Section 4: Patient Management Considerations

INTRODUCTION

Regional anesthesia is best practiced in the context of a standardized anesthetic and surgical protocols; these plans are generally referred to as anesthetic pathways. For a patient having surgery that uses an anesthetic pathway, many of the decisions about the patient’s care are made not at the bedside in the immediate preoperative period, but instead long before the surgery by carefully considering the risks and benefits of various anesthesia and perioperative treatment options.

When well designed, anesthetic pathways can improve patient care by ensuring that patients receive consistent, coordinated, evidenced-based care. They can also reduce costs by eliminating unnecessary interventions and reducing complications. Of course, pathways should not be indiscriminately adhered to as some patients will require modification to atone for specific medical conditions or patient preferences. Regardless, anesthetic pathways allow clinicians to focus on the unique characteristics of a patient instead of the common characteristics of an entire cohort, which were already examined during pathway development.

At their core, anesthetic pathways (or clinical pathways in any field) are a series of medical decisions. As leaders of the perioperative surgical home, anesthesiologists are best suited to lead their design. There are often many subtle issues that arise in the development of a pathway that may not be familiar to anyone other than a clinician who is frequently and personally involved in patient care. In addition, anesthesiologists’ working relations with surgeons, administrators, and the entire operating room team are paramount in development and success of patient pathways. Interspecialty coordination is vital to the successful development of anesthetic pathways. Anesthetic decisions will frequently affect patients’ ability to rehabilitate in the immediate postoperative period, so anesthetic and surgical pathways must be designed by a team effort.

Because there is evidence that use of regional anesthesia may affect the mortality and morbidity^1,2,3,4,5 of common surgeries, and because pain control in the postoperative period is often challenging, regional anesthesia (either neuraxial or peripheral block) is often a key feature of anesthetic pathways. Therefore, development of pathways is of particular interest to practitioners whose clinical practice includes regional anesthesia.

Designing and implementing clinical pathways require skills often not taught during residency training. Physicians tailor their treatments with the unique characteristics of each patient in mind. This is related to physician training designed to elicit and synthesize data for a specific patient. Clinical pathways, in contrast, must be designed to optimize the average experience of a cohort of patients, often making trade-offs and compromises in the process. Knowledge of epidemiology and statistics are vital to effective clinical pathway design. Numerically estimating probable outcomes, and choosing those that rate most favorably, is central to the development of the pathway.

Benefits of an anesthesia pathway will of course depend on the peculiarities of the pathway itself, the institution, the surgical and anesthetic techniques, and the other health-care providers using the pathway (such as nursing care, physical therapy, etc.). A pathway designed for one institution may not be appropriate for another institution, which is why in this chapter we have chosen to emphasize the process of pathway development instead of presenting specific pathways. Furthermore, the goals of an anesthetic pathway may vary—some pathways may be designed to reduce morbidity or mortality, while others may be focused on reducing cost while maintaining a high level of patient care. Common goals of an anesthetic pathway include reducing in-hospital morbidity and mortality, reducing length of hospital stay, reducing costs, improving patient satisfaction, reducing readmissions, and improving long-term functional outcomes.

Despite this heterogeneity, there is evidence that, generally speaking, clinical pathways improve patient care. A recent meta-analysis of clinical pathways found that they were associated with lower rates of patient complications (eg, wound infections, bleeding, and pneumonia), as well as improved documentation.⁶ Most of the studies included in the meta-analysis also showed a reduction in the length-of-stay and hospital costs without increased risk of readmission rates and mortality. However, it is possible that some clinical pathways actually could improve these outcomes as well. The considerable heterogeneity of successful clinical pathways has not allowed investigators to identify features common to successful (or unsuccessful) clinical pathways.⁶ Nevertheless, basic principles of risk management may be deployed to aid in the design of clinical pathways, and developing a reusable, common framework for approaching clinical pathways seems likely to increase the probability of success.

In this chapter, we present a framework for developing clinical pathways and review some of the prerequisite knowledge required for this process. We also present case scenarios that illustrate the subtleties in applying existing medical literature to clinical pathways. Finally, we present components of a surgical pathway for total knee arthroplasty.

FRAMEWORK FOR ANESTHETIC PATHWAYS

An example of a single component of a clinical pathway is shown in Table 15–1. This is a component of a larger pathway for total joint arthroplasty, which is further discussed in the final section of this chapter. This component describes the standard oral premedications for the surgery and contains specific information about dose, common contraindications, and common additions to the pathway that may be needed for some patients. Although developing a clinical pathway often involves lengthy analyses with uncertainties, final pathway elements should be brief and specific. Besides recommended premedications, pathways may have many different elements; for example, see those shown in Table 15–2.

It should be noted that although the pathways developed by anesthesiologists are primarily concerned with the anesthetic management of the patient, they are designed to dovetail with the corresponding surgical pathway. For example, the choice of regional anesthesia may allow the patient to complete physical therapy on postoperative day 1.

A process for developing clinical pathways is shown in Figure 15–1. This process consists of the following:

1. Identifying the goals of the pathway and different treatment options to help achieve those goals. This should include all stages of anesthesia and surgery, including postoperative recovery.

2. Identifying ways in which each treatment interacts with the others (eg, the type of regional anesthesia may affect the patient’s ability to perform physical therapy postoperatively, premedications may delay discharge due to sedation).

3. Identifying possible risks, costs, and benefits of each treatment, including mortality, morbidity, patient satisfaction, institutional capabilities, financial cost, and other factors.

4. Making numerical estimates of the risks, costs, and benefits identified in step 3. Some of this information (eg, information on cost) can be gathered and tabulated. However, most of the information cannot be known with any certainty. In many cases, the medical literature can provide estimates of the probabilities involved, as long as the physician understands the limitations of a particular study.

5. Use the estimates developed in step 4 to develop probable outcomes and worst-case and best-case scenarios for each pathway.

6. Choose the pathway most likely to benefit the patient based on step 5.

7. Continually refine the estimates of the risks, costs, and benefits as new information becomes available and refine the clinical pathways.

If we could quantify the risks and benefits of each intervention as easily as we could quantify the financial costs of procedures and equipment, steps 4, 5, and 6 would be trivial. However, this is rarely the case. In many cases, there may be not adequate published data to guide the process. Sometimes, there may be some incongruity between available studies and the desired information—the only studies available may have been done on similar, but different, patient populations; have analyzed similar, but different, surgical procedures; or may describe interventions that you cannot exactly replicate at your institution. Nevertheless, the closest match to one’s institutional conditions can be used to estimate probabilities used in step 5.

Another risk to consider includes those complications that may not manifest until well after the treatment period. For instance, recently introduced drugs, procedures, or therapies by definition will have unknown long-term risks. Recognizing the limitations of the existing evidence for each intervention in the literature is crucial in protocol development. Although inferential statistics enhances a physician’s judgment beyond what can be achieved simply by relying on their historical personal observations, unfortunately any given study may have unforeseen biases that may make the study less than an ideal guidance for the protocol being developed. As such, when developing “worst-case” and “best-case” scenarios, one needs to take into account the possibility that a study has made a type I or (more commonly) a type II error.

REVIEW OF STATISTICAL CONCEPTS RELEVANT TO THE DEVELOPMENT OF ANESTHETIC PATHWAYS

A good analogy for the role of statistics in enhancing clinician judgment is comparing it to the role that a magnifying lens plays in enhancing vision. Drugs or interventions that have large, consistent effects (eg, the effect of insulin on glucose or epinephrine on heart rate) can be easily appreciated by the clinician without any sort of corroborating study, just as a magnifying lens is generally not necessary to see frank pus in a wound. Likewise, a study that is underpowered may be unable to detect subtle effects, just as a simple hand lens is not powerful enough to image individual bacteria. While few clinicians would attempt to diagnose a bacterial infection with only a magnifying glass, clinicians frequently make the error of assuming that a reported negative result is synonymous with no effect, without considering the limit of detection of the study. Rare but catastrophic complications are of particular concern as extremely large numbers of patients may be required to properly power a study.

A statistical test may report either that observed data are consistent with random chance (the null hypothesis, a “negative” result) or reject the null hypothesis and assert that there is an association between a treatment and an outcome (a “positive” result). In reality, there may or may not be an association between a treatment and an outcome. There are therefore four possibilities for any statistical test, two of which involve drawing the correct conclusion, and two of which are errors. These are traditionally shown using a 2 × 2 table as shown in Table 15–3.

The two types of possible errors are a type I error (alpha), which involves incorrectly concluding that an association exists when one does not, and a type II error (beta), which involves incorrectly concluding that no association exists when in fact one does. Obviously, the probabilities of making the two types of errors are related. Imagine a statistical test that always asserts there is an association between the treatment and outcome, regardless of the data. This technique will frequently make type I errors but will never make a type II error (because it never asserts a negative result).

By convention, statistical tests compute the probability that a set of data is due to random chance (the p value) and if this is below some fixed threshold (alpha), the notion that the data are due to random chance is rejected. Generally, a confidence interval is reported as well. When alpha is fixed, most commonly at 0.05, beta will be a function of the other features of the statistical test. One of the simpler formulas relating alpha, beta, change in mean, standard deviation of the data, and sample size is shown in Equation 15–1. Equation 15–1 describes power relationships for a test of a large sample of a continuous outcome variable in a single population with known mean and standard deviation:

where n is sample size, σ is sample standard deviation, μ is the sample mean, μ₀ is the population mean, ES is effect size, and Z is the Z-score corresponding to the value in subscript. Different statistical tests (eg, t tests for continuous variables, t tests for proportions, χ² tests, analysis-of-variance [ANOVA] tests, etc.) will have somewhat different formulas for beta, but in general beta (and hence the probability of a type II error) will decrease with larger sample sizes, less-restrictive choices of alpha, smaller standard deviations in the data, and larger effect sizes.

