeon visually inspected all temperature graphs. Temperature values below 30°C, greater than 43°C, or sudden fluctuations in temperature that could not be attributed to natural physiology were considered registration errors (i.e., temporary dislocation of the nasal probe outside the nasal cavity) and were removed from the dataset. Cases with incomplete AIMS temperature data (<100 temperature measurements) were also excluded. These cases were considered missing completely at random and therefore could be excluded without affecting the results of this study. The missing completely at random assumption was based on the fact that it was standard procedure to measure the temperature of every patient and failure to do so was caused entirely by complete or partial dislocation of the nasal probe or other technical difficulties. These events would occur randomly. During transit to theater and during stay on the recovery unit, a conventional ear thermometer was used; these temperatures were not included in the study because they do not reflect core body temperature.

Pre-operative antibiotic prophylaxis by administration of a single dose of intravenous metronidazol and cefazoline 60 to 15 minutes prior to incision was standard care in our hospital. Compliance with antibiotic prophylaxis was assessed using AIMS data. The surgeons in our institution had a standardized procedure regarding pre-operative bowel preparation, pre-operative skin preparation, and anastomosis creation. Furthermore, they routinely inspect mesenteric vascularization by cutting the mesentery. They also routinely close the skin incision primarily.

Temperature management in our hospital consisted of the Bair Hugger system, which actively warms the patient using forced-air warming. The Bair Hugger system was used at the holding (full body) and during surgery (upper body). The Bair Hugger system did not warm at a fixed temperature, rather the temperature at which warming was performed was variable. The most common target temperature was 36°C, but this was increased to 40°C based on the patients observed core body temperature. Fluid warmers were not used peri-operatively. Pre-heated blankets are used to keep the lower extremities warm during surgery.

The Dutch Colorectal Audit (DCRA) is a nationwide surgical registry [17]. The following data was acquired from the DRCA: patient, tumor, treatment, and 30-day post-operative outcome data. In our analysis we considered cases in which a laparoscopic procedure was converted to an open procedure as open procedures.

Patient population

We evaluated all consecutive patients who underwent curative surgery for primary CRC in the period May 2011 through January 2017. This period was chosen because a new AIMS was implemented in 2017. Patients who received hyperthermic intra-peritoneal chemotherapy (HIPEC) treatment were excluded because the warmed fluid used during the procedure influences central body temperature. We also excluded patients for whom no AIMS temperature data were available or who had fever (temperature ≥38.5°C) at the start of the operation.

Definitions of outcomes

Primary outcome was the occurrence of SSI within 30 days of the operation. The SSI definition of the European Centre for Disease Prevention and Control (ECDC) was used, which recognizes superficial, deep incision, and organ/space SSIs [18]. Assessment of SSIs took place during daily ward rounds while the patient was still hospitalized and during a check-up appointment at the outpatient clinic two or three weeks after discharge. The assessment was conducted by a surgical resident or a colorectal surgeon. Secondary outcomes for this study were the occurrences of overall complications, serious complications (Clavien-Dindo ≥3) and cardiac complications and mortality within 30 days of the operation and re-admission within 30 days of discharge as defined by the DCRA [17]. A weighted composite end point consisting of 30-day re-admission (weight 1), 30-day serious complications (weight 2), and 30-day mortality (weight 3) was also used.

Definitions of exposure variables

To capture periods of intra-operative hypothermia adequately, we used several definitions of hypothermia as exposure parameters. Based on expert opinion of the panel of staff anesthesiologist and surgeon and a review of the published literature on the subject of intra-operative hypothermia [12 –15,19], we selected the following definitions of potential hypothermia: mean intra-operative temperature, temperature nadir (minimum measured temperature), percentage of time spent at temperature nadir, and percentage of time spent at a temperature higher than 36.0°C.

Data analysis

Dichotomous data were presented as number and percentage and analyzed using the χ² test. Continuous data were presented as medians with interquartile range and analyzed using the Mann-Whitney U test or as means with standard deviation and analyzed with the independent samples t-test. Incomplete parameters from the DCRA database were supplemented by the primary researcher (M.F.) using pathology and operation reports. Data that remained missing after supplementation by the primary researchers were not at random and therefore case-wise exclusion took place. Multivariable logistic regression analysis was used to analyze the effect of mean intra-operative temperature on post-operative adverse events, while adjusting for potential confounding factors. These factors were: gender, diabetes mellitus, body mass index (BMI), rectal cancer, duration of surgery, open surgery, emergency surgery, and period of surgery (2011–2013 vs. 2014–2017) to account for possible changes in peri-operative care over the years. Factors were chosen based on known risk factors from the literature [20,21] and baseline differences observed in our study cohort. Ordinal logistic regression was used to analyze the effect of mean intra-operative temperature on the weighted composite end point. Cardiac complication as an adverse post-operative event was specifically included as this outcome is associated with hypothermia. All p values reported are two sided. A p value of <0.05 was considered significant. Statistical analysis was performed using SPSS 24.0 (IBM, Armonk, NY).

Results

A total of 1,270 patients with CRC underwent surgery during the study period and were evaluated for inclusion. After exclusion of 43 patients who underwent HIPEC treatment, 69 patients for whom no data were available, and 143 patients who had fewer than 100 temperature measurements, the final study cohort consisted of 1,015 patients. Mean age was 68 years (standard deviation [SD] 10.2), 59% (601/1,015) was male, median duration of surgery was 159 minutes (interquartile range [IQR] 133–198), open surgery was performed in 24% (246/1,015) of patients and emergency surgery was performed in 7% (66/1,015) of patients. Other baseline characteristics can be found in Table 1.

Table 1.

Baseline Table of 1,015 Patients

	All (n = 1,015)	SSI (n = 101)	No SSI (n = 914)	p
Male	601 (59)	71 (70)	530 (58)	0.019
Age, mean (SD), y	68.2 (10.2)	68.0 (9.8)	68.2 (10.3)	0.88^a
ASA classification				0.24
ASA 1	173 (17)	11 (11)	162 (18)
ASA 2	626 (61)	68 (67)	558 (61)
ASA 3	203 (20)	20 (20)	183 (20)
ASA 4	13 (1)	2 (2)	11 (1)
BMI, mean (SD)	26.6 (4.4)	26.4 (4.2)	26.6 (4.4)	0.66^a
Diabetes mellitus	154 (15)	22 (22)	132 (14)	0.057
Primary tumor location				0.003
Colon cancer	685 (67)	55 (54)	630 (69)
Rectal cancer	330 (32)	46 (46)	284 (31)
TNM stage				0.29
Stage 1	256 (25)	20 (20)	236 (26)
Stage 2	267 (26)	25 (25)	242 (27)
Stage 3	396 (39)	48 (48)	348 (38)
Stage 4	96 (10)	8 (8)	88 (10)
Single dose prophylactic antibiotics, 60 to 15 min prior to incision	945 (93)	94 (94)	850 (93)	0.76
Duration of surgery, median (IQR), min	159 (133–198)	180 (146–220)	157 (132–197)	<0.001^b
Procedure				-
Hemicolectomy right	276 (27)	14 (14)	262 (29)
Transverse colon resection	9 (1)	2 (2)	7 (1)
Hemicolectomy left	69 (7)	12 (12)	57 (6)
Low anterior resection/sigmoid resection	448 (44)	43 (43)	405 (44)
Abdominoperineal resection	176 (17)	27 (27)	149 (16)
Subtotal colectomy	21 (2)	2 (2)	19 (2)
Other	16 (1)	1 (1)	15 (1)
Emergency surgery	66 (7)	9 (9)	57 (6)	0.29
Open surgery	246 (24)	52 (52)	264 (29)	<0.001
Conversion	71 (7)	10 (10)	61 (7)	0.23
Intra-operative blood transfusion	41 (4)	3 (3)	38 (4)	0.42
Time period of operation				0.012
2011–2013	376 (37)	49 (49)	327 (36)
2014–2016	639 (63)	52 (51)	587 (64)

Values are presented in frequencies (percentage) unless stated otherwise. All p values are calculated using the χ² test, unless stated otherwise.

SSI = surgical site infections; SD = standard deviation; ASA = American Society of Anesthesiology; BMI = body mass index; TNM = tumor, node, metastisis; IQR = interquartile range.

