Surgical site infections (SSIs) are perhaps the most common serious complication of anesthesia and surgery. They cause considerable morbidity and are expensive to treat.1,2 The transition from contamination to established infection occurs during a decisive period that probably lasts only a few hours, even though infections are typically detected a week or longer after surgery.3,4 If antibiotics are administered during this decisive period, they are more effective in reducing infection risk than when given later.5 Tissue oxygen tension levels are one of the best factors established for predicting SSI.6,7 Oxidative burst function of neutrophils is one of the primary defenses against SSI.8 Oxidative burst depends on the PO2 over the entire physiological range of tissue values.9 Interventions to improve tissue oxygenation during or immediately after surgery are thus most likely to reduce the morbidity and mortality associated with SSI.10,11
Tissue oxygenation has traditionally been measured with Clark-type electrodes or similar systems. However, these methods are invasive, expensive, and require expertise to use.12,13 Near-infrared spectroscopy (NIRS) is an alternative noninvasive technique.14 – 17 We tested the hypothesis that tissue oxygen saturation (StO2) measured soon after surgery with NIRS predicts ultimate development of SSI. Confirming this hypothesis would allow early clinical interventions, which might reduce the risk of infection.
With approval by the Human Studies Committees at the University of Louisville and the Cleveland Clinic, and written informed consent by the participants, we included 116 colorectal surgery patients. Forty-three of these patients had laparoscopic-assisted colorectal procedures; the remainder had laparotomies (Table 1).
In a preliminary study, we found that patients who developed SSI had lower StO2 measurements at the thenar eminence ∼15% ±20% (mean ± SD) than those who remained uninfected postoperatively; the analogous absolute difference was ≈20% ±30% at the upper arm.18 Using these estimates, a sample size of 80 measurements at the thenar eminence and 132 at the upper arm was calculated to achieve 90% power with an α of 0.05. We therefore enrolled 116 patients to complete the study with sufficient power for both outcomes.
The study enrollment period was from July 2007 to May 2008. Adults between 18 and 80 years of age with an ASA physical status I to III were included in the study. Patients with intestinal obstruction, those in whom the surgeon did not anticipate a primary wound closure, and those with a diagnosed or suspected intraabdominal abscess were excluded from the study. Patients were also excluded if they had severe chronic obstructive pulmonary disease, recent myocardial infarction, unstable angina, or required oxygen preoperatively.
All patients received antibiotics before surgery according to the protocols of the 2 participating institutions, each of which required administration of appropriate prophylactic antibiotic within an hour before surgical incision. Patients were given midazolam for premedication, propofol or etomidate for induction of anesthesia, and succinylcholine or rocuronium for initiation of muscle relaxation. Muscle relaxation was maintained with rocuronium or vecuronium.
Anesthesia was maintained with sevoflurane, desflurane, or isoflurane in 30% to 80% oxygen, supplemented with fentanyl or morphine. Intraoperative IV fluid management was at the discretion of the attending anesthesiologist, and consisted of 8 to 10 mL/kg. Core temperature was maintained near 36°C by using forced-air warming blankets and fluid warmers. Hair was clipped from the surgical site immediately preoperatively, and the skin was prepared with a chlorhexidine-based antiseptic kit. Postoperative analgesia was provided with IV intermittent boluses or via patient-controlled analgesia with morphine or hydromorphone. If an epidural catheter was placed preoperatively, epidural analgesia with fentanyl (∼25 to 50 μm/h) was used intraoperatively and approximately for the first 2 hours of the recovery if it was the preference of the attending anesthesiologist. A combination of local anesthetic and opioid via the epidural was only administered after the study was completed.
Spontaneously breathing patients were given oxygen via nasal cannula or Venturi mask. The inspired oxygen concentration was adjusted to maintain pulse oximeter saturation (SpO2) ≥95%. StO2 was measured 15 minutes after weaning from oxygen and thereafter patients received supplemental oxygen as required to maintain SpO2 ≥92%.
The duration of surgery, blood loss, intraoperative crystalloid and colloid administration, hemodynamic variables, blood transfusion requirements, and urine output were recorded.
Two systems were used to evaluate the SSI risk: the Study on the Efficacy of Nosocomial Infection Control (SENIC) and National Nosocomial Infection Surveillance System (NNISS). The SENIC scoring system assigns 1 point for each of the following factors: ≥3 underlying diagnoses, surgery that lasts ≥2 hours, an abdominal site of surgery, and the presence of a contaminated or infected wound.19 The NNISS predicts risk on the basis of the contamination of surgery, the rating of physical status on a scale developed by the American Society of Anesthesiologists, and the duration of surgery.20
StO2 and tissue hemoglobin index (THI) were measured by an InSpectra™ tissue spectrometer model 650 (Hutchinson Technology Inc., Hutchinson, MN) 75 minutes after surgery and on the first postoperative day (Fig. 1). A time point of 75 minutes postoperatively was chosen because patients are usually weaned from supplemental oxygen at the end of the first postoperative hour, and waiting an additional 15 minutes generally allows full washout of supplemental oxygen.
The InSpectra tissue spectrometer measures StO2 using wide-gap second-derivative NIRS.21,22 The InSpectra spectrometer makes use of the characteristic absorption properties of hemoglobin in the near-infrared wavelength range between 680 and 800 nm. The absorption spectrum of light remitted from the tissue sample varies mainly with oxyhemoglobin and deoxyhemoglobin concentration; other chromophores have minimal effect. StO2 is a measure of hemoglobin oxygen saturation of the blood contained in the volume of tissue illuminated by the near-infrared light. The maximum depth of the tissue sampled is the distance between the probe's send and receive fibers. Mean measurement depth is half the probe's spacing. We used a 15-mm probe that measures StO2 of 5- to 8-mm tissue depth. For the forearm and wound sites, this corresponds to subcutaneous tissue above the skeletal muscle. For the thenar muscle site, this depth corresponds to muscle.
StO2 near the wound was measured 2.5 cm lateral to the incision at the upper, middle, and lower third of the incision. The upper lateral arm site was chosen for measurement because this site reflects the StO2 of operative wounds in the chest and abdomen even though it is approximately 10 mm Hg higher than in the wound area.6,12 The thenar muscle site was chosen because it is one of the best established sites for tissue oximetry measurement.23,24 At each of these sites, the probe was placed for 15 to 30 seconds until a stable oxygen saturation value was obtained.
THI was measured simultaneously throughout the study from the same probe as the StO2 was monitored. THI is not yet a well-established value. As with several others, this NIRS-based device can provide a hemoglobin value obtained from the probe's detection site, but this hemoglobin value does not necessarily represent the body's total hemoglobin concentration. THI monitors the total amount of hemoglobin in the tissue site where the NIRS probe is applied. Therefore, it may be considered more of a perfusion variable.
During each set of measurements, mean arterial blood pressure, heart rate, and SpO2 were recorded simultaneously. We asked the patients to rate their pain using a 10-cm visual analog scale.
An independent investigator not aware of the StO2 measurements evaluated patients' wounds daily throughout their hospitalization. SSI was diagnosed according to the surgical wound infection definitions from the Centers for Disease Control and Prevention (CDC).19,25
Primary outcomes were the StO2 measured around the surgical incision, at the upper arm, and at the thenar muscle. Surgical site StO2 measurements were summarized as a mean value and presented as a post hoc analysis. Specifically, subcutaneous StO2 values at the upper one-third, middle one-third, and lower one-third of the surgical incision were averaged into a single “incision” value for each patient.
Normally distributed data are presented as means ± SD. Skewed data are presented as medians and interquartile ranges. After descriptive analysis of all parameters, univariate analysis was performed using the χ2 test for categorical variables and unpaired, 2-tailed t and Kruskal-Wallis tests for continuous variables. P values <0.05 were considered statistically significant. Additionally, a multivariate analysis was performed to assess the independent contribution of each potential variable (SPSS Inc., Chicago, IL).
Receiver operating characteristic (ROC) curves were developed for StO2 in the upper arm and SpO2 on the first postoperative day to predict surgical wound infections. We compared our predictions based only on early postoperative upper arm StO2, using an StO2 of 66% as the cutoff point, with SENIC predictions. The CDC in the SENIC developed a predictive model for the risks of SSI that has become the standard.19
Of the 116 patients enrolled, 23 developed SSI (20%). If the diverticulitis cases were excluded, the SSI rate would decrease to 14%. All of the 23 patients who developed SSI had superficial incisional site infections. Three of these patients also developed deep incisional site infections, and 4 developed peritoneal infections as defined by CDC criteria. Infections were diagnosed an average of 9 ± 5 days after surgery.
Age, ASA physical status, and SENIC and NNISS risk scores were similar in the patients who developed SSI and those who remained uninfected (Table 1). Patients with SSI had a greater body mass index. There were no statistically significant or clinically significant differences in the duration of surgery, IV fluid administration, intraoperative temperature, or blood transfusion requirements. Surgical technique and use of epidural analgesia were also similar in the patients who developed SSI and those who did not (Table 1).
A significant proportion of the patients (35%–38%) could not be weaned from supplemental oxygen at the 75th-minute measurement period (Table 2). Additionally, from this group of patients, there were 14 patients (3 with SSI and 11 with no SSI) who required oxygen rates of more than 2 to 3 L/min. During the first postoperative day measurements, 70% to 75% of the patients were weaned from supplemental oxygen. Therefore, some of the study measurements were done under supplemental oxygen because of the oxygenation needs of the patients as specified above.
In the early postoperative period (Table 2), StO2 at the surgical incision did not differ significantly between patients who eventually developed SSI and those who remained uninfected. The THI near the surgical incision was 25% lower in patients who developed SSI, but this difference did not reach statistical significance.
In contrast, StO2 at the upper lateral arm was significantly lower in the patients who developed SSI (52 ± 22 mm Hg) than in those who did not (66 ± 21 mm Hg; P = 0.033). ROC curve for StO2 at the upper lateral arm had a sensitivity of 71% and specificity of 60% using an StO2 of 66% as the cutoff point for predicting SSI (Fig. 2). The positive predictive value of this cutoff value was 29%, with a negative predictive value of 90%. The THI measured in the early postoperative period at the upper arm was also statistically lower in the patients who developed SSI (3.8 ± 1.3 vs 5.5 ± 3.2 g/dL). ROC curves for THI at the upper lateral arm in the early postoperative period had a sensitivity of 88% and specificity of 55% for predicting SSI at a THI of 4.3. Figure 3 shows the difference between observed and expected (based on SENIC scores) infection risk as a function of early postoperative StO2 at the upper arm. Because intraoperative oxygen concentrations were not controlled per protocol, we calculated whether there was any correlation between inspired intraoperative oxygen concentrations and postoperative StO2 at the upper lateral arm. There was no correlation (r 2 = 0.007).
Thenar muscle oxygenation and THI values were both higher than those of the subcutaneous tissue values in both groups of patients. Neither the StO2 nor the THI measured at the thenar eminence 75 minutes after surgery differed significantly in patients who did or did not develop SSI (Table 2). Early postoperative visual analog scale pain scores were slightly, but statistically significantly, higher in patients who developed SSI (Table 2).
Patients who developed SSI had lower SpO2 values on the first postoperative day (95% ± 3% vs 97% ± 2%; P = 0.001). The ROC curve for the first postoperative day SpO2 had a sensitivity of 75% and specificity of 73% using an SpO2 of 95% as the cutoff point for predicting SSI.
Multivariate logistic regression analyses indicated that the first postoperative day SpO2 value was the only statistically significant independent factor contributing to SSI. Although body mass index, postoperative pain, intraoperative blood loss, and upper arm StO2 data provided a good clinical and statistical difference in univariate analysis, they did not reach independent significance levels with multivariate statistics (Table 3).
The link between tissue oxygenation and surgical wound infection is well established. This concept, developed by Thomas Hunt in the 1960s and 1970s26,27 led to a landmark article by Hopf et al.6 more than a decade ago. Hopf et al. used a subcutaneous needle-guided tonometric silicon catheter system into which they inserted a polarographic Clark-type electrode to monitor tissue oxygen partial pressure. They obtained measurements at 3 different times: within 6 hours of surgery, on the first postoperative day, and on the second postoperative day. They observed that tissue oxygenation was a strong predictor of SSI.
A subcutaneous tissue oxygen monitoring system (LICOX; Medical Systems Corp., Greenvale, NY) has been used by various investigators, including us, for decades and is considered the “gold standard” for tissue oxygen monitoring. However, the LICOX system is invasive, expensive, and requires approximately 45 minutes of calibration and equilibration with tissue as well as considerable operator experience to be accurate. Therefore, a simple and noninvasive tissue oxygen monitoring system might be easier and more feasible for perioperative use. The InSpectra StO2 system is noninvasive and relatively easy to use. Our main study question was whether NIRS StO2, measured immediately postoperatively, would be able to predict SSI. Our principal finding was that patients who eventually developed SSI according to the CDC criteria had lower StO2 at the upper arm only 75 minutes after surgery, which was approximately 9 days before the diagnosis of SSI was made clinically.
Upper arm StO2 provided a “fair” area under the ROC curve and was a better predictor of infection than the established SENIC or NNISS risk scores. This point is important because the high-risk patients we identified would generally not have been detected using the SENIC risk score or other routinely available clinical systems.
As we have shown previously, subcutaneous tissue in the upper lateral arm is relatively well oxygenated and perfused under general anesthesia and in the awake state.1,28,29 An average of 48 ± 19 perforator arterioles from 15 vascular territories supply the integument of the upper extremity. Septocutaneous arteries predominate in the shoulder, elbow, distal forearm, and hand regions. Musculocutaneous perforators are more numerous in the upper arm and proximal forearm. The average perforator size in the upper extremity is approximately 0.7 ± 0.2 mm in diameter and supplies an average area of 35 cm2.30,31 Therefore, we can extrapolate that our upper arm StO2 measurement likely included a site perfused with at least 1 perforator artery.
Leukocyte-mediated oxidative burst and collagen formation require oxygen partial pressures of at least 40 mm Hg.32 Upper arm subcutaneous tissue oxygen tension is typically >50 mm Hg under a fraction of inspired oxygen <0.4 even during sympathetic vasoconstriction. Our tissue oxygen tension values were lower than those reported previously (27 to 35 mm Hg). This difference might result from differences in oxygen monitoring techniques. StO2 measures hemoglobin's oxygen saturation in a focal area. StO2 systems calculate the hemoglobin's oxygen saturation in the volume of tissue illuminated by near-infrared light. Because in the majority of the peripheral tissues tested (surgical wound area and upper arm subcutaneous tissue) the THI values were low, we can extrapolate that there was less perfusion in the site of interest. Therefore, StO2 provides a different oxygenation value than tissue oxygen tension, which monitors the partial pressure of free oxygen in the tissue. Free oxygen was reported to be the main source of oxygen available for the tissues.33 This interesting concept of tissue oxygenation will continue to be an intensely debated topic until applicability of monitoring, reproducibility of oxygenation data, and until it is proven with clinical outcomes.
We are not the first to use StO2 to predict SSI. Ives et al.16,34 reported that StO2 of 53% at the surgical incision site, measured 12 hours postoperatively, provided 71% sensitivity and 76% specificity as a test to predict SSI. Our study extends previous work by showing that infection can be predicted shortly after surgery, during the decisive period. But interestingly, Ives et al. could not find any difference in the upper arm StO2 measurements between the patients who did and did not develop SSI. A possible explanation is that Ives et al. measured tissue oxygenation 10 cm below the shoulder tip over the bulk of the biceps muscle. In contrast, we used the lateral upper arm, which was approximately 15 cm below the shoulder tip, the area between the biceps and triceps brachii's lateral head. This is the site used in most previous studies.6,28,35 The reason behind our failure to find a statistically significant difference at the surgical site can be explained (1) by the lack of power and small sample size, and (2) because of the stretch of the peri-incisional tissues during surgery, there might have been tissue edema to blunt the extent of oxygenation difference. If the difference between the groups continued consistently, 170 to 180 patients would have provided a statistically significant difference.
Another interesting finding of the current trial is that SpO2 values of the first postoperative day apparently predicted SSI. Before taken into consideration, some major limitations of these data need to be addressed: (1) SpO2 was not planned as one of the a priori outcomes of this study; (2) the data were gathered from only a few values from a snapshot period; and (3) although the difference was statistically significant, clinical meaning may be of limited value.
Early detection of patients at special risk of wound infection is important because there are well-established interventions that improve tissue oxygenation and may thus reduce infection rate and possibly improve surgical outcomes. For example, sympathetic nervous system activation triggers vasoconstriction and reduces tissue oxygenation.36 A major mediator of sympathetic activity, and one that can often be treated, is surgical pain. In fact, it is well established that adequate analgesia improves tissue oxygenation,37,38 which is supported by the fact that patients in our study who eventually developed SSI had higher pain scores in the early postoperative period.
Thermoregulatory vasoconstriction is another factor that decreases tissue oxygen tension and perfusion.39,40 As might thus be expected, maintaining perioperative normothermia41 and local warming42 decreases SSI rate. Supplemental fluid administration increases tissue oxygenation,43,44 but it does not necessarily improve the SSI rate.45 However, supplemental fluids may have short-term tissue oxygenation benefits that should be considered despite the ongoing perioperative fluid debates.46 Finally, supplemental oxygen (i.e., 80% inspired oxygen) approximately doubles tissue oxygen partial pressure1 without causing atelectasis.37,47
There are thus at least 4 established interventions that improve tissue oxygenation and could be implemented relatively easily in patients found to have low StO2 during the decisive period. We caution, however, that although the link between tissue oxygenation and SSI is clear, whether titrating interventions perioperatively to improve StO2 actually reduces infection risk is yet to be proven.
Despite the promising data provided in this trial supporting the link between oxygenation and SSI, there are some important limitations that need to be addressed. The values of the upper arm StO2 were relatively weak (low ROC area), which were also apparent with the nonsignificant odds ratio obtained from the multivariate analysis. A larger trial aiming to reconfirm the current results in a larger and wider surgical population will be needed. More importantly, no study in human subjects has validated the accuracy of StO2 by comparing it with the “gold standard” tissue oxygen tension monitoring. Additionally, it is important to recognize that the reflectance spectroscopy-based oximeters calculate the mean value of oxyhemoglobin across all the vessels of the microcirculation of the skin. Therefore, the derived oximeter saturation is a mean blood oxygen saturation across arterioles, capillaries, and venules.48
Another important limitation is in the claims made by diagnosing potential infections in a decisive period. This decisive period was established for antibiotic prophylaxis as the intervention. Therefore, the decisive period responding to increased oxygenation needs to be tested before considering the validity of the proposed interventions. Using an animal model, Knighton et al.7 showed that oxygen might have a decisive period of at least 6 hours.
In summary, StO2 measured at the upper arm only 75 minutes postoperatively predicts development of surgical wound infection after colorectal surgery, even though infections were typically diagnosed more than a week later. Because high-risk patients can potentially be identified noninvasively, it may also be possible to intervene to improve tissue oxygenation.
Samual Chen, MD, Luke Reynolds, MSc, Adrian Alvarez, MD, and Gena Harrison, BA (Department of Outcomes Research, Cleveland Clinic) are acknowledged for their assistance with data acquisition. We appreciate the efforts of Nancy Alsip, PhD, and Gilbert Haugh, MS (OCRSS, University of Louisville), in medical editing and statistical assistance; and Joseph Ortner and Hutchinson Technology Inc. (Hutchinson, MN) for technical support and for providing tissue oximeters and their probes.
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