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.

62 y/o female for breast reconstruction with daily marijuana use

 This morning my patient was a 62 year old female who uses marijuana daily.  She also reported to me that after a recent general anesthetic she experienced a two week period of amnesia immediately following her anesthetic. She stated that she performed all of her normal activities and that friend and family told her she behaved normally, however, she states that she has no recall of the events during these two weeks.

My anesthetic was a straight general endotracheal anesthetic using a propofol infusion for its benefits on PONV, and inhalation anesthesia to facilitate neuromuscular blockade during surgery as well as reduce the required propofol infusion dose.  I gave hydromorphone 2 mg up front with 2 mg of versed. I also gave 4 mg of decadron as we rolled to the OR. I placed a BIS monitor to evaluate her EEG in real time as well as her BIS.  I was particularly motivated to avoid burst suppression given her recent history of memory loss after anesthesia.  I suspected that perhaps the patient had developed some mild post operative delirium (POD), and increasing frequency of burst suppression during anesthesia is associated with increased rates of POD.

On induction, I gave the patient 110 mg of propofol. I noted that the BIS quickly went to about 20 and the burst suppression ration (BSR) increased to nearly 40%.  I was also able to note a flat EEG indicating burst suppression.  This indicated immediately to me that the patient likely had a vulnerable brain.  Therefore, I immediately planned for a lower setting on the sevoflurance concentration and propofol infusion. I titrated the sevoflurane to an ET% of 0.9 (MAC 0.4) and propofol of 75 mcg/kg/min.  However, with more time, her BIS recovered but then drifted lower.  I titrated the propofol infusion down to a minimum of 30 mcg/kg/min with the SEVO at 0.5 MAC (age adjusted).  At this level the BIS hovered  near 40 with BSR remaining at 0.  Due to the very low anesthetic dose I was providing I opted to give 5 mg vecuronium with small intermittent doses to reduce the chance of sudden movement. In fact, prior to incision and no stimulus to the patient and the BIS reading 39, the patient began coughing spontaneously. This highlights the fact that a BIS of 40 will NOT prevent patient movement during surgery.  This event prompted me to decide to maintain some degree of paralysis.  In my previous post on POD, I cited a study showing that the incidence of POD was decreased when the BIS was titrated to 50 vs. a BIS of 35.  I would emphasize that the patient's heart rate and blood pressure all remained suppressed but WNL during induction and the entirety of the case and did not seem to be entirely associated with her BIS level.

This patient was a daily marijuana user.  Marijuana is smoked for its THC content, which is an agonist at both the endocanabinoid 1 and 2 receptors. The CB1 receptor is found in the CNS. CB 1 receptors seem to primarily modulate pain, memory, and energy metabolism.  CB 2 receptors are located in both the CNS and immune cells and modulate the immune signaling as well as the inflammatory response. CBD also has actions on the 5-HT1a receptor (serotonin) in the CNS and platelets resulting in its anti nausea effects.  

Acute Marijuana use (canabinoid intoxication) results in a number of effects. These include tachycardia and vasodilation. In patients with CAD, this has resulted in increased incidence of angina and even MI (via demand ischemia).  Typically these affects resolve after 1 hour from canibinoid use.  Nevertheless, in a large retrospective review of over 27,000 records, the active cannabinoid users had increased odds of experiencing a myocardial infarction in the preoperative period.  Bronchodilation with hyperreactivity of the airways is also associated with acute cannabis use.  In the CNS, cannabis use causes anxiolysis or anxiety, paranoia or even frank psychosis, euphoria, dizziness, headache, memory dysfunction and analgesia. Furthermore, in young users the risk of stroke compared to tobacco smokers was 4.7 times higher.  This effect may be a result of the vasoconstriction effect on cerebral vessels of cannabis when hypoxia or hypercapnia is present. Furthermore, prolonged heavy use of cannabinoids results in hippocampal thinning and neuronal death. Acute cannabis use can also be an antiemetic as well as increasing appetite. Chronic daily users may see increased atheromatous disease, COPD or emphysema, and some may experience increased nausea and vomiting (hyperemesis).  In patients experience hyperemesis, severe abdominal pain is often an accompanying symptom. 

Typically chronic marijuana users presenting for surgery are stopping their use prior to arrival.  This presents the anesthesiologist with the possibility of withdrawal symptoms. Withdrawal symptoms include irritability, anger, aggression, anxiety, nervousness, insomnia, disturbed dreams, restlessness, depressed mood, anorexia, abdominal cramping, tremors, sweating, fevers, chills and headache. This withdrawal syndrome can last for several weeks in high dose chronic users.

Cannabis use and its effects on anesthetic requirements in humans have not been well studied.  In one study on admitted cannabis users demonstrated that they required significantly higher propofol doses than non users to achieve a BIS of < 60.  In another study, patients given a synthetic THC during a general anesthetic resulted in an increase in the BIS. From this study, it was not clear whether the increase in BIS represented a lightening of anesthesia, or the effects of the cannabis on the processed EEG.  Despite these studies, in my patient, it was clear that a small propofol dose had a profound effect on her BIS. Perhaps this is reflective of the effects of prolonged chronic cannabis use on the brain.  Unfortunately, we have no well done studies to establish this.  Nevertheless, I believe that given her reaction, it is at least prudent to be alerted to this possibility in older chronic daily marijuana users.  This may be a relative indication to place a pre induction BIS monitor on for better titration of induction agents.

Recently, during another case where I was working with a CRNA, we had a patient who used marijuana with some frequency.  The CRNA stated that the patient was at risk from aspiration and should be treated as if they were a "full stomach"; i.e. RSI with endotracheal intubation to prevent aspiration.  In a recent search of the literature, I was able to find a case report where a patient who was a heavy chronic marijuana user having an elective surgery with LMA, vomited during surgery and required emergent RSI intubation during the surgery.  The providers placed an OG tube and suctioned out 600cc's of gastric content.  In this article, the blame for the patient have gastric contents was placed on his use of marijuana.  In some cases, marijuana is associated with a hyperemesis syndrome. However, it is not clear that this is due to delayed gastric emptying, but rather results from cannabis effects on the vomiting center of the brain.  In 2023, an RCT was published where cannabidiol was used to treat patients with gastroparesis.  The authors were able to show in these patients that symptoms improved with cannabidiol.  Whether cannabinoids can decrease gastric emptying, it seems unclear.  Therefore, in patients with heavy cannabis use, it seems prudent to question them to determine if they have trouble with early satiety, nausea, vomiting or repeated belching and reflux.  If they are free of any of these symptoms, there is no evidence that heavy chronic cannabis users need to treated as if they have a full stomach.

With regards to intraoperative analgesia, again there are no well done studies to guide us. However, recent studies do indicate that cannabis users report higher pain scores, have worse sleep, and require more rescue analgesics in the immediate post operative period. Studies on cannabinoid agonists have shown that they facilitate endogenous opioid signaling and increase concentrations of endogenous opioids. In animal studies cannabinoids and opioids are synergistic 

Ketamine induces endogenous cannabinoid release which may partially explain its role in an anti-nociception.  However, the psychomotor side effects of ketamine are enhanced with CBD administration.  It also appears that gabapentin and cannabinoids act synergistically both acting in similar manner as activation of CB receptors results in inhibition of the voltage dependent calcium channel similar to gabapentin.  Thus care should be taken when gabapentinoids are part of an ERAS protocol and the patient is a heavy cannabis user.

In summary, patient coming to surgery who are chronic heavy users of marijuana seem to be at increased risk of perioperative strok and MACE.  Fortunately, the 1/2 life of THC is rather short, and therefore, it is unlikely that patients presenting for elective surgery will be directly affected by high levels of cannabinoids. However, it is well documented that acute cannabis intoxication will likely result in tachycardia with vasodilation, placing these patients at potential risk for hemodynamic instability. At this time it is unclear if chronic heavy users of cannabis have higher anesthetic requirements, although some studies suggest this.  In this case report, the patient have very low anesthesia requirements, and in fact, processed EEG monitoring suggested the patient had a vulnerable brain, driving me to significantly titrate down the anesthetic level to avoid post operative delirium.

1. Zheng T, BouSaba J, Taylor A, Dilmaghani S, Busciglio I, Carlson P, Torres M, Ryks M, Burton D, Harmsen WS, Camilleri M. A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis. Clin Gastroenterol Hepatol. 2023 Dec;21(13):3405-3414.

Surgery and post op delirium

 Recently, there have been more articles published on post operative delirium (POD) in the anesthesia literature.  The ASA has added additional training related to this topic as we become more aware of the significant consequences of post operative delirium in our aging population.  We have learned that those who experience POD will likely see an increased duration of hospitalization of two to three days.  In addition, it has become apparent that POD is associated with 30 day mortality of 7 to 10% vs. only 1% in those without POD.  Other associated consequences include increased healthcare costs, increased likelihood of requiring longer term nursing care and significant functional decline.

Furthermore, much research into this topic has identified several factors that increase the risk for POD. Among the largest risks include patients with preexisting neurocognitive disorders, elderly patients, those undergoing complex and prolonged surgery or emergency surgery especially if requiring post operative ICU admission. A simple scoring tool has been developed and validated named the delphi score to help identify patients at 'high' risk for POD. I have listed the items considered in this scoring tool to place patients at higher risk to provide further guidance on factors increase risk in our patients.

• age > 70, 1 pt age > 80 2 pts
• Needs assistance for physical activity - 2 pts
• heavy alcoholism - 1pt
• hearing impairment - 1pt
• history of delirium - 2 pts
• Emergency surgery - 1 pt
• Open Surgery - 2 pts
• ICU admission - 3 pts
• C reactive Protein - >/= to 10 mg/dL

Any patient with greater than 7 pts on this scoring system would be considered at high risk for POD (i.e. at least 80% incidence).

Our understanding of POD has also increased over the last several years.   For example multiple studies have found that POD is associated with increased levels of inflammatory markers such as CRP and IL-6. It has been shown that with peripheral trauma, there is damage to the BBB resulting in leakage of inflammatory modulators into the CSF.  Alteration of neurotransmitter balance has also been associated with POD.  For example Ach is thought to be involved in neuroplasticity and is involved in several pathways responsible for attention and memory. Studies have also found that patients experiencing POD had lower levels of acetylcholinesterase both preoperatively and up to two days post operatively.  Also, it has been found that low levels of acetylcholinesterase was an independent risk factor for developing POD.  In addition, central acting anticholinergic medications have also been associated with increased incidence of POD. In addition, there is some evidence that non optimized perioperative perfusion pressure of the brain may be associated with increased frequency of POD.  It has been suggested that subclinical cerebral ischemia may manifest in the post operative period as delirium. This thesis is still being explored. What is clear, is that perioperative delirium can be mitigated by perioperative interventions over which we as anesthesiologist control.

A recent review of the literature on POD provided a list of interventions with evidence supporting benefit [1].  From this article is a list of preoperative interventions we can consider in at risk patients.

1. Avoid perioperative polypharmacy

2. Avoid prolonged fluid fasting (i.e. > 6 hrs)

3. Adequate and aggressive perioperative pain management

There are also intraoperative interventions we can take that have evidence supporting its ability to reduce the incidence of POD. From the same article these include:

1. Monitoring depth of anesthesia. In a meta-analysis it was reported that depth of anesthesia monitoring is associated with a significantly lower risk of delirium [3].  In Anesthesiology, a meta analysis of 13 RCT was published demonstrating that the OR for POD was 0.62 when processed EEG was used to guide anesthesia  [2]. In cardiac surgery three studies demonstrated that patients who had intraoperative burst suppression had an increased incidence of POD [4,5,6].  In a study specific to low BIS values in aortic surgery, it was shown that patients with a lower BIS were more likely to suffer from post op stroke, TIA, increased ICU length of stay, and increased incidence of POD [7]. In an RCT looking at non cardiac surgery patients experiencing cognitive decline both acutely (1 week) and prolonged (up to 1 year), found that significant cognitive impairment occurs after major non cardiac surgery in patients greater than 60 years old which can still be evident up to one year after surgery compared to aged match controls [8]. Importantly,  patients receiving the monitoring intervention were within the optimal BIS target range (40–60±5) for a significantly higher proportion of the intra-operative period and there was a significant relationship between the proportion of the intra-operative period spent in this optimal window and both cognitive outcome and S100B, a marker of brain injury [8]. This study prompted another study one year later (2013) which was an RCT  of BIS v. no BIS in major non cardiac surgery.  The study fount that in multivariate analysis, the percentage of episodes of deep anaesthesia (BIS values <20) were independently predictive for postoperative delirium (P=0.006; odds ratio 1.027). BIS monitoring did not alter the incidence of postoperative cognitive dysfunction, however [9].  In yet another study looking at elderly frail patients undergoing spine surgery, comparing those patients who had burst suppression on EEG it was found that the group that suffered burst suppression also had increased POD compared to the no burst suppression group.  This study also demonstrated that elderly frail patients were more likely to have burst suppression during surgery [10].  In another observational study, Fritz et al in 2016 [11] found that after adjusting for confounders using statistical methods, patients who who had greater degrees of intraoperative burst supression suffered increasing POD in a dose dependent fashion (greater time in burst suppression).  Importantly, the authors noted that increased volatile agents concentration AND lower opioid dosages both were predictive of greater burst suppression.  As part of this theme, Fritz et al. in the BJA were able to show that intraoperative processed EEG monitoring can allow the astute anesthesiologist to predict which patients are very likely to suffer from POD.  In a paper published in 2018 [26], they found that patients who suffered suppression at lower volatile anesthetic concentrations than there age calculated value would indicate are 2.6 times more likely to develop POD in ICU.

In yet another study, Chen at al. were able to demonstrated that implementation of BIS type monitoring dramatically reduced the incidence of POD in elderly patients. This benefit only became statistically significant in the cohort aged 75 years or older. For patients aged 60 to 74, there was only a trend showing improvement with BIS type monitoring [12].  In a particularly interesting RCT study patients aged 50 or older undergoing major surgery were targeted to a BIS of 50 or 35.  The group targeted to a BIS of 35 had an increased incidence of delirium (57% v. 34%; p=0.009 OR=0.53).  Importantly, in this same population, those who experienced POD, experienced other negative outcomes including: increased unplanned ICU admissions, increased hospital stay, and higher post op MI rate.  They also did a sub analysis of time in burst suppression and found that time in burst suppression was significantly longer in those who went on to experience delirium and those who experienced delirium had an higher mortality rate at one year (12% v. 6%). It should be noted that this trial differed from the results of the ENGAGES trial that randomized patients 60 years and older to BIS guided v. non BIS guided anesthesia for major surgery and did not find a statistically significant difference in POD.  This is likely due to the fact that the difference in MAC of the volatile anesthetics between groups was similar (difference of 0.11 MAC). Other studies have shed light on depth of sedation and its correlation to incidence of POD.  Sieber et al. [14] found that in hip fracture patients (high risk for POD), using a BIS targeted light sedation during spinal anesthesia did not decrease incidence of POD compared to deeper sedation. The BIS was on average 82 in the light sedation group vs. 57 in the deep sedation group.  Two takeaways from this study that inform our practice today are the following: 1) both groups had a BIS greater than 50 which may represent a threshold above which no further improvement can be achieved. 2) the subset of patients in this study with lowest co morbidity had a 2.3 fold increase in POD in the deep sedation group. This suggests that in very frail patients that also have significant co morbidities have such a high baseline risk for POD, that reducing BIS may provide little protection. 

To utilize processed EEG to inform us in the OR on our patients risk for POD, it is important to spend a little time understanding how the EEG is affected by different brain states.  In particular, as the brain ages the component of the EEG that makes up what are called alpha oscillations is decreased.  It has been well established that decreasing alpha oscillations is typical of older brains and as the degree of alpha oscillations are depressed, you see increased risk of POD.  Additionally, younger patients with a vulnerable brain (by trauma, disease, etc) can be identified by a decrease in alpha power on spectral array and mimicks the aged brain in many way.  It is well known that as alpha power falls, the chances of burst suppression increases.  Furthermore, in older brains, the component oscillations known as beta may be elevated.  This is a normal pattern in older brains, but on average can cause the processed EEG to read out a higher number by essentially fooling the algorithm.  In the BIS, the average increase in BIS reading for patients older than 70 is about 3.5 units on the BIS. In other words, if you have a 72 year old patient with a BIS reading of 40, on average, you can expect that the true BIS value is closer to 36.5.  Below is from a study where it was demonstrated that beta power is increased in elderly patients (>70 yrs) compared to younger patients which confuses the BIS algorithm.

In patients with dementia of various types, the EEG is heavier in delta and theta bands which also can confuse the BIS monitor by making it read lower by nearly 5 units than what is correct.  Placing the BIS monitor on the awake patient can demonstrate this effect prior to induction of anesthesia.

In standard commercially available BIS monitors, the suppression ratio is also provided. This number is not typically followed as closely as the BIS  in standard clinically practice. The suppression ratio represents  the percentage of time in the previous 63 seconds in which the EEG signal is considered suppressed. Suppression is recognized as those periods longer than 0.5 seconds, during which the EEG voltage does not exceed approximately ± 5 μV. Typically a period of suppression is followed by a burst of activity which varies depending on the anesthetic agent used.  For example Propofol produces bursts that are shorter in duration and of lower amplitude than volatile anesthetics. This "burst" of activity is the thalamus activating as it tries to kick start the cortex back into action.

This figure demonstrates a quirk in the BIS algorithm.  Essentially, if the suppression ratio is greater than 40%, then the BIS value displayed will drop 1 index value for every 2% increase in the suppression ratio.  In other words, there is a linear inverse relationship between suppression ratio and BIS value where as suppression ratio increases, BIS drops as a result.  However, if the suppression ratio is less than 40%, the displayed BIS value will not consider the suppression ratio in its algorithm and may be artificially high. An example is provided below.

This displays a BIS of 40, however, the raw EEG data on the display shows a rather flat line that looks depressed and the suppression ratio is 20%.  This would represent a patient who is most likely deeply anesthetized, far more than the BIS value of 40 might indicate.  In other words, when the BIS value reads between 30 and 40, it can represent a wide range of brain states. This is where looking at the suppression ratio becomes critical to better determine the state of your patient's brain. The take home is maintaining the BIS above 40 helps maintain the integrity of the data.  Additionally, shooting for a suppression ratio of 0 is also important.  If the the suppression ratio is less than 40% but greater than 0, the displayed BIS value is likely artificially high.

Also important to note is that burst suppression can be augmented by different agents. For example, the MAC burst suppression (MACbs) for ISO is 1.3 x MAC, while for Sevo it is 1.4 x MAC (i.e. patients would be more vulnerable to burst suppression when using iso v. sevo).  Propofol causes burst suppression at 4.9 mcg/mL, in 50% of patients, but requires 15.2 mcg/mL to inhibit movement in 50% of patients. This indicates that propofol is excellent at cerebral suppression (i.e. burst suppression), but very ineffective at suppression of spinal function.  

We should also recognize what clinical factors might put a patient at higher risk for suffering burst suppression.  The following are risks for increased likelihood of going into burst suppression:  Increasing age, particularly above about 60 years, coronary artery disease, and male sex. Of course significant co morbidities also place patients at risk as well as critically ill patients.  In  most patients it has been shown that below a BIS of 40, you start to run into problems with burst suppression.  However, given the above information, the cut off may change depending on clinical risk factors.  In relation to age, Besch et al. were able to demonstrate that when the BIS is maintained between 40 and 60 in patients greater than 80 years old, they are 10 times more likely to be in burst suppression than patients younger than 60 years old. Furthermore, patients 60 to  80 were nearly five times as likely to be in burst suppression as younger patients at the same BIS levels (i.e. BIS targeted to 40 to 60)  [27].

It should be noted that many events during an anesthetic can result in burst suppression. These include significant hypothermia, hypotension, significant anemia, hypoglycemia, hypoxia and vascular brain injury.

To summarize the various results from multiple studies it becomes clear that in at risk patients, particularly as the age approaches 70 years old, targeting a BIS of closer to 50 is likely to make a difference.  In otherwise healthy and younger patients (60 year and younger), targeted BIS is not likely to make a clinically significant difference in the incidence of POD.  In the highest risk patients, frail, elderly patients with hip fracture (or other major surgery) with significant co morbidities, targeting BIS to a higher level may have little impact on decreasing incidence of POD, however, it is unlikely to provide harm and thus, it would still seem reasonable to spend the money and effort on BIS monitoring. 

Processed EEG is also useful in our ability to recognize the vulnerable brain.  A vulnerable brain is one that may exhibit increased sensitivity to anesthesia or be more likely to develop problems after anesthesia.  A vulnerable brain may be present in other (atypical) patient populations such as those with a TBI, a significant brain tumor or even significant metabolic process or infection.  There is data to suggest that neurons in vulnerable brains have a lower mitochondrial production of energy substrate leading to lower electrical activity from decreased synaptic transmission. Since it is known that the alpha band (alpha power on spectral array analysis) is related to thalamocortical electrical activity and thus reflective of overall brain health, we can look at this specific band to diagnose the probability of the vulnerable brain.  During a propofol or volatile anesthetic, we should expect to see a clear "alpha band" that is stable.  When this alpha power is diminished from the expected value given the age of the patient, we should consider this an indicator of the vulnerable brain state. In this same vein, patients with low alpha power during the intraoperative power are known to have reduced cognitive function in the PRE operative period, and thus, again, lower alpha power is a significant indicator for higher POD risk in the post operative period.

2. Use of a multimodal opioid sparing analgesia. Multiple observational studies have demonstrated that increased pain scores after surgery are associated with increasing POD incidence and severity. Conversely, the use of post operative opioids particularly long acting opioids are also associated with increasing POD.  Therefore, controlling pain with non opioid methods is ideal in at risk patients.  Furthermore, two larger observational studies have been able to demonstrate a 20 to 40% lower incidence of delirium when regional anesthesia is used. Another important aspect of multimodal analgesia is the use of NSAIDs and tylenol.  In animal studies, NSAIDs have been shown to reduce neuroinflammation secondary  to cerebral ischemia-reperfusion, and neuroinflammation secondary to remote insults.   In another large observational study of more than 1 million surgical patients, parecoxib was associated with a significant reduction in POD.  Paracetamol was shown to reduce the risk of POD from 28% to 10% (NNT=5.6) in cardiac surgical patients.

Also part of multimodal analgesia is dexmedetomidine; a highly selective alpha 2 adrenoceptor agonist. In animal models dexmedetomidine administration reduced the expression of inflammatory mediators, microglial activation and neuroapoptosis. Wang et al. [15] conducted a meta-analysis of 67 studies, and found that intraoperative dexmedetomidine was associated with decreased concentrations of stress hormones (cortisol, epinephrine), CRP, and TNF-Alpha after surgery.  Duan and colleagues [16] conducted a meta-analysis of 18 clinical trials and found that intraoperative and post operative dexmedetomidine administration significantly reduces the risk of POD (OR 0.35). Several recent clinical studies have followed and also demonstrated an improvement in POD with intraoperative dexemedetomidine [17, 18, 19].   Another meta analysis was published by Zeng et al. [20] showing that dexmedetomidine could reduce the incidence of POD in elderly patients after non cardiac surgery with a NNT=10.

3.  Avoidance of certain medications in perioperative period

Today, most institutions have instituted a pre formulated pathway to enhance recovery from surgery.  Known as ERAS, institutions and many surgeons have jumped all in to this paradigm.  ERAS calls for a multitude of things including perioperative multimodal analgesia.  Many ERAS multimodal regimens at most institutions are pre determined and fixed as a one size fits all formula.  This has unintended consequences in some cases.  As a case in point, gabapentin is often given pre op by the pre operative nurse prior to any one evaluating the patient risks and benefits of this medication.  This is largely because the orders are presriptive and come from the surgeons office.  As a result many elderly and frail patients will receive a cocktail of medications orally in the pre op holding bay usually including between 600 mg to 900 mg of gabapentin.  However, a large observational study has reported that perioperative gabapentinoids are associated with a slightly increased risk of of POD [21]. 

Scopolamine is an anticholinergic anti emetic.  There have been several case reports of scopolamine-induced delirium in the perioperative setting and several expert guidelines have recommended against its use in older patients. 

4. Choice of general anesthetics (volatile agents vs propofol)

Miller and collegaues conducted a meta analysis and identified five relevant studies and found no difference between propofol and volatiles anesthetics in the incidence of POD [22].  Furthermore, xenon is considered to have neuroprotective properties due to its ability to inhibit neuroinflammation and apoptosis.  However, when compared to xenon, sevoflurance is non inferior in terms of the incidence of POD. This provides support to the idea that volatile anesthetics are likely not inferior to propofol.  Currently, at my institution, there is a widely held belief that in any patient who is elderly and therefore, at percieved risk for POD, propofol TIVA is the anesthetic of choice.  However,  in one RCT, Mei and colleagues compared propofol to Sevoflurane [23], and found  that the incidence of delirium was less in the Sevoflurane group compared to propofol, but the difference did not reach statistical significance.  In another RCT comparing propofol to Sevoflurane when combined with an epidural for anesthesia for intraabdominal laparoscopy, patients in the propofol group had worse scores on the delirium rating scale used to evaluate the patients compared to Sevoflurane [24]. Nevertheless, there have been several retrospective and prospective observational trials showing that patients receiving propofol had a lower incidence of POD.  Recently (2021) in Anesthesiology, a paper was published to address the problem with previous poorly done studies comparing propofol to volatile anesthetics to reduce POD.  In this regard a large multicenter RCT was performed where all aspects of POD were carefully considered to reduce confounding influences.  In this large RCT, there was no difference in the incidence of post operative cognitive dysfunction between propofol and sevoflurane in at risk patients having abdominal surgery [25].  However, the authors did note that elevated IL-6 at one hour after incision was predictive of patients who would go on to develop post operative cognitive dysfunction confirming previous evidence that neuroinflammation plays a large role in POD.  Given the above literature, in summary, one can conclude that lower quality studies with small numbers of patients have shown conflicting results. However, in larger and higher quality studies, there is no difference or sevoflurane is preferred to propofol to reduce POD.

In summary, POD occurs frequently in certain patient populations. Anesthesiologists are becoming more aware of this problem.  While much of the risk for POD cannot be mitigated by modifying our clinical approach, we have gotten much better at identifying which risk factors are modifiable.  It appears that one of the larger risk factors relates to over dosing of anesthetics leading to significant time under burst suppression.  Better education on the use of intraoperative processed EEG can help us avoid burst suppression or at least reduce the time under burst suppression.  Avoiding polypharmacy, aggressive use of regional anesthesia in appropriate cases, and the addition of multimodal analgesia (especially with precedex) are other important factors to be considered when attempting to reduce POD in at risk patients.  

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