Statistical power is simply 1–β and is more frequently referenced than β. While alpha is most commonly fixed at 0.05, a statistical power of 0.8 is generally considered adequate for detection of associations, although in some cases⁴ this is increased to 0.9. Unfortunately, while the choice of alpha is almost always explicitly stated in a publication, it is often left to the clinician to infer the power of the study, particularly for secondary outcomes. Fortunately, formulas such as Equation 15–1 can be readily found in common textbooks or in statistical software packages. In addition, many academic statistics departments have made online tools available to calculate statistical power (eg, References 7 and 8). Formulas such as Equation 15–1 can be used to calculate the smallest effect size that a particular study is likely to detect. It then falls to the clinician to decide whether this effect size is small enough that smaller effect sizes are clinically irrelevant. If smaller effect sizes are still clinically relevant, then the clinician developing a pathway needs to take into account the possibility that there is a small but real effect size, a type II error was made, and adjust the best- or worst- case scenarios accordingly.

EXAMPLES OF PATHWAY DEVELOPMENT

We now provide a few illustrative examples of the analysis discussed previously. First, we present a case scenario that illustrates the type of analysis described. Then, we review some examples of drugs that were introduced to routine surgical protocols that caused patient harm; this illustrates pitfalls in pathway development. Last, we present components of a pathway for total knee replacement.

Illustrative Case: Adjuvants to Spinal Anesthesia

Suppose a novel drug (drug X) has been developed that increases the duration of spinal anesthesia when added to bupivacaine. Your group performs total hip and knee arthroplasty under spinal anesthesia but occasionally has to convert to general anesthesia due to unexpectedly long surgical times. The total joint pathway currently uses bupivacaine-only spinals but is considering adding drug X to the total joint pathway to prolong the length of spinal anesthetic and reduce unexpected conversions to general anesthesia.

An initial study compared spinal anesthesia with bupivacaine versus drug X plus bupivacaine, with 500 patients in the treatment group and 500 in the control group. The study found that spinal anesthesia with bupivacaine provided adequate surgical anesthesia only for 180 minutes, while bupivacaine with drug X provided adequate surgical anesthesia for 200 minutes (95% CI 195–205 minutes, p < .05). Secondary outcomes included incidence of vomiting on postoperative days 1–3 and urinary retention requiring Foley catheterization. In the control arm, 3% and in the treatment arm 4% of patients vomited postoperatively, but this result was not statistically significant. In the control arm, 2% and in the treatment arm 3% of patients had urinary retention; however, this was also not statistically significant. The drug costs $50 per dose.

Analysis of Costs and Benefits

Even for a relatively simple (and contrived) question such as this, a complete analysis can become complex. We therefore present an abbreviated version of the procedure:

1. Identify goals and treatment options. We limit ourselves to the goal of lengthening spinal anesthesia to reduce conversions to general anesthesia. Alternatives to the inclusion of drug X should be explored. Drug X must be evaluated not in a vacuum but instead in competition with other techniques. For example, other drugs may be available that lengthen spinal anesthesia for a comparable time, or simply increasing spinal dosage may be feasible to lengthen surgical anesthesia. Alternatively, the subpopulation likely to have longer operative time may be identified, and these patients could automatically receive general anesthesia or drug X could be reserved for them only. The risks and benefits of each of these options must be individually considered and compared with the routine use of drug X.

2. Identify ways each treatment interacts with the rest of the pathway. Although no restrictions were mentioned, we would need to confirm that the use of drug X does not require special postoperative monitoring (such as continuous pulse oximetry), an alteration in nursing care (such as changing fall precautions), or change in physical therapy (such as delaying mobilization) or require alterations to other parts of the anesthetic and surgical pathway. If any restrictions or interactions are identified, they must be accounted for in step 3.

3. Identify risks, costs, and benefits. For this illustration, we restrict the analyses to the risks, benefits, and costs alluded to in the study. The primary benefit would be increased duration of surgical anesthesia and a reduced need to convert to general anesthesia, which of course carries a number of attendant risks and costs. The risks include increased risk of urinary retention and postoperative vomiting. Although the initial study did not link either of these outcomes to drug X, we shall see in step 4 that the worst-case scenario must include the risk that this study made a type II error. The costs are easiest to quantify: This will add $50 in drug costs to each surgery.

4. Make numerical estimates of the risks, costs, and benefits identified in step 3. The benefits of this drug will depend on the specifics of your institution. For example, suppose in reviewing your records, you find that you performed 500 total joint arthroplasties in the past year, and 5 of them required unexpected conversion to general anesthesia. The total surgical times for the five cases were 195, 250, 200, 190, and 220 minutes. Using the published confidence interval, use of drug X may have eliminated need to convert to general anesthesia in 2 of the cases (if it lengthens time to 195 minutes) to 3 of the cases (if it lengthens time to 205 minutes).

   The costs of this drug, if used on all patients, would be an extra $25,000 annually. If a high-risk subpopulation could be identified for use of the drug, this could potentially be reduced.

   The study found no link between urinary retention or postoperative vomiting with drug X, so in the best-case scenario, adding drug X does not introduce any new risks of complications. However, let us consider the power of this study. Presumably, the data on urinary retention and postoperative vomiting were analyzed using a t test for proportions.

   Using online power calculators or statistics packages,⁶ we can estimate the effect size that would be detected. Assuming a baseline rate of urinary retention of 2% (based on the control arm of the study), the drug would need to increase the rate to 5%–6% to achieve a power of approximately 0.8. Effect sizes lower than this will not be reliably detected. For postoperative vomiting, a power of 0.8 corresponds to the drug increasing the rate of vomiting to 7%.

   If rates of postoperative vomiting and urinary retention more than doubled, most clinicians would consider that a clinically relevant increase, but it would not be reliably detected by the study discussed. Therefore, we must consider the possibility that the study made a type II error and adjust our worst-case scenario appropriately.

   If the study did make a type II error, what should we use for our estimates of effect size? The most reasonable estimate can be obtained by examining the study itself; as subjects are added, the rates converge toward their true values and eventually may cross a threshold of statistical significance. In the study discussed, postoperative vomiting was 3% in the control arm and 4% in the treatment arm, and urinary retention was 2% in the control arm and 3% in the treatment arm. We can use these increases to inform our estimates.

   Assuming that our institution has similar rates of vomiting on postoperative days 1–3 (3%) and similar rates of urinary retention (2%), we would estimate that they would increase to 4% and 3%. With a surgical volume of 500 patients per year, this corresponds to 5 extra cases of urinary retention and 5 extra cases of postoperative vomiting per year.

5. Use the estimates to construct best- and worst-case scenarios. Best case: Eliminate three conversions to general anesthesia per year. Add $25,000 to health-care costs. Worst case: Eliminate two conversions to general anesthesia per year. Add $25,000 to health-care costs. Create five extra cases of urinary retention and five extra cases of postoperative vomiting.

   In this particular case, we note that the benefits of the drug may be improved if we can accurately identify a subpopulation likely to benefit. For example, if the drug is only given to the 10% of patients with the highest risk of long surgical times, both the cost and the morbidity associated with postoperative vomiting and urinary retention would decrease by a factor of 10. If the subpopulation is accurately identified, the number of general anesthesia conversions may be unaffected or minimally affected.

6. Choose the pathway most likely to benefit the patient. Depending on the risks involved in conversions to general anesthesia, this drug may or may not be worth adding to the anesthetic pathway. Ultimately, clinical judgment is required to make a decision. However, by using the framework discussed, the clinician is significantly better informed than if the clinician simply made a decision based on intuition alone.

7. Continually refine the estimates of risks, costs, and benefits. In this scenario, the institution’s annual surgical volume (500) is equal to the number of patients involved in each arm of the study. Given this, if the institution tracks its own complication rates before and after the change, it should be able to quickly ascertain the true risks, benefits, and costs of the intervention and make a more informed decision than the initial analysis.

   Surprisingly, it is often the case that the number of patients enrolled in studies in the published literature is much smaller than the number of surgeries performed at even small institutions. For example, a recent meta-analysis on the effects of spinal opioids only included approximately 100–150 subjects and controls for an analysis of postoperative vomiting and urinary retention for intrathecal fentanyl, despite the long and widespread use of fentanyl in spinal anesthesia.⁹ Because of this, analysis of internal data is often helpful in evaluating pathway success or failure. Use of internal data also sidesteps the problem of published studies using slightly different patient populations, drugs, or techniques than used at the home institution.

EXAMPLES OF PATHWAYS THAT CAUSED PATIENT HARM

The previous section was a hypothetical illustration of the development of one part of a pathway. In this section, we take a moment to discuss historical instances in which patient harm resulted from the introduction of a new drug as part of routine perioperative care. Although these drugs were introduced before the notion of surgical and anesthetic pathways became common, the experience with these drugs provides insight into some of the hazards of applying new treatments to large patient cohorts.

Enoxaparin and Venous Thromboembolism Prophylaxis

Enoxaparin was the first low molecular weight heparin approved by the United States Food and Drug Administration for general use. Shortly after the drug’s approval in May 1993, it entered widespread, routine use as prophylaxis for venous thromboembolism. Because many orthopedic surgeries, including total joint arthroplasty, pose a high risk for venous thromboembolism, and epidural or spinal anesthesia was frequently the preferred anesthetic for these cases, enoxaparin was often used in conjunction with neuraxial anesthesia.

Prior to the development of enoxaparin, unfractionated subcutaneous heparin had been widely used for venous thromboembolism prophylaxis. While the risk of epidural hematoma associated with enoxaparin administration was felt to be comparable to that of subcutaneous heparin administration initially, the pharmacological differences between low molecular weight and unfractionated heparin had been underestimated.¹⁰

Shortly after introduction, the US Food and Drug Administration began to receive reports of epidural hematoma associated with enoxaparin administration. In December 1997, the administration issued a public health advisory stating that it had received over 30 reports of postneuraxial epidural hematoma associated with enoxaparin and required that enoxaparin carry a black box warning indicating significant risk of patient harm.¹¹ By April 1998, the number of reports had increased to more than 40.^10,12 The United States Food and Drug Administration approached the American Society of Regional Anesthesia and Pain Medicine to develop new guidelines for use of enoxaparin with neuraxial anesthesia. These guidelines were published in November 1998 and recommended much more conservative use of enoxaparin.⁸

Aprotinin and Reduction of Perioperative Transfusions

Aprotinin is a small peptide molecule that acts as an antifibrinolytic by inhibiting trypsin and related proteolytic enzymes. It was used most commonly in cardiac surgery^13,14, where it was shown to significantly reduce transfusion requirements, and its use was investigated in other types of surgeries, such as orthopedic procedures.^15,16 Although one meta-analysis showed no increased risk of mortality, myocardial infarction, or renal failure,¹⁷ large observational studies^18,19 contradicted these findings and demonstrated an increased risk of postoperative renal failure. Further observational studies²⁰ focused on long-term follow-up and confirmed increased morbidity and mortality associated with aprotinin, particularly with regard not only renal failure, but also stroke, death, and nonfatal myocardial infarction. Sales of aprotinin were halted in 2008; aprotinin has been largely superseded by tranexamic acid and aminocaproic acid. There remains some controversy regarding whether the observed increases in renal failure were due to the effect of aprotinin or some other confounder.²¹

Discussion

In both of these examples, significant patient harm resulted from the introduction of a new drug into an anesthetic and surgical pathway because there were insufficient data to indicate potential for patient harm. Risks became apparent only after a larger number of patients were treated and significant patient complications had occurred.

In the first case, low molecular weight heparins and neuraxial anesthesia, the difficulty in predicting patient harm was due in large part to the extremely low frequency of the adverse event. If it is assumed that the baseline risk of spinal hematoma is 1:150,000, even a relatively large increase in the risk of hematoma requires large sample sizes to detect an increased risk.²² Sample sizes this large often cannot be realistically obtained prior to a drug’s introduction, and only postapproval surveillance or the development of high-quality clinical registries will detect such uncommon rare, but potentially catastrophic, adverse events.

In the second case, aprotinin and renal failure, a number of factors can be identified. Initial investigations were not focused on increased risk of renal failure and either they did not investigate this risk or the study was underpowered. In addition, some believed that the complications associated with aprotinin were transient in nature,¹⁷ and that there were no long-term risks associated with aprotinin. Obviously, this could not be investigated until years after aprotinin came into use.

These cases highlight the risks associated with new therapeutic agents or old therapeutic agents used in new situations. Preliminary studies may investigate the wrong risks or may be underpowered, or risks may be long term and may not become evident until well after the study period. Given this, when considering the risks and benefits to the patient, the clinician must also consider unknown or unquantified risk and include the agent only if the ratio of known, quantifiable risks and benefits is overwhelmingly positive. For drugs with a long history of use and well-defined risks, less caution is warranted.

COMPONENTS OF A FULL PATHWAY: TOTAL KNEE ARTHROPLASTY

In this section, we present components of a surgical pathway for total knee arthroplasty. This is shown in Table 15–4. However, instead of presenting final recommendations (as would be done in a completed pathway), we highlight the common issues that are faced when developing different aspects of the pathway, as well as drugs and techniques that are frequently employed. This is done to avoid implying that there is a final consensus around the “correct” pathway for total joint arthroplasty—even if such a consensus existed, it would rapidly become out of date as new studies, drugs, and techniques become available. Providers with different patient populations and different subspecialties may develop different pathways appropriate to their institution.

The individual elements of the pathway include such diverse topics as preoperative planning, patient education, intraoperative anesthetic management, postoperative pain management, and fluid and hemodynamic goals. A completed pathway, in addition to containing firm, detailed recommendations on management, would contain an addendum that outlines the evidence that was used to make pathway decisions. As we have seen, however, even after identifying the appropriate literature, there is often a significant amount of analysis and judgment that must be used in applying the literature to the pathway.

A final pathway is only useful if it is distributed widely to all relevant providers. In addition to electronic distribution, pathways can be displayed in the form of a poster. This allows the anesthesia provider to have the steps in the pathway easily available at different phases of the patient’s care. Common places to display pathway information include preoperative areas, regional anesthesia bays, operating rooms, and anesthesia workrooms. In addition, with the advent of electronic health record systems, many institutions have the capability to create order sets, which automatically create orders associated with the pathway.

CONCLUSION

Perioperative anesthesia and analgesia pathways provide a unique way of improving patient care and lowering cost by deploying existing resources and technology in an evidence-based way. Pathway development should therefore be considered a vital component of the anesthesiologist’s practice.

REFERENCES

INTRODUCTION

Infectious complications related to regional anesthesia are rare. Because most of the information is available in case reports and retrospective surveys, it is likely that these complications are underreported. It is hoped that recent surveillance¹ and prospective registry projects² using standardized surveillance definitions and the integration of such in national quality assurance projects (American Society of Regional Anesthesia [ASRA] Acute-POP/AQI)³ will generate more comprehensive data for risk assessment and evaluation of infection control recommendations in the future. Integration of a structured surveillance tool into the electronic medical record and a hospital’s quality management system⁴ will ease the workload for clinicians and facilitate surveillance compliance (Table 16–1).

While we have to work on reducing infectious complications associated with regional anesthesia because of the potential severe individual consequences, some studies demonstrate a reduction of surgical site infections with the use of local anesthesia—opening the research arena regarding whether the avoidance of general anesthesia, intrinsic properties of local anesthetics, or a combination of both is responsible for this observation.⁵

The objective of this chapter is to summarize information from the literature on infections complications associated with regional anesthesia, as well as to discuss the mechanism and suggest strategies to prevent these complications.

PATHOGENESIS OF INFECTIONS ASSOCIATED WITH CENTRAL NEURAXIAL BLOCKADE

Microorganisms from exogenous or endogenous sources may gain access to the subarachnoid, epidural, or tissue space surrounding peripheral nerves in several ways. Microorganisms from the patient’s or anesthesia practitioner’s flora can be inoculated directly when a catheter or needle is inserted into those spaces.⁶ Several reports in the literature suggested that infections are on occasion caused by the anesthesia practitioner’s flora.^7,8,9 For example, Trautmann and colleagues reported a case of meningitis caused by a Staphylococcus aureus strain that was identical by pulsed-field gel electrophoresis to the S. aureus isolated from the anesthesiologist’s nose.⁸ Rubin et al could trace to a single anesthesiologist Streptococcus salivarius as the responsible agent for six cases of meningitis following spinal anesthesia,¹⁰ and the Centers for Disease Control and Prevention (CDC) reported five cases in Ohio and one case in New York between 2008 and 2009 with the same organisms.¹¹

Microorganisms can also enter the epidural space by hematogenous spread from other body sites, such as infected skin,^8,12 or by migrating along the catheter tract.^13,14 Several case reports suggested that infection was caused by spread of bacteria from infected sites through the bloodstream to the epidural space.^15,16,17 Others maintained that infections at distal sites are not contraindications to epidural anesthesia. For example, Newman concluded that distal infections did not increase the risk of epidural infection because traumatic injuries are often infected, and no epidural catheter-related infections were identified among over 3000 patients who had epidural neural blockades for postoperative or posttraumatic analgesia.¹⁸ Gritsenko and coworkers analyzed the charts of 474 patients who underwent removal of an infected hip or knee prosthesis under neuraxial anesthesia and found in 0.6% of the cases clinical signs of central neuraxial infections (meningitis or epidural abscess) and three other anesthesia-related complications, including a psoas abscess beside an epidural hematoma and back pain.¹⁹

The anesthetic agents injected into the subarachnoid or epidural space are another possible source of infection. Infections from contaminated multidose vials are likely rare because most anesthetic drugs are weak bases dissolved in acidic solutions that inhibit growth of bacteria and fungi.^20,21,22 Besides most multidose local anesthetic solutions contain a bacteriostatic agent. Nevertheless, the case report by North and Brophy suggested that contaminated multidose vials still can be a source of infection. These authors reported an infection in which S. aureus with matching phage types were Isolated from an abscess and a multidose lidocaine vial.⁷

A report by Wong et al²³ described, besides other infection control violations, the use of single-dose medications for multiple patients as the culprit in an outbreak of Klebsiella pneumoniae and Enterobacter aerogenes bacteremia in a pain clinic. Breaches in aseptic technique for medication preparation can be detrimental, especially if a compound pharmacy is involved: In 2012, more than 200 patients suffered fungal infections with Exserohilum rostratum after use of contaminated methyprednisolone injections for interventional pain procedures in multiple institutions in the United States.²⁴

To assess whether contamination of the anesthetic agent or the equipment (needles, syringes, tubing) is related to subsequent infections, investigators have cultured these items after they have been used with patients or during simulations. In four studies, 0%–29% of used catheters were contaminated,^25,26,27,28 and James and coworkers found that 5 of 101 syringes used to inject anesthetic agents were contaminated.²⁵ Ross and coworkers drew up 0.25% bupivacaine into control syringes and into syringes used to induce continuous lumbar epidural neural blockade (test syringe) in 18 obstetric patients.²⁹ After each dose from the test syringe, the investigators cultured the contents of both the test and the control syringes. Six of 18 test syringes were contaminated with bacteria, compared with only 1 of 18 control syringes. Raedler and associates cultured 114 spinal and 20 epidural needles after use for single lumbar injections.³⁰ Twenty-four cultures (17.9%) grew microorganisms: 15.7% coagulase-negative staphylococci; 1.5% yeasts; and 0.8% each enterococci, pneumococci, and micrococci. The authors concluded that it is easy to contaminate the needle, and that anesthesiologists need to improve their hygienic measures. Despite finding contaminated equipment or anesthetic solutions, no infected patient was identified^{25,26,27,28,29}; thus, none of the authors was able to correlate contamination with infection. However, Loftus and coworkers examined the contamination of intravenous stopcocks during general anesthesia and showed, for the first time, postoperative infections with the same organism.⁶ It is therefore conceivable that contamination during the placement of a regional block, and, even more likely, during handling of continuous catheter systems, can cause infections. Although the risk for such infections would be less likely than that of manipulating intravenous lines.

INFECTIONS ASSOCIATED WITH EPIDURAL BLOCKADE

The numerous case reports in the literature of infections occurring after epidural neuraxial blockade, attest to the fact that such complications do occur and can be severe (Table 16–2).^{7,15,17,30-69} Of 57 patients in these case reports, 41 acquired epidural or intraspinal abscesses, 1 developed a subcutaneous abscess, 2 had meningitis without epidural abscess formation, and 1 developed sepsis. Four patients had injections only, 1 patient had injections and several catheters, and the remaining patients had catheters. Among the 38 patients who had catheters and for whom the duration of catheterization was specified, the median duration of catheterization was 3 days (range 50 minutes to 6 weeks). The median time to onset of the first signs or symptoms of infection was 4 days (range 1 day to 4.8 months) after catheter placement. Staphylococcus aureus caused 27 of 43 infections from which bacterial pathogens were isolated. Pseudomonas aeruginosa caused five infections and Streptococcus spp. caused five. Methicillin-resistant S. aureus (MRSA) was isolated in one case; three patients died.

It should be kept in mind that the number of reported cases does not allow us to assess the true frequency of infections after epidural neural blockade. However, several investigators have performed studies to assess this risk. When reviewing 350 reports in the literature, Dawkins in 1969 found no reports of infection after thoracic or lumbar epidural block but identified 8 (0.2%) reports of infection after 3767 sacral epidural blocks used for operative procedures and for obstetrics.⁷⁴ More recently, Dawson reviewed the literature and found rates of deep infection ranging from 0% to 0.7% and rates of superficial infection ranging from 1.8% to 12%.⁷⁵

Scott and Hibbard surveyed all obstetric units in the United Kingdom and identified one epidural abscess in approximately 506,000 epidural neural blocks.⁷⁶ In contrast, Palot and colleagues identified three cases of meningitis in 300,000 patients who had undergone epidural blocks.⁷⁷ Three smaller series of obstetric epidural neural blockades (some 12,000 patients) did not identify any infections.^78,79,80 Similarly, in a recent study by the French SOS group on complications of regional anesthesia, Auroy and coworkers did not identify any infections in 29,732 epidural neural blocks given for obstetrical procedures.⁸¹ Together, the results of these five studies suggest that four or five serious infectious complications (ie, epidural abscesses or meningitis) occur per 1 million obstetric epidural neural blocks.

A number of studies have assessed infections associated with epidural neural blockades performed for operative procedures or for short-term pain relief. However, these studies reported fewer patients than the studies of epidural neural blockade for obstetric procedures. Findings from 10 studies are summarized in Table 16–3.^58,62,81-87 Brooks and collaborators found four infections among 4832 (0.08%) patients undergoing epidural neuraxial blockade for surgical procedures or for labor and delivery.⁸⁸ All four infections occurred in healthy young women who underwent cesarean sections; two infections were superficial (0.04%), and two involved the epidural space (0.04%). In contrast, Holt and colleagues reported 53 (1.8%) local infections and 11 (0.4%) central nervous system infections related to approximately 3000 epidural catheters.^89,90 The median duration of catheterization was 8 days for patients with local infections and 15 days for those with generalized symptoms (p = .01). Catheters removed from patients with clinical symptoms were more heavily colonized than those removed from asymptomatic patients. However, 59 of 78 catheters with positive cultures were removed because patients were symptomatic, suggesting that this observation may have been affected by ascertainment bias.

Given that the incidence of infections identified in all studies has been low, the results reported by investigators who calculated the upper boundaries of the infection risk associated with epidural neural blockade are particularly important because they provide a better estimate of the true risk than do studies that reported only the number of infections and the number of procedures. For example, Strafford and coworkers did not identify skin infections or epidural abscesses among 1458 pediatric patients who had epidural analgesia to control perioperative pain.⁹¹ These investigators calculated the incidence of clinical infection to be 0 with a 95% confidence interval from 0% to 0.03%, or three infections per 10,000 procedures. Auroy and colleagues, as noted previously, did not identify any infections among 29,732 procedures done for deliveries.⁸¹ They calculated 95% confidence intervals of 0/10,000 to 1/10,000 procedures. Darchy and associates evaluated 75 patients, 9 (12%; incidence density rate of 2.7/100 catheter-days) of whom acquired local infections. None of the patients acquired deep infections.⁸³ Based on these data, Darchy and associates estimated the upper risk of spinal space infections to be 4.8% for catheters that remained in place for 4 days. Of note, these estimates are considerably higher than those of Strafford and coworkers⁹¹ and higher even than the rates found by Du Pen and collaborators among patients with epidural catheters for long-term pain control.⁹²

In general, epidural catheters inserted for long-term pain control become infected more frequently than those used for short periods of time. Du Pen and associates identified 30 superficial (9.3/10,000 catheter-days), 8 deep catheter track (2.5/10,000 catheter-days), and 15 epidural space (4.6/10,000 catheter-days) infections among 350 patients who had long-term epidural catheters.⁹² Similarly, Zenz and colleagues identified two cases of meningitis among 139 patients (1.4%, or 2.1/10,000 catheter-days) treated for pain due to malignancy.⁹³ Coombs reported that 10 of 92 (10.9%) cancer patients acquired local infections, and 2 (2.2%) acquired meningitis.⁹⁴ Malignancy and reduced immunocompetence might be additional risk factors in the population with long-term catheters.

Whether newly developed transparent dressings with integrated chlorhexidine patches might be beneficial for this vulnerable population remains to be seen.

INFECTIONS ASSOCIATED WITH SUBARACHNOID BLOCKADE

Case reports in the literature indicated that serious infections can occur as complications of subarachnoid neural blockade (Table 16–4).^{8-11,13,14,95-112} Of the 471 infections reported in these case reports, 272 were meningitis, 4 were epidural abscesses, 2 were soft tissue abscesses, 2 were infections of a disk or of a disk space, 1 developed cerebral and spinal abscesses, and 1 was a case of severe necrotizing fasciitis. In the last case mentioned, the authors speculated about a contaminated reused multiuse vial of local anesthetic as the cause.¹¹² The median time to onset of signs or symptoms of infection was 1 day (range 1 hour to 2 months) for all infections and 18 hours (range 1 hour to 10 days for meningitis). Streptococcal species caused 24 of the 37 infections from which bacterial pathogens were identified; S. aureus caused 2 infections; Pseudomonas spp. caused 4; and an extended spectrum betalactamase Serratia marcescens caused 1. Compared with infections after epidural neural blockade, infections associated with subarachnoid neural blockade were more likely to be caused by streptococci, and patients were more likely to recover fully. Table 16–5 reviews data from 10 studies or reviews that, if taken together, suggest that the rate of infection was approximately 3.5 per 100,000 subarachnoid neural blockades.^{81,109,115-123}

INFECTIONS ASSOCIATED WITH COMBINED EPIDURAL AND SUBARACHNOID BLOCKADE

At present, there are few reports in the literature about infectious complications as a result of using combined epidural-subarachnoid (CSE) neural blockade. In 11 case reports of infections with a total number of 12 patients after combined procedures^62,124-130 (Table 16–6), the median time to onset of signs or symptoms of infection was 21 hours (range 8 hours to 9 days) for all infections and 18 hours (range 8 hours to 3 days) for meningitis. Signs or symptoms of epidural abscesses were first noted 1–9 days after the procedures. Streptococcal species caused three of six cases of meningitis, and S. aureus caused all three epidural abscesses. Ten of twelve patients recovered fully. Cascio and Heath assessed rates of infection associated with combined procedures and identified one case of meningitis after about 700 (≈0.1%) CSE neural blockades.¹²⁴

INFECTIONS ASSOCIATED WITH PERIPHERAL NERVE BLOCKS

Continuous regional anesthetic techniques utilizing peripheral nerve blocks have become more popular in recent years for postoperative pain management, especially for orthopedic procedures.^132,133 Only a few studies have addressed infectious complications related to these procedures. The study by Auroy and coworkers of French anesthesiologists did not identify any infections after 43,946 peripheral blocks.⁵² Bergman and colleagues identified 1 patient among 368 patients (405 axillary catheters) who had a local S. aureus skin infection in the axilla after 48 hours of axillary analgesia.¹³⁴ The patient recovered fully with antibiotic treatment. Meier and colleagues reported eight superficial skin infections among 91 patients who had continuous interscalene catheters for an average of 5 days.¹³⁵ Nseir described a case of fatal streptococcal necrotizing fasciitis following axillary brachial plexus block.¹³⁶ Adam reported a psoas abscess complicating a femoral nerve block catheter.¹³⁷

Cuvillion and coworkers obtained cultures of 208 femoral catheters when they were removed after 48 hours.¹³⁸ Of the catheters, 54% were colonized with potentially pathogenic bacteria (71% Staphylococcus epidermidis, 10% Enterococcus spp., and 4% Klebsiella spp.). These investigators also reported three episodes of transient bacteremia, but they did not identify any abscesses or episodes of clinical sepsis.¹³⁶ None of the groups provided information about the aseptic techniques used for catheter insertion.

Compère reported a single infection in 400 continuous popliteal sciatic nerve blocks (0.25%),¹³⁹ while Volk and coworkers from the German regional anesthesia network reported in 2009 a 1.3% incidence of infectious complications for peripheral blocks in 3724 procedures compared to a higher rate for neuraxial techniques (2.7% in 5057 procedures).¹⁴⁰

Between 2002 and 2009, Reisig141 and coworkers collected data on 10,549 peripheral catheter procedures in an observations study that included the implementation of a comprehensive infection control bundle. While the definitions of inflammation and infection used in this study remain somewhat vague, they could show a rate of 4.2% for inflammation and 3.2% for infections in 3491 procedures before the intervention and a reduction to 2.6% for inflammation and 0.9% for infections in 7053 procedures after the interventions.

Other reports included cases of osteomyelitis following digital blocks¹⁴¹ and hematoma block for fracture repair,¹⁴² as well as orbital cellulites from sub-Tenon anesthesia,^143,144 mediastinitis following continuous interscalene block,¹⁴⁵ Aspergillus caldioustus infection after unspecified lower back nerve block,¹⁴⁶ and two cases with sepsis after femoral nerve catheters.¹⁴⁷

All these reports emphasize the importance of maintaining strict asepsis when performing continuing peripheral nerve blocks.

PREVENTION OF INFECTIONS ASSOCIATED WITH REGIONAL ANESTHESIA

Anesthesiologists disagree about the necessity of certain infection control precautions.^148,149-154 For example, several surveys indicated that only 50%–66% of anesthesia staff wore masks when performing epidural and subarachnoid neural blockades.^155,156,157

The review of studies on infections associated with epidural anesthesia indicated that there is no consensus regarding patient risk factors for infectious complications of epidural neural blockade.¹³³ Few studies assess risk factors for infection associated with epidural or subarachnoid neural blockades, possibly in part because these infections are uncommon. In fact, only one case-control study was performed to evaluate risk factors for infections associated with epidural neural blockade.¹⁵⁸ Dawson and colleagues evaluated epidural neural blockades performed for postoperative pain relief and found that procedures done between April and August had a sixfold higher risk than those done during other months (95% CI 1.28–28.12, p = .009). The risk of infection was lower if a bag rather than a syringe was used to administer the anesthetic agent (odds ratio 0.17, 95% CI 0.02–1.34, p = .05). Of the two risk factors identified by this study, only the latter, use of syringes, could be addressed by practice changes.

Assuming that the respiratory tract of anesthesia personnel could be a source of infection, Philips and associates conducted a simulation to assess the efficacy of masks.¹⁵⁹ They seated anesthesia staff with and without masks in a room with controlled environment and asked them to speak in front of blood agar plates placed 30 cm away. The number of bacteria on the plates was significantly lower when masks were worn. However, the clinical significance of this finding is unknown.

Chlorhexidine has been shown to reduce the risk of catheter-associated bloodstream infections significantly compared with povidone-iodine.¹⁶⁰ Several investigators have tried to determine whether a particular disinfectant provides more effective skin antisepsis before epidural neural blocks than do other agents.^{161,162,163,164} However, none of the studies was large enough to assess rates of infection; instead, the outcomes evaluated were catheter or skin colonization.

Kasuda and colleagues randomly assigned 70 patients to have their skin prepared with either a 0.5% alcoholic solution of chlorhexidine or 10% povidone-iodine.¹⁶² After a median of 49 ± 7 hours, the investigators removed the catheters and obtained cultures of the insertion sites and catheter tips. There was no difference in rates of positive cultures.

Kinirons and associates (the only investigators who reported a power calculation) obtained cultures from catheters removed from 96 children who had epidural catheters longer than 24 hours.¹⁶³ The colonization rate was lower for catheters removed from children whose skin was prepared with a 0.5% alcoholic solution of chlorhexidine (1/52 catheters, 0.9/100 catheter-days) than for those removed from children whose skin was prepared with povidone-iodine (5/44 catheters, 5.6/100 catheter-days) (relative risk 0.2, 95% CI 0.1–1.0).

Sato and coworkers enrolled 60 patients who were undergoing back operations under general anesthesia.¹⁶⁴ After preparing the site with either 0.5% alcoholic chlorhexidine or 10% povidone-iodine, the investigators obtained skin biopsies. Cultures from skin prepared with the alcoholic chlorhexidine were less likely to be positive (5.7%) than were cultures from skin prepared with povidone-–iodine (32.4%; p < .01). However, microscopy was as likely to identify bacteria in the hair follicles of skin prepared with the alcoholic solution of chlorhexidine (14.3%) as skin prepared with povidone-iodine (11.8%).

This has led to the recommendation to use alcoholic chlorhexidine for skin preparation despite some concerns about potential neurotoxicity. The latter might be the reason American Society of Anesthesiologists (ASA) members were equivocal on the issue during the consensus process, while external experts were in favor of the recommendation.

Sviggum et al published the experiences from the Mayo Clinic analyzing almost 12,000 spinal anesthetics between 2006 and 2010 that used alcoholic chlorhexidine.¹⁶⁵ They did not observe any change in neurological complications, considering the practice to be safe. Unfortunately, no data about infectious complications were reported.

The safety of alcoholic chlorhexidine was underlined in an experimental study by Doan and coworkers. They found damage to neuronal cell cultures with chlorhexidine as well as with 10% iodine they could also show that a relevant toxic concentration of skin disinfectants cannot be reached if the puncture is performed through dry skin.¹⁶⁶ Therefore, allowing the skin to completely dry once disinfected before performing the block is more important than the choice of the solution in order to prevent any neurotoxic effect.

Malhotra et al¹⁶⁷ demonstrated in a study of 309 healthy volunteers that single application of 0.5% chlorhexidine gluconate in 70% ethanol was as effective as two applications.

The fact that infections rarely complicate neuraxial blockades suggests that the infection control practices used for these procedures are usually adequate. Given the very low rates of infection associated with epidural and subarachnoid neural blockade, it will be difficult to prove that additional infection control practices such as wearing masks and using full barrier precautions (ie, the anesthesiologist wears a cap, mask, sterile gloves, and sterile gown and uses a large drape to cover the patient) reduce the risk of infection. However, bacteria that colonize the skin, respiratory tract, or water caused most reported infections after epidural and subarachnoid neural blockades. Masks have been shown to decrease spread of organisms when anesthesiologists are talking.¹⁵⁹ Thus, a mask would allow the anesthesiologist to talk to the patient while doing the procedure and could decrease the risk of contaminating the insertion site with oral or respiratory flora. This has also been incorporated in the ASA “Practice Advisory for the Prevention, Diagnosis, and Management of Infectious Complications Associated With Neuraxial Techniques.”¹⁶⁸

Furthermore, epidural and subarachnoid neural blockades are at least as invasive as placing central venous catheters, and the consequences of subsequent infections are at least as bad as those for catheter-associated bloodstream infections. Because the use of full barrier precautions reduces the incidence of catheter-related bloodstream infections,¹⁶⁹ aseptic measures similar to those used for placing central venous catheters should be used during the placement of catheters that will remain in place for several days or longer.⁷⁵ While the ASA practice advisory still uses the term hand washing before putting on sterile gown and gloves, hand disinfection with an alcoholic hand rub (with 70% alcohol) is the internationally preferred standard.^4,170

Anesthesia personnel should observe their patients closely for signs and symptoms of infection so that infections can be diagnosed and treated immediately. Pegues and coworkers reviewed medical records from 1980 to 1992 of patients who had short-term epidural catheters to identify those who acquired infections. They followed patients prospectively from January 1993 until June 1993.¹⁷⁰ In 1990, they introduced a standardized procedure for inspecting temporary epidural catheters. During the entire 12.5-year period, the investigators identified seven infections, all of which occurred after catheters were inspected routinely. The increased incidence of infection could have resulted from ascertainment or misclassification bias associated with the retrospective review or from increased use of epidural catheters for pain management during the later time period. On the other hand, it could indicate that infections were not diagnosed when catheters were not inspected routinely for signs of infection.

Because it may be difficult to draw up opioids in a sterile manner from ampoules, some have suggested that these drugs be drawn through a filter into a syringe, which is then double wrapped and sterilized in ethylene oxide.¹⁷¹ However, the benefit of such extreme precautions is highly hypothetical.

Brooks and coworkers were among the first to implement and report on structured infection control measures for continuous neuraxial blocks in their hospital.⁸⁸ In 2008, we reviewed the literature and compared the infection control recommendations of the ASRA and the German Society of Anesthesiology and Intensive Care (DGAI)¹⁷² and noticed some discrepancies, especially regarding the use of masks and gowns or filters. In 2010, new guidelines by the ASA were developed in a consensus process among ASA members and external experts to clarify some of the issues. However, the evidence supporting many of the recommendations remains sparse, and extrapolation from other areas of practical implementation of infection control is needed.

The ASA “Practice Advisory for the Prevention, Diagnosis, and Management of Infectious Complications Associated With Neuraxial Techniques”¹⁶⁸ has published the following guidelines for the placement of neuraxial blocks:

• Before performing neuraxial techniques, a history and physical examination relevant to the procedure and review of relevant laboratory studies should be conducted to identify patients who may be at risk of infectious complications. Consider alternatives to neuraxial techniques for patients at high risk.

• When neuraxial techniques are indicated in a known or suspected bacteremic patient, consider administering preprocedure antibiotic therapy.

• Selection of neuraxial technique should be determined on a case-by-case basis, including consideration of the evolving medical status of the patient.

• Lumbar puncture should be avoided in the patient with a known epidural abscess.

• Aseptic techniques should always be used during the preparation of equipment (eg, ultrasound) and the placement of neuraxial needles and catheters, including the following:

  • Removal of jewelry (eg, rings and watches); hand washing; and wearing of caps, masks (covering both mouth and nose and consider changing before each new case), and sterile gloves

  • Use of individual packets of antiseptics for skin preparation

  • Use of chlorhexidine (preferably with alcohol) for skin preparation, allowing for adequate drying time

• Sterile draping of the patient.

• Use of sterile occlusive dressings at the catheter insertion site.

• Bacterial filters may be considered during extended continuous epidural infusion.

• Limit the disconnection and reconnection of neuraxial delivery systems to minimize the risk of infectious complications.

• Consider removing unwitnessed accidentally disconnected catheters.

Catheters should not remain in situ longer than clinically necessary.

The following recommendations are given for the diagnosis and management of infectious complications after neuraxial block:

• Daily evaluation of patients with indwelling catheters for early signs and symptoms (eg, fever, backache, headache, erythema, and tenderness at the insertion site) of infectious complications should be performed throughout the patients’ stay in the facility.

• To minimize the impact of an infectious complication, promptly attend to signs or symptoms.

• If an infection is suspected:

  • Remove an in situ catheter and consider culturing the catheter tip.

  • Order appropriate blood tests.

  • Obtain appropriate cultures.

  • If an abscess is suspected or neurologic dysfunction is present, imaging studies should be performed, and consultation with other appropriate specialties should be promptly obtained.

• Appropriate antibiotic therapy should always be administered at the earliest sign or symptom of a serious neuraxial infection.

• Consultation with a physician with expertise in the diagnosis and treatment of infectious diseases should be considered.

However, guidelines and standard operating procedures alone are not enough to ensure proper aseptic technique. Friedman and coworkers showed in a videotape analysis of 35 epidural placements by second-year residents a significant increase in manual skills with growing experience, but there was no increase in aseptic technique.¹⁷³ This highlights the need for a special focus on aseptic technique in residency and during infection control audits of anesthesia providers.

PERIPHERAL BLOCKS AND PERIPHERAL CONTINUOUS CATHETERS

Recent studies indicated that infection control protocols similar to the recommendations for neuraxial block can reduce the incidence of infectious complications associated with placement of continuous peripheral nerve catheters.¹⁷⁴ Unfortunately, the effectiveness of each step is hard to assess, a problem familiar from all the other recommended approaches in infection control, such as the ones for prevention of central line–associated bloodstream infections¹⁷⁵ or ventilator-associated pneumonia.¹⁷⁶

With the increasing use of real-time ultrasound, the correct handling of the ultrasound probe becomes an additional concern. To maintain the aseptic field, the cable and the probe should be covered with a sterile sheath to avoid contamination in the case of needle contact. Sterile contact gel or sterile saline should be used within the sheath. Puncture aids fixating the needle to the probe must be sterile.⁴ After the procedure, ultrasound probes need to be cleaned removing any residual gel and disinfected with an appropriate disinfectant that cannot damage the probe. Alternative techniques using ultraviolet light to disinfect ultrasound probes are under investigation.^177,178

SUMMARY

Although rare, infectious complications from regional anesthesia and analgesia do occur and can be serious. Recent guidelines offer practice recommendations especially for neuraxial blocks. Table 16–7 summarizes the key recommendations for decreasing the risk of infections related to regional anesthesia procedures. Surveillance systems should be implemented as part of national quality assurance programs to allow benchmarking and process optimization as well as providing data from large population databases, which would be beneficial in addressing some of the unanswered questions about infections after regional anesthesia procedures.

REFERENCES

INTRODUCTION

Surgical excision is the cornerstone of treatment for solid tumors. Metastatic disease is the most important cause of cancer-related death patients affected with cancer. The likelihood of tumor metastases depends on the balance between the metastatic potential of the primary tumor and the antimetastatic host defenses. Among them, cell-mediated immunity and natural killer (NK) cell function are critical components.

A wealth of basic science data supports the hypothesis that the surgical stress response increases the likelihood of cancer dissemination during and after cancer surgery. Therefore, anesthetic management can potentially influence mid- and long-term outcome. Au contraire, surgery can inhibit major host defenses and promote the occurrence of metastases. Anesthetic techniques and drug choice also can affect the immune system. Together, these two interventions can have profound interactions with a patient’s immune defenses. The aims of this chapter are to review how the immune system can be influenced by surgery and anesthesia and discuss the possible mechanisms behind a potential benefit of one intervention over the other in this setting.

THE IMMUNE SYSTEM: THE IMPORTANCE OF Th1/Th2 RATIO

Intact immune responses to cancer cells are crucial in preventing and inhibiting tumor occurrence. The modern concept of immunoediting includes these processes: elimination, equilibrium, and escape.^1,2 This implies that impairment in immune surveillance during the elimination process allows the escape of cancer cells from the protective immune attack. The appearance of clinically apparent tumors through the equilibrium process may occur, rendering the tumor cells more resistant to the immune system.

The NhK, CD4⁺ Th1 (T helper 1), and CD8⁺ CTL (cytotoxic lymphocyte) cells are the major antitumor immune effector cells, whereas Th2 (T helper 2), tumor-associated macrophages (TAM), and regulatory T (Treg) cells are the among the most important cells in the promotion of tumor settlement, growth, and progress by inhibiting the immune responses against cancer.^3,4 Other mediators like proinflammatory cytokines,⁵ catecholamines,⁶ prostaglandins,⁶ and high levels of signal transducer and activator of transcription 3 (STAT3) factor activity⁷ are also involved in the process of postoperative metastases. NK cells have a crucial role particularly in eliminating metastases without prior sensitization and major histocompatibility complex (MHC) restriction.⁸ Therefore, preservation or activation of the function of NK cells is important. In this context, Th1 cells, characterized by interleukin (IL) 2, IL-12, and interferon gamma (IFN-γ) secretions are mandatory to induce antitumor CTL⁹ and to activate NK cells.⁸ On the other hand, Th2 cells differentiated by IL-4 and IL-10 can induce Th17 cells, Treg cells, TAMs, and myeloid derived suppressor cells (MDSCs),¹⁰ which have a major role in promoting tumor growth and metastasis by inhibiting antitumor immune responses like Th1 induction, CTL function, and NK activity.¹¹

The role of proinflammatory cytokines (IL-6, tumor necrosis factor alpha [TNF-α], IL-13) should be outlined because release from infiltrating leukocytes close to the primary tumor site can activate nuclear factor κB (NF-κB) and STAT3 in cancer cells and can contribute to cancer proliferation and survival.¹² NK cell function can also be downregulated by prostaglandins, especially prostaglandin E₂ (PGE₂) by shifting cytokine balance toward Th2 dominance¹³ and promoting tumor angiogenesis.¹⁰

Th1-type responses are necessary for antitumor immunity. It has been shown that, in general, cancer patients have a Th2-dominant status.¹⁴ Surgery per se induces the Th1/Th2 balance toward Th2 immune response.¹⁵ This is explained by the surgical activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis.¹⁶

ANESTHETIC INTERVENTIONS AND POTENTIAL EFFECTS ON IMMUNOMODULATION

Anesthetic techniques or drugs may have a direct impact on the immune balance of cancer patients. This section reviews the established and hypothetical effects of various anesthetic interventions, pharmacological agents and perioperative occurrences that may affect immunomodulation.

Hypotension, Hypovolemia, and Hypoxia

The occurrence of hypotension/hypovolemia during surgery is are some of the factors responsible for the activation of the sympathetic system. The resulting tissue hypoxia may increase the expression of the intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) as well as P-selectin and E-selectin in vascular endothelium.¹⁷ This initiates the systemic inflammatory response syndrome (SIRS), responsible for a depressed Th1 response¹⁸ and therefore a shift toward the Th2 response phenotype.

Hypothermia

Hypothermia is a common occurrence during surgery. In vitro human investigation has demonstrated that monocytes incubated at temperature lower than 36°C reduced human leukocyte antigen (HLA)-DR expression, delayed TNF-α clearance, and increased IL-10 release.¹⁹ In vivo animal studies have shown a suppression of NK cell activity.¹⁹

Hyperglycemia

Hyperglycemia during surgery is the result of the activation of the stress response. Acute hyperglycemia inhibits glucose-6-phosphatase dehydrogenase, the enzyme necessary for the formation of nicotinamide adenine dinucleotide phosphate,²⁰ which will block the functions of monocytes and neutrophils. The risk of infection is increased, and the occurrence of microvascular inflammation engenders an increased release of proinflammatory cytokines (IL-6, TNF-α) from immune cells.²⁰

However, no data showing that perioperative hyperglycemia is associated with tumor spread or metastasis are available.

Blood Transfusion

Allogenic blood transfusion is recognized to have diverse negative immunomodulatory effects. However, blood transfusion is also a marker for sicker patients. In this context, it has been shown that anemia per se also has negative immune effects. Therefore, it is important to find the right balance, and avoiding unnecessary transfusions.

Volatile Anesthetics

Volatile anesthetics have been shown to have suppressive effects on immune cells. Halothane,²¹ isoflurane,²² and sevoflurane²³ suppress NK cell activity. The precise mechanism by which these agents interact with the immune system is not clear. However, a recent study showed that pretreatment with isoflurane can enhance resistance to apoptosis of colon cancer cells after exposure to anticancer drugs in vitro via a caveolin-dependent mechanism.²⁴

Propofol

Propofol at a clinical concentration does not appear to have significant effects on NK cells and lymphocytes. Propofol, but not thiopental or ketamine, does not suppress NK cell activity in whole blood and does not increase susceptibility to tumor metastases.²¹ A comparison between propofol and isoflurane²⁵ showed that propofol, but not isoflurane, increased the Th1/Th2 ratio, which is beneficial for patients with cancer. On the other hand, sevoflurane anesthesia²⁶ increased proinflammatory cytokine IL-17 and decreased the Th1/Th2 ratio. Propofol also has inhibiting activity against cyclooxygenase (COX) 2.²⁷ This is beneficial because in most human cancer cells COX-2 is overexpressed. COX-2 expression is critical for the production of PGE₂, which promotes tumor progression, VEGF (vascular endothelial growth factor) production in cancer cells, NK cell inhibition, and Th2 polarization.²⁷

Midazolam and Ketamine

Midazolam²⁸ and ketamine²⁹ impair dendritic cell induction of Th1-type immune response in vitro and in vivo. Dendritic cells and Th1-type cells are important players in host defense against tumor. Ketamine also upregulates PGE₂³⁰ and increases lung metastases through NK cell inhibition in rat models.

Opioids

Morphine-induced immunosuppression is mediated by its binding to a member of the seven-transmembrane G-protein-coupled μ-opioid receptors (MORs) on immune cells.³¹ The μ-receptor, which is morphine sensitive, is responsible for its immunomodulation.³² Interestingly, fentanyl, despite sharing analgesic properties with morphine, does not bind to μ₃-receptor.³³ However, morphine administration reduces CTL and NK cell functions^31,34 and IL-2 and IFN-γ expression in T cells.^35,36 It also enhances IL-4 expression in T cells³⁷ favoring Th2 differentiation. Fentanyl was shown to have a suppressive effect on NK activity in nonsurgical individuals but to have a positive effect in operative subjects.³⁸ In contrast, remifentanil did not impair NK activity.³⁹

Epidemiologic studies suggested that patients who receive general anesthesia with opioids rather than local anesthetics (LAs) or regional anesthetics may have a greater rate of cancer recurrence.⁴⁰ Beilin et al⁴¹ investigated NK cell cytotoxic activity in 40 patients undergoing major surgery, who were randomized to receive either a high-dose fentanyl anesthesia regimen, including midazolam as a single dose and isoflurane if necessary, or low-dose fentanyl, with isoflurane and nitrous oxide used for anesthetic maintenance. In vitro NKA was suppressed in all patients, but high-dose fentanyl resulted in a slower rate of recovery of NK cell activity compared to low-dose fentanyl.

Sacerdote et al⁴² studied the effects of morphine and tramadol in patients undergoing abdominal surgery for uterine carcinoma. Phytohemaglutinin-induced T-lymphocyte proliferation and NKA were evaluated. In the morphine group, lymphoproliferative values were attenuated by surgical stress and stayed depressed after the administration of morphine, whereas in the tramadol group these values came back to baseline after the administration of tramadol. NKA was increased by tramadol.

Gupta et al⁴³ demonstrated that morphine stimulates angiogenesis by activating proangiogenic signaling via Gi/Go-coupled G-protein receptors and nitric oxide. In clinically relevant plasma concentrations, morphine stimulated human microvascular endothelial cell proliferation and promoted tumor neovascularization in a human breast tumor xenograft model in mice, which led to the progression of the tumor.

Singleton et al⁴⁴ showed that μ-opioid agonists in clinical concentrations transactivate the VEGF receptors, and that the opioid-induced angiogenesis was blocked by both naloxone and the peripheral MOR antagonist methylnaltrexone. This group suggested that because μ-opioid agonists can alter the endothelial barrier integrity and affect vascular permeability, during tumor surgery, they could potentially facilitate transmigration of cells through the endothelium. This process was shown to be attenuated by methylnaltrexone.⁴⁵

Mathew et al⁴⁶ reported that the expression of MORs was increased in lung cancer cells (Lewis lung carcinoma) and that the silencing of MOR in those cells reduced tumor growth and metastasis in mouse models.

Subsequently, Lennon et al⁴⁷ published the results of their more recent study where the effect of overexpression of the MOR on lung cancer progression was examined. The authors tested their hypothesis in vitro (H358 human non-small cell lung cancer [NSCLC] cells) and in vivo (human lung cancer xenograft models/nude mouse model). They demonstrated that MOR1 overexpression in H358 human NSCLC cells increased proliferation, migration, invasion, transendothelial migration, and activation of two serine/threonine kinases implicated in cancer progression (Akt [protein kinase B] and mammalian target of rapamycin [mTOR]). In addition, the same effect of increased tumor growth and lung metastasis was observed in human NSCLC xenografts. The authors suggested that these results may provide a plausible explanation for the differences in recurrence rates observed in different contexts.^40,48,49,50

In conclusion, there are currently epidemiologic, animal, and cellular studies that suggest a possible role of MOR on tumor growth and metastasis that warrants further investigation.

REGIONAL ANESTHESIA AND CANCER METASTASES

Local Anesthetics and Cancer In Vitro

In vitro studies have demonstrated the antiproliferative or cytotoxic effect of LAs on cancer cells. Martinsson et al⁵¹ evaluated the effect of ropivacaine on the proliferation of human colon adenocarcinoma cells in vitro. Ropivacaine inhibited the growth of these cells in a dose-dependent manner. The effective concentrations were within the therapeutic range, similar to the ones found in the colon of the patients treated rectally with ropivacaine. In the same study, lidocaine was found to be less potent than ropivacaine in inhibiting cell proliferation.

Sakaguchi et al⁵² investigated the effects of lidocaine on proliferation of a human tongue cancer cell line that has a high level of epidermal growth factor receptor (EGFR) expression. Lidocaine in clinical concentrations suppressed EGF-induced proliferation of the malignant cells and inhibited EGF-stimulated tyrosine kinase activity of EGFR without cytotoxicity.

Lucchinetti et al⁵³ reported the results of the antiproliferative effects of LAs on mesenchymal stem cells (MSCs) and the potential implications for tumor spreading and wound healing. MSCs play a key role in tumor growth and metastasis by releasing growth factors, enhancing angiogenesis, immunomodulation, and epithelial-to-mesenchymal transformation. MSCs also contribute to tissue repair. The authors tested the effect of increasing concentrations of the amide LAs lidocaine, ropivacaine, and bupivacaine on proliferation, colony formation, in vitro wound healing, and bone differentiation assays of culture-expanded bone-marrow–derived murine MSCs. They demonstrated that MSCs are sensitive to the antiproliferative effects of LAs at concentrations of 10–100 μM. Their results suggested that mechanisms involved in this antiproliferative action may include the inhibition of NF-κB-ICAM-1 signaling pathway as well as the inhibition of mitochondrial respiration with adenosine triphosphate (ATP) depletion.

Effects of Anesthetic Techniques on Cellular Immunity

In the absence of surgery, general or epidural anesthesia has only minor effects on immune cell functions.⁵⁴ However, several preliminary studies in humans have indicated the beneficial effects of epidural anesthesia on immune cell functions in the setting of surgery-induced tissue trauma/stress.

Koltum et al⁵⁵ compared, in 20 patients who underwent colectomy under laparotomy for various diagnosis, the effect of awake epidural anesthesia (AEA) versus general endotracheal anesthesia (GETA) on natural killer cell cytotoxicity (NKCC). They found that AEA significantly preserved perioperative NKCC compared to GETA.

Hole et al⁵⁶ evaluated the phagocytic capabilities as well as the ability of monocytes to induce lysis of malignant cells in 18 patients undergoing total hip arthroplasty performed under either general or epidural anesthesia. While the phagocytic function of the monocytes derived from patients in the epidural group was found to be increased, the ability to induce lysis in malignant cells of the monocytes derived from patients who underwent general anesthesia was significantly reduced.

Wada et al²³ demonstrated in a rat model that sevoflurane anesthesia and laparotomy diminished tumoricidal activity in liver mononuclear cells (Th cells). On the contrary, a spinal block attenuated this effect. Bar-Yosef et al⁵⁷ showed the beneficial effects of spinal anesthesia on lung tumor retention in rats. The group with laparotomy plus general anesthesia had a 17-fold increase in lung metastasis. Spinal block reduced this effect by 70%. The authors concluded that surgical stress in rats promoted the development of metastasis, which was significantly attenuated by regional anesthesia.

Data from Retrospective Studies

In recent years, a number of retrospective studies suggested that regional anesthesia may have a beneficial effect on reducing cancer recurrence and metastasis.

Such studies are often limited by the accuracy of the available medical records, the lack of control in selection and measurement bias, and multiple uncontrolled confounding factors that could have an impact on cancer recurrence.

In one of the first published retrospective studies indicating the beneficial effects of regional anesthesia, Schlagenhauff et al⁵⁸ evaluated the prognostic impact of general and regional anesthesia for the excision of primary cutaneous melanoma. The authors examined follow-up data of 4329 patients. The study concluded that there was a significantly increased risk of death for patients treated with general anesthesia for the primary excision of melanoma, thus favoring regional anesthesia for this procedure.

Exadaktylos et al⁵⁹ conducted a small retrospective study based on the review of the medical records from patients that underwent mastectomy and axillary dissection for breast cancer. The patients had received either general anesthesia combined with paravertebral anesthesia/analgesia or general anesthesia combined with patient-controlled morphine analgesia. The authors examined the records of 129 patients who had a follow-up time of 32 ± 5 months. Their results suggested that the use of paravertebral anesthesia and analgesia for breast cancer surgery versus opioid use was associated with a metastasis/recurrence-free survival benefit of 94% versus 77% at 37 months.

Christopherson et al,⁴⁸ in a retrospective study, evaluated the long-term survival after resection of colon cancer under general anesthesia with or without epidural anesthesia in 177 patients. Analysis was performed separately for patients with and without metastasis because the presence of distant metastasis had the greatest effect on survival. Their results suggested that the patients with epidural analgesia had an improved survival (p = .012), up to 1.5 years; thereafter, the type of anesthesia did not appear to affect survival (p = .27).

Biki et al⁴⁹ evaluated retrospective date for prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia (n = 102) or general anesthesia with postoperative opioid analgesia (n = 123). The primary outcome measure was the incidence of “biochemical recurrence,” that is, an increase in prostate-specific antigen (PSA) after radical prostatectomy compared with its immediate postoperative peak value, which was the cause for initiation of adjuvant treatment. Adjustment for confounding factors was performed, and the results showed that patients who received general anesthesia combined with epidural analgesia had a 57% (95% CI, 17%–78%) lower risk of cancer recurrence than patients who had general anesthesia and postoperative opioids.

Tsui et al⁵⁰ evaluated the effect of adjunctive epidural LA and opioid infusion on disease recurrence following radical prostatectomy for adenocarcinoma under general anesthesia. This study was a retrospective analysis of a small randomized trial conducted for other purposes, such as pain control, blood loss, and the need for perioperative blood transfusion. The authors conducted a prolonged follow-up chart review to determine clinically evident or biochemical recurrence of prostate cancer. The median follow-up time was 4.5 years, and no difference in disease-free survival between the epidural and the control group was observed. Because the study had a different endpoint, it was significantly underpowered for evaluating cancer recurrence.

Ismail et al⁶⁰ examined retrospective data to determine the effect of neuraxial anesthesia in the progression of cervical cancer in 132 patients who were treated with brachytherapy. The use of neuraxial anesthesia during the first brachytherapy (most invasive one) was not associated with a reduced risk of local or systemic recurrence, long-term mortality from tumor recurrence, or all-cause mortality after adjusting for other prognostic factors. The study have failed to demonstrate a difference between the general and the regional anesthesia groups due to the underpowered sample size. Other factors that might have contributed to this result are the minimally invasive nature of the therapeutic procedure used for this treatment and the short duration of the neuraxial anesthesia.

Gottschalk et al⁶¹ reviewed the records of 669 patients undergoing colorectal surgery to determine the association between perioperative epidural analgesia and cancer recurrence. The primary outcome of the study was time to cancer recurrence. In this study, the epidural and nonepidural groups were compared in all available potential confounders, and their relationship with cancer recurrence was analyzed by using a multivariable Cox proportional hazards regression model. Overall, no association between epidural use and recurrence was found (p = .43), with an adjusted estimated hazard ratio (HR) of 0.82 (95% CI 0.49–1.35). However, the authors found that the epidural-by-age interaction was statistically significant (p = .03). Epidural analgesia was associated with reduced cancer occurrence in patients older than 64 years, suggesting that age and tumor type may play an important role.

Wuethrich et al⁶² evaluated the effect of anesthetic technique on disease progression and long-term survival in patients receiving general anesthesia plus intraoperative and postoperative thoracic epidural analgesia (n = 103) in comparison to patients receiving general anesthesia alone (n = 158). The patients underwent open retropubic radical prostatectomy with extended lymph node dissection. The authors’ assessment was more detailed in that they evaluated biochemical recurrence-free survival, clinical progression-free survival, cancer-specific survival, and overall survival. It was demonstrated that general anesthesia combined with epidural analgesia resulted in improved clinical progression-free survival (HR 0.45, 95% CI 0.27–0.75, p = .002). No significant difference was found between general anesthesia plus postoperative ketorolac-morphine analgesia and general anesthesia plus intraoperative and postoperative thoracic epidural analgesia in biochemical recurrence-free survival, cancer-specific survival, or overall survival. The authors used a historical control group, which represented a limitation.

Myles et al⁶³ conducted a large (n = 503) retrospective study as a follow-up to the Multicenter Australian Study of Epidural Anaesthesia and Analgesia in Major Surgery (MASTER). This multicenter randomized clinical trial tested the hypothesis that combined epidural and general anesthesia reduced the frequency of major postoperative complications compared with general anesthesia and opioid analgesia. The goal was to compare long-term recurrence of cancer and survival in patients who underwent major abdominal surgery under general anesthesia with the supplement consisting of intraoperative and postoperative epidural analgesia (epidural group n = 263) or under general anesthesia and postoperative opioids for analgesia (control group n = 240). The median time to recurrence of cancer or death was 2.8 (95% CI 0.7 to 8.7) years in the control group and 2.6 (0.7 to 8.7) years in the epidural group (p = .61). Recurrence-free survival was similar in both epidural and control groups. However, the fact that 50% of the epidurals did not work is a major weakness of this study and raised serious doubts concerning the validity of the results.

De Oliveira et al,⁶⁴ in a recent retrospective study, studied any association between intraoperative neuraxial regional anesthesia and decreased ovarian cancer recurrence. The study reviewed data from 182 patients who underwent primary cytoreductive surgery for ovarian cancer. All the patients received general anesthesia. Of those, 127 received intravenous opioids for postoperative pain control, and 55 received epidural catheters. Of these patients, 26 received epidural anesthesia intra- as well as postoperatively for analgesia. The rest of the patients had the epidural only for postoperative pain control. The authors found that in the intraoperative/postoperative epidural group the mean time to cancer recurrence was 73 (56–91) months, which was longer than for either the epidural postoperative group at 33 (21–45) months (p = .002) or the nonepidural group at 38 (30–47) months (p = .001).

In a recently published retrospective study, Cummings et al⁶⁵ compared the effects of epidural analgesia and traditional pain management on survival and cancer recurrence after colectomy. A cohort of 42,151 patients over 66 years old who underwent colectomy was identified from the Medicare-Surveillance, Epidemiology and End Results database. Of these patients, 22.9% (n = 9670) had an epidural at the time of resection. The results of this study demonstrated that the epidural use was associated with improved survival in patients with nonmetastatic colon cancer. Five-year survival was 61% in the epidural group and 55% in the nonepidural one.

Day et al⁶⁶ undertook a retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer. The data of 424 patients were analyzed. The three groups (epidural = 107, spinal block = 144, and patient-controlled analgesia = 173) were similar regarding patient and surgical characteristics. In the epidural group, patients received a mixture of bupivacaine and fentanyl for 48 hours. The authors did not find any difference between the groups in overall survival.

Some of the discussed retrospective studies provided results suggesting that regional anesthesia might have a beneficial affect in reducing cancer recurrence and some did not. The interpretation of the results of these investigations is complex because neither the LAs nor the concentration and the time and duration of application are known. Moreover, some analgesic regimens were a mixture of LA and opioid. Consequently, no clear-cut conclusions or recommendations for clinical care can be made (Table 17–1).

Clinical recommendations are also precluded because the clinical assessment of these results is even more difficult as no information regarding surgical technique is available. Although the possibility that regional anesthesia may reduce the incidence of metastasis is exciting, currently it is a hypothesis as adequately powered prospective randomized clinical trials are needed to validate the current observational results. What is known however, is that LAs have anti-inflammatory properties and do affect the mediators of inflammation at the molecular level. There is also evidence that inflammatory mechanisms may play a role in cancer metastasis.

INFLAMMATION AND CANCER

Epidemiological studies and molecular investigations of genetically modified mice and led to the conclusion that the mechanisms leading to inflammation and cancer may be linked.^67,68,69,70 The presence of inflammatory cells and inflammatory mediators in tumors, tissue remodeling, and angiogenesis is similