Surgical Site infection: where are we now in terms of intraoperative oxygen therapy

 Since I last updated my blog related to perioperative surgical site infections and oxygen tension, several articles have appeared related to this topic. I would like to update my blog with the latest information to provide context to the highly charged debated related to intraoperative FiO2.

Just this year, an editorial review was published [1], going over the pros and cons of perioperative hyperoxia as it relates to SSI.  Larvin et al. appropriately note that oxygen delivery (DO2) does not depend on PaO2, but rather on the Cardiac Output and oxygen content of blood, which is largely dependent on saturation and hemoglobin. Futhermore, they correctly note studies have found that NAPDPH oxidase enzymes driving 'respiratory burst' to produce reactive oxygen species (ROS) that are critical in bacterial killing by neutrophils depend on PaO2 NOT CaO2.  Unfortunately, Larvin et al. stop here and fail to review the literature looking at oxygen tension at tissue levels and how it relates to bacterial killing by neutrophils, as well as how tissue oxygen tension is related to PaO2.  In truth, PaO2 while better than CaO2 as a surrogate, is still a surrogate for tissue oxygen tension (To2) where the actual bacterial killing is to take place.

The editorial review also covers the WHO recommendations in 2016 and revision in 2018 where it is recommended to use FiO2 of 0.8 in order to reduce SSI.  Several months prior to the WHO recommendations, a cochrane review was published wherein they stated that there was insufficient evidence that hyperoxia was beneficial.  To make it more confusing, in 2017,  CDC  also released a statement supporting the use of high FiO2 in intubated surgical patients.   

Shortly after these recommendations, in 2019, De Jonge et al. [2] republished their previous meta analysis after including studies that had been done since their previous review.  They determined that SSI indeed were decreased by using 80% oxygen vs. 30 to 35% oxygen.  However, this was the case only in intubated patients.  Obviously, the ability of high FiO2 to reduce SSI is dependent on the risk of SSI being high to start with.  In surgical cases where patients do not require intubation, the risk for SSI at baseline is likely low, and thus, any intervention is not likely to be found to be helpful. 

Much of the controversy related to hyperoxia during surgical procedures is related to the idea that oxygen is toxic to the lungs.  In 2017 Staeher-Rye et al [3] published a study concluding that the incidence of post op pulmonary complications (PPCs) at day 7 was higher in those with a higher median FiO2 during surgery even after adjusting for potentially confounding variables.  However, this was a retrospective database review where only 8% of the charts reviewed had appropriate data to analyze.  While statistical techniques can adequately control for a number of variables, the prospective RCT is still the gold standard and thus, retrospective reviews should not typically drive clinical practice. Indeed, one can easily imagine that in typical surgeries, most anesthesiologists will titrate the FiO2 to the patients condition. Thus, patients who are not doing well from an oxygenation stand point and thus very likely to go on to develop complications post op are also most likely to have higher intraoperative FiO2.  The cues that prompt this titration may be subtle and not easily extracted from an administrative database.   In 2018 Kurz, A et al. published a study where the oxygen concentration in an isolated suite of ORs was alternated between 0.8 and 0.3 every two weeks.  Unfortunately, while this was a well done study there were a few issues that made the results less compelling. First, the 30% group received a higher percentage than 30% and even ranged up to near 80% in some patients. Second, they looked at 30 day composite which included SSI.  There is some question as to whether counting SSI that occur 20 to 30 days after surgery is a realistic end point to measure the impact of intraoperative oxygen delivery.  Third, there was no attempt to control oxygen delivery after surgery which was part of the protocol in previously done studies that did find a benefit of perioperative hyperoxia.  Fourth, the rate of infection in both groups was very low (4.1% in FiO2 0.8 vs. 3.9% in FiO2 0.3).  This low rate may not be reflective of SSI rate at other hospitals. Furthermore, although not highlighted in the study, in a small blurb near the end of the paper, it is noted that patients in the 0.8 group had a lower SSI risk for superficial SSI (5.2%) vs. those in the 0.3 group (6.4% p=0.047). In the discussion the authors state that a decrease in superficial SSI is not serious enough to merit the use of hyperoxygenation.  I would argue that this statement reveals a clear underlying bias of the authors against oxygen therapy; likely a reflection of the authors fears that hyperoxia will cause post op pulmonary complications.  Also in the discussion the authors make an important point.  They state, "Even 30% inspired oxygen typically produces tissue partial pressure near 60 mmHg."  At a tissue partial pressure of 60 mmHg, they argue, bactericidal affects are adequate to prevent infection by oxidative killing by neutrophils.  This line of reasoning comes from a study done earlier where it was identified that neutrophil oxidative killing increases up to a maximum of tissue oxygen tension of 300 mmHg.  This same paper noted that 1/2 oxidative killing occurred in a range from 45 mmHg up to 80 mmHg.  Provided this information, shooting for a tissue partial pressure of oxygen of 60 mmHg as mentioned above and to be expected with an FiO2 of 0.3 in a normal healthy patient gives no room for error and does not account for the outliers where 1/2 oxidative killing does not occur until partial pressure of oxygen in the tissues is closer to 80 mmHg.

In 2023, [4]  another meta analysis was published revisiting all studies on oxygen delivery in patients undergoing abdominal surgery.   The authors concluded that the application of high concentration of oxygen was able to reduce SSIs with the caveat that the quality of the studies included were considered moderate to poor.  This same year, yet another meta analysis was published [5] and found no benefit of high inspired oxygen; however, in a subgroup analysis, they found that high oxygen levels did reduce the incidence of SSI when excluding anesthetics done under regional anesthesia.  They noted that a large number of the procedures that were included in the 'regional anesthesia' group included cesarian sections done under spinal or epidural anesthesia. For a number of reasons SSI after c/s is not likely.  Furthermore, it has been well demonstrated that regional anesthesia and particularly neuraxial anesthesia can dramatically increase  tissue partial pressure of oxygen likely as a result of significant vasodilation below the block level.  

 Recently,  Mattishent K et al published a large systematic review [6] concluding that high (80%) oxygen concentration is not associated with increased harm compared to lower oxygen concentrations (30-35%).  The same year as this systematic review was published a post hoc analysis was completed on a large cohort study [9], wherein it was confirmed that FiO2 of 0.8 is not associated with increased pulmonary complications post operatively.  Furthermore, there has been concern raised that hyperoxia can worsen myocardial ischemia in the at risk patient due to oxygen induced vasoconstriction.  However, a meta analysis of three studies found no increased cardiovascular adverse events in patients treated with intraoperative hyperoxia [6].  When pigs were subjected to haemodilution until their electrocardiogram showed ischaemic changes, hyperoxia, although it caused coronary vasoconstriction and reduced coronary blood flow, preserved myocardial oxygenation and improved electrocardiogram abnormalities [10].  Some have argued that since hyperoxia is associated with vasoconstriction, it shoud be avoided in patients at risk for stroke.  However, a recent published review of the literature was able to show that hyperoxia proved beneficial in the setting of acute ischemic stroke [8]. Another common concern is related to hyperoxia induced altelectasis.  In 2003 in Anesthesiology, Edmark et al. were able to quantify atelectasis from FiO2 of 1.0 compared to 0.8.  Here, when 0.80 FiO2 was used during anaesthesia induction, the atelectatic area in the basal lung fields as measured by computed tomography was reduced from 9.8 ± 5.2 cm2 (1.0 FiO2) to 1.3 ± 1.2 cm2(0.8 FiO2).  While hyperoxia has been demonstrated to induce vasoconstriction with a reflex decrease in stroke volume and cardiac output, this does not translate into a decrease in tissue oxygen partial pressure of oxygen. In fact, studies have made it clear that despite a slight decrease in cardiac output, oxygen partial pressure at the tissue level (PtO2) is increased.  This is because at the tissue level oxygen partial pressure levels are most related to PaO2, not oxygen delivery or DO2.

Finally, a further commentary on the current literature to date on the hyperoxia reducing SSIs.  The initial trials showing a benefit of hyperoxia were well done DB RCTs in colorectal surgery done in an open fashion.  Furthermore, patients in these earliers trials were treated with liberal fluid regimens to avoid hypovolemic vasoconstriction and minimize vasoconstrictors, both known causes of decreasing tissue level oxygen partial pressure. Importantly, in the first trial, oxygen partial pressure was actually measured and seen to improve in the hyperoxia group v. the lower oxygen group.  Later negative trials suffered from a number of problems.  Some included young healthy patients undergoing surgery at very low risk for SSI. None of the negative trials measure PaO2 or oxygen partial pressure in the tissues. Therefore, it is unknown if the hyperoxia treated patients actually reached therapeutic levels of oxygen in the tissues.  Lastly, some of the negative trials utilized more restricted fluid regimens, thus increasing risk of patients not having optimized perfusion of tissues thus lowering tissue oxygen partial pressure. 

Therefore, current evidence to this date looking at potential adverse events associated with intraoperative hyperoxia suggests that FiO2 of as high as 0.8 is safe.  This makes physiological sense given that surgeries are typically of short duration.  This cannot likely be extrapolated to critically ill patients coming to the OR suite from the ICU already requiring mechanical ventilation. These present unique situations where the lungs are exposed to hyperoxia over long periods of time often days on end.  In these situations, modification of inspired oxygen concentration is needed, recognizing that increasing tissue partial pressure of oxygen may be improved by improving other ventilatory paramters such as optimizing respiratory rate, Vt, and most importantly optimizing PEEP for the individual patient.

In summary, it is clear that in certain patient populations, hyperoxia does result in lower SSI incidence. Therefore, identification of this high risk sub group is important. Much of the debate related to high oxygen concentration vs low is related to a fear of causing patient harm with hyperoxia. However, given the current evidence demonstrating safety with hyperoxia, it makes sense to recognize the potential benefits in certain patients while recognizing the potential for harm in limited and specific scenarios.    As usual, a nuanced approach to oxygen delivery is probably best.  For example, hyperoxia and optimization of PaO2 (supramaximal) should be considered in an emergent ex lap colectomy after colon perforation.  Whereas, lower oxygen levels might be considered (i.e. FiO2 0.3) for a critically ill patient being mechanically ventilated for the last week going to the OR for wash out of scalp laceration.  In the end, as the anesthesiologist, you must use your best judgement on how to titrate the oxygen levels weighing in between five and ten different clinical parameters that may affect your choice.

1. Larvin J, Edwards M, Martin DS, Feelisch M, Grocott MPW, Cumpstey AF. Perioperative oxygenation-what's the stress? BJA Open. 2024 Mar 20;10:100277. 

2. de Jonge S, Egger M, Latif A, Loke YK, Berenholtz S, Boermeester M, Allegranzi B, Solomkin J. Effectiveness of 80% vs 30-35% fraction of inspired oxygen in patients undergoing surgery: an updated systematic review and meta-analysis. Br J Anaesth. 2019 Mar;122(3):325-334.

3. Staehr-Rye AK, Meyhoff CS, Scheffenbichler FT, Vidal Melo MF, Gätke MR, Walsh JL, Ladha KS, Grabitz SD, Nikolov MI, Kurth T, Rasmussen LS, Eikermann M. High intraoperative inspiratory oxygen fraction and risk of major respiratory complications. Br J Anaesth. 2017 Jul 1;119(1):140-149

4. Kuh, J.H., Jung, WS., Lim, L. et al. The effect of high perioperative inspiratory oxygen fraction for abdominal surgery on surgical site infection: a systematic review and meta-analysis. Sci Rep 13, 15599 (2023). https://doi.org/10.1038/s41598-023-41300-4

5. El Maleh, Y., Fasquel, C., Quesnel, C. et al. Updated meta-analysis on intraoperative inspired fraction of oxygen and the risk of surgical site infection in adults undergoing general and regional anesthesia. Sci Rep 13, 2465 (2023). 