Independent samples t-test.

Mann-Whitney U test.

Overall 30-day SSI occurred in 10% of patients (101/1,015), superficial SSIs in 4% (41/1,015), deep incisional SSIs also in 4% (41/1,015), and organ/space SSIs in 2% (19/1,015). The 30-day complication rate was 26% (266/1,015), serious complications (Clavien-Dindo 3–4) occurred in 11% of patients (114/1,015), and 30-day mortality was 1% (10/1,015). Intra-operative blood transfusion was rare and occurred in only 4% (44/1,015) of patients. A single dose of prophylactic antibiotic agent prior to surgery was standard care, however, compliance in our study cohort was not 100% because of registration errors by physicians.

Temperature outcomes for the entire study cohort were as follows: temperature mean was 36.3°C (SD 0.5°C), median temperature nadir was 35.8°C (IQR 35.6°C–36.1°C), median percentage of time at nadir was 2.0% (IQR 0.8%–10.7%), and median percentage of time less than 36.0°C was 1.0% (IQR 0.0%–33.3%). Associations between SSI and the following factors were found: male gender (p = 0.019), increased duration of surgery (p < 0.001), open surgery (p < 0.001), and rectal cancer (p = 0.003). We also conducted univariable analyses to examine if associations between the four intra-operative temperature variables and SSI could be found (Table 2). None of the four variables (i.e., temperature mean, temperature nadir, percentage of time at nadir, and percentage of time <36.0°C) had an association with SSI.

Table 2.

Intra-Operative Temperature Outcomes in SSI and Non-SSI Group

	SSI (n = 101)	No SSI (n = 914)	p
Temperature mean (SD) °C	36.3 (0.4)	36.3 (0.5)	0.99^a
Temperature nadir, °C	35.8 (35.5–36.2)	35.9 (35.6–36.1)	0.77
Time at nadir, percentage	2.0 (0.8–10.6)	2.0 (0.8–10.7)	0.35
Time <36.0°C, percentage	1.7 (0.0–50.7)	1.0 (0.0–31.6)	0.41
Absolute minutes under threshold temperature
37.5	160 (119–199)	136 (110–169)	<0.001
37.0	143 (106–190)	125 (97–157)	<0.001
36.5	98 (23–161)	88 (20–132)	0.10
36.0	2 (0–84)	1 (0–46)	0.15
35.5	0 (0–0)	0 (0–0)	0.40
35.0	0 (0–0)	0 (0–0)	0.36
Percentage of time under threshold temperature
37.5	100.0 (100.0–100.0)	100.0 (100.0–100.0)	0.60
37.0	100.0 (83.8–100.0)	100.0 (97.8–100.0)	0.19
36.5	60.8 (15.3–100.0)	73.0 (16.0–100.0)	0.58
36.0	1.7 (0.0–50.7)	1.0 (0.0–31.6)	0.41
35.5	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.44
35.0	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.36

Values are presented in median (IQR) and p values are calculated using the Mann-Whitney U test, unless stated otherwise.

SSI = surgical site infections; SD = standard deviation; IQR = interquartile range.

Independent samples t-test.

When assessing the absolute and relative time that patients spent under different threshold temperatures the most notable finding is the strong significant association (p < 0.001) between SSI and the absolute number of minutes below the highest two temperature thresholds. This high cutoff value is correlated with the total procedure time, with SSI patients having a median duration of surgery of 180 minutes versus 157 minutes in non-SSI patients. In the multivariable analysis we showed that increased duration of surgery is substantially associated with increased risk of SSI.

As summarized in Table 3, a multivariable model was constructed for each of the four intra-operative temperature variables (i.e., temperature mean, temperature nadir, percentage of time at nadir, and percentage of time <36.0°C) and their possible associations with SSI. Each model included the same covariables: gender, diabetes mellitus, BMI, rectal cancer, duration of surgery, open surgery, emergency surgery, and period of surgery (2011–2013 vs. 2014–2017). All four models showed no association between the temperature variable and SSIs. All four models did show an association between open surgery, duration of surgery, and rectal cancer in relation to SSIs.

Table 3.

Overview of Four Multivariable Logistic Regression Models, Each with a Different Temperature Variable

Temperature variable in the model	Variable	OR (95% CI)	p
Mean intra-operative temperature	Mean intra-operative temperature	1.00 (0.62–1.62)	0.97
	Male	1.59 (0.99–2.56)	0.054
	Diabetes mellitus	1.69 (0.98–2.93)	0.060
	BMI	0.97 (0.92–1.03)	0.34
	Rectal cancer	1.69 (1.06–2.68)	0.027
	Duration of surgery (10 min increase)	1.06 (1.01–1.10)	0.007
	Open surgery	2.65 (1.68–4.17)	<0.001
	Emergency surgery	1.26 (0.55–2.87)	0.59
	Period of surgery (2011–2013 vs. 2014–2017)	0.65 (0.42–1.01)	0.054
Temperature nadir	Temperature nadir	1.11 (0.68–1.82)	0.68
	Male	1.58 (0.99–2.53)	0.056
	Diabetes mellitus	1.70 (0.98–2.93)	0.059
	BMI	0.97 (0.92–1.03)	0.30
	Rectal cancer	1.69 (1.06–2.69)	0.026
	Duration of surgery (10-min increase)	1.06 (1.02–1.10)	<0.001
	Open surgery	2.66 (1.69–4.19)	<0.001
	Emergency surgery	1.24 (0.55–2.80)	0.61
	Period of surgery (2011–2013 vs. 2014–2017)	0.64 (0.41–0.99)	0.046
Percentage of time spent at nadir	Percentage of time spent at nadir	0.99 (0.97–1.01)	0.26
	Male	1.58 (0.99–2.53)	0.056
	Diabetes mellitus	1.64 (0.95–2.85)	0.077
	BMI	0.97 (0.92–1.03)	0.32
	Rectal cancer	1.63 (1.02–2.60)	0.039
	Duration of surgery (10-min increase)	1.05 (1.01–1.10)	0.009
	Open surgery	2.70 (1.71–4.26)	<0.001
	Emergency surgery	1.21 (0.53–2.74)	0.65
	Period of surgery (2011–2013 vs. 2014–2017)	0.64 (0.42–1.00)	0.047
Percentage of time >36°C	Percentage of time >36°C	1.00 (1.00–1.01)	0.54
	Male	1.63 (1.01–2.62)	0.044
	Diabetes mellitus	1.71 (0.99–2.96)	0.055
	BMI	0.98 (0.93–1.03)	0.39
	Rectal cancer	1.69 (1.06–2.68)	0.027
	Duration of surgery (10-min increase)	1.06 (1.01–1.10)	0.007
	Open surgery	2.62 (1.66–4.13)	<0.001
	Emergency surgery	1.30 (0.57–2.95)	0.53
	Period of surgery (2011–2013 vs. 2014–2017)	0.66 (0.43–1.03)	0.068

The outcome variable is SSI.

SSI = surgical site infections; OR = odds ratio; CI = confidence interval; BMI = body mass index.

Several multivariable analyses were performed to examine possible associations between mean intra-operative temperature and 30-day post-operative complications, serious complications, anastomotic leakages, cardiac complications, re-admission, mortality, and a composite end point consisting of serious complications, re-admission and 30-day mortality (Table 4). In these models, adjustment was made for known risk factors of these adverse post-operative outcomes. There was no association between mean intra-operative temperature and any of the adverse post-operative outcomes.

Table 4.

Adjusted Associations between Mean Intra-Operative Temperature (per °C) and Several Thirty-Day Adverse Post-Operative Outcomes as Outcome Variables

Outcome variable	n (%)	OR (95% CI)	p
All complications	248 (24)	1.26 (0.88–1.82)	0.21
Serious complications (Clavien-Dindo ≥3)	114 (11)	1.41 (0.86–2.31)	0.18
Anastomotic leakage	31 (3)	1.29 (0.54–3.05)	0.57
Cardiac complications	28 (3)	1.26 (0.50–3.15)	0.63
Readmission	74 (7)	1.25 (0.71–2.12)	0.45
Mortality^a	10 (1)	—	—
Weighted composite end point^b	160 (16)	0.24 (−0.18 to 0.67)^C	0.25

Multivariable logistic regression adjusted for gender, age, ASA classification, BMI, emergency surgery, open surgery, and period of surgery (2011–2013 vs 2014–2017).

OR = odds ratio; CI = confidence interval; ASA = American Society of Anesthesiologists; BMI = body mass index,

Insufficient number of events for multivariable analysis.

Composite endpoint consists of serious complications, re-admission, and 30-day mortality.

Ordinal regression with estimate (95% CI).

Increased length of stay was defined as more than seven days and occurred in 32% (234/1,015) of patients. There was no difference in mean intra-operative temperature between those with increased length of stay and those without (Mann-Whitney U test, p = 0.62).

Discussion

This study examined whether compliance with normothermia as part of temperature management measures is an effective strategy to reduce SSI in patients who underwent surgery for CRC in a hospital in which temperature management was standard care. Intra-operative hypothermia and, subsequently, SSI rates were low and could not be associated with each other. Even when using four different definitions of hypothermia, this study failed to show an association between intra-operative hypothermia and SSI. Compliance with normothermia seems an effective strategy to reduce SSI.

This study is in agreement with other recent studies that have also shown low intra-operative hypothermia rates in hospital that use temperature management measures (i.e., forced-air warming and intravenous fluid warming). Under these conditions of active temperature management, no association could be found between the low intra-operative hypothermia rates and SSI [14,15,19].

The findings of this study are in contrast to those of the three initial RCTs that we discussed previously in this article [3 –5]. The most obvious explanation for this discrepancy might be that those studies were conducted in the late 1990s and early 2000s. Since that time, organizations such as the WHO and the AHRQ have formulated guidelines that recommend maintenance of normothermia to prevent SSIs [1,2]. In addition, hospitals have invested money, time, and energy in implementing temperature management systems during the peri-operative period. In the original three RCTs, patients who were randomly assigned to the control group received standard of care at that time and were much more hypothermic than patients who receive a different standard of care today. For example, the introduction of active warming systems such as the Bair Hugger system had not yet occurred; nowadays it is standard practice in many hospitals. Another example of the differences in patient care was the use of peri-operative antibiotic prophylaxis over four days; nowadays the standard practice is 24 hours. The introduction of the Enhanced Recovery After Surgery protocol in the early 2000s has also contributed to reducing hypothermia.

Surgical site infections of any kind occurred in 10% of patients in this study, which is in accordance with rates reported in the literature ranging from 7% to 18% [15,19,22,23]. The incidence of intra-operative hypothermia in our study was low. Median temperature nadir was 35.8°C, however, median time spent at this nadir was low (2.0% of operating time). Even when using a cutoff value of 36.0°C, only 1.0% of median operating time was spent at that temperature.

Mean intra-operative temperature was also not associated with other adverse outcomes such as 30-day post-operative complications, re-admissions, or mortality. However, because of the aforementioned low incidence of intra-operative hypothermia, no definitive conclusions can be drawn.

Our study has several strengths and limitations. The first strength of our study is that core temperature was measured continuously with one-minute intervals during the peri-operative period. This allowed us to conduct more detailed analysis without loss of data. The second strength is that a staff anesthesiologist and surgeon visually inspected all individual temperature graphs to identify erroneous measurements. This is time intensive but also the most reliable method to clean the dataset. Limitations of this study include the inherent bias of a retrospective nonrandomized comparison. Furthermore, no data regarding smoking or immunosuppression, which are associated with incision healing, were available to us.

Conclusions

In a hospital in which temperature management is the standard of care, intra-operative hypothermia and SSI rates in patients undergoing colorectal cancer surgery were low. Compliance with normothermia seems an effective strategy to reduce SSI.

Footnotes

Acknowledgments

The Medical Ethics Committees United (MEC-U), located in Nieuwegein at the St. Antonius Hospital and consisting of partnerships between seven large regional hospitals in The Netherlands, and the local medical ethical committee of the hospital reviewed and approved this study. Informed consent was deemed unnecessary according to the Dutch Medical Treatment Agreement Act.

Funding Information

No funding was received for this study.

Author Disclosure Statement

The authors declare no conflict of interest.

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