6. Mattishent K, Thavarajah M, Sinha A, Peel A, Egger M, Solomkin J, de Jonge S, Latif A, Berenholtz S, Allegranzi B, Loke YK. Safety of 80% vs 30-35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis. Br J Anaesth. 2019 Mar;122(3):311-324. doi: 10.1016/j.bja.2018.11.026. Epub 2019 Jan 3. PMID: 30770049.

7. Weenink RP, de Jonge SW, van Hulst RA, Wingelaar TT, van Ooij PAM, Immink RV, Preckel B, Hollmann MW. Perioperative Hyperoxyphobia: Justified or Not? Benefits and Harms of Hyperoxia during Surgery. J Clin Med. 2020 Feb 28;9(3):642. doi: 10.3390/jcm9030642.

8. Qijian Wang, Xiao Zhang, Yijun Suo, Zhiying Chen, Moxin Wu, Xiaoqin Wen, Qin Lai, Xiaoping Yin, Bing Bao, Normobaric hyperoxia therapy in acute ischemic stroke: A literature review, Heliyon, Volume 10, Issue 1, 2024,

9. Cohen B., Ruetzler K., Kurz A., Leung S., Rivas E., Ezell J., Mao G., Sessler D.I., Turan A. Intra-operative high inspired oxygen fraction does not increase the risk of postoperative respiratory complications: Alternating intervention clinical trial. Eur. J. Anaesthesiol. 2019;36:1–7. 

10. Kemming G.I., Meisner F.G., Meier J., Tillmanns J., Thein E., Eriskat J., Habler O.P. Hyperoxic ventilation at the critical hematocrit: Effects on myocardial perfusion and function. Acta Anaesthesiol. Scand. 2004;48:951–959

11. Edmark L., Kostova-Aherdan K., Enlund M., Hedenstierna G. Optimal oxygen concentration during induction of general anesthesia. Anesthesiology. 2003;98:28–33.

hyperoxic ventilation and SSI

In this months Journal of Anesthesiology, Thibon et al. [1] published a study that was unable to find a benefit to intraop hyperoxia in the reduction of SSI in patients undergoing gyenecologic, breast and abdominal surgery.  The authors also included  their data in a new meta analysis looking at the reduction of SSI with the use of hyperoxia and concluded that with their data, there was no benefit to routine hyperoxic ventilation.  I've posted twice previously on this issue.  See a General overview of the topic and the discussion of the PROXI trial.
The concept of hyperoxic ventilation has been debated a number of years.  Hofp et al. was able to show that wound oxygen tension was a better predictor of SSI than a scoring system.  In this study, patients who had oxygen tension lower than 60 mmHg had much higher infection rates compared to patients whose wound oxygen tension was above 90 mmHg.  Furthermore, it has been shown that hyperoxia can be as effective as antibiotics in infected wounds in rats.  Two well done RCTs also showed a reduction of SSI in colon surgeries.  After this many anesthesiologists began to believe that by providing a high FiO2 they might be preventing SSI.  However, in medicine, things are not always quite as simple as they might seem.  In the PROXI trial they found no benefit to oxygen therapy. Harriet Hopf included an editorial on this study noting in particular that the protocol used for fluid management was questionable in allowing for sufficient volume to ensure adequate transport of the elevated oxygen levels to the peripheral tissues.  This is based on a number of studies that have shown that tissue oxygen tension does not increase in response to elevated FiO2 if not accompanied by euvolemia.
This study, therefore, should address these important issues.  1) Should we expect a difference with oxygen when patients with breast surgery were included (typically low infection rates).  2)  infection rates were only 7.2%, a very low rate making it difficult to detect a difference.  3)  What were the infection rates in the different groups (gynecolgoic vs. breast vs. general)?  Was their a trend to improvement in the subgroups with higher infection rates? 4)  What was the fluid regimen? Was euvolemia ensured? 
This study aknowledged a few important flaws.  First, the study was likely underpowered to detect a difference.  First, the power analysis was completed with an expected infection rate of 12% in the control group, but the infection rate in the control group was only 7.2%.  Second, the recruitment was difficult and the time elapsed prior to enrolling sufficient patients.  The power analysis called for 270 patients per arm (total 540) when the infection rate was expected to be 12%.  The enrolled only 414 patients. 
The authors rightly aknowledge that in the two studies that demonstrated that hyperoxia significantly reduced SSI the protocol required post operative oxygen therapy for 2 hrs or 6 hrs, while this study did not utilize post op oxygen because, "...is not routine practice in France..." It is hard to know how important this is, but there are several reasons to expect it to be important.  First, this was the protocol in place when oxygen did reduce SSI.  Second, intraoperatively, oxygen is delivered via an ETT in mechanically ventilated patients; thus, lung volumes are typically optimized to some degree by the anesthesiologist in such a way that even FiO2 of 30% may achieve adequate PaO2.  However, in the PACU, patients spontaneously breathing, sedated, and not managed as intensively as they are during the course of surgery by an anesthesiology provider.  This allows for the potential for brief episodes of oxygen desaturation, hypoventilation with subsequent atelectasis.  Patient splinting from pain may also reduce lung excursion.  The potential end result is decreased PaO2 if supplemental is not provided.
Infections vary by the type of infection and therefore, oxygen therapy may be beneficial in some types of surgery but not helpful in others.  The authors did not include a breakdown of infections based on type of surgery.  They do note that nearly have of the surgeries included in the trial were "breast" surgery.  However, infection rates vary depending on the type of breast surgery from as high as 12% for implant surgery to as low as 1% for breast reductions.  Simple lumpectomies are also likely very low risk. Oxygen therapy is likely not as beneficial in healthy patients undergoing routine breast surgery.
Lastly, This study looked at infections that occurred up to 30 days post operatively.  Interestingly, the 80% group had a median time of infection diagnosis of 16.9 days post op while the 30% groups had a diagnosis made at 13.9 days.  It is plausible to conclude that after 15 days post op infections at the site of surgery may arise due to factors not related to oxygen tension at the wound during the time of surgery.  While this theory has not been studies direclty, it is certainly likely.  Other well done studies where benefit has been demonstrated had a cut off of 14 days.  Interestingly, using the criteria of 14 days as a cut off would have dramatically altered the results of this study because the diagnosis of SSI would have occurred after the cut off period for a more of the patients in the 80% group.  Said in another way, it would have decreased the capture rate of infection in the 80% compared to the 30% group.
The metanalysis included the study by Pryor et al.  I believe this study should be excluded as the study was flawed.  The authors included sicker and more obese patients in the "high oxygen" group. 

Lastly, so far, all previous studies have compared high FiO2 (i.e. 80%) vs. low FiO2 (30%).  In reality, tissue oxygen tension is better correlated with PaO2 and even then not perfectly so particularly in obese patients.  Studies in populations with infection rates that average higher than 10% should be carried out, and the end points should be PaO2 with wound oxygen tension measurements as well.  Studies show that not all patients given a set FiO2 have the same PaO2. Furthermore, not all patients with the same PaO2 will have the same wound oxygen tension.   Since SSI rates vary based upon wound oxygen tension, it seems hazardous to attempt to draw conclusions about infection rate when varying only delivered oxygen concentration.
Studies looking at SSI are critical as SSI increase healthcare speding tremendously. However, SSI remain a bigger problem in certain subsets of patients undergoing certain types of surgeries.  It is important to determine if we can improve outcome with improving PaO2 (one step beyond FiO2).

1. Thibon P, et al. Anesthesiology. 2012; 117(3): 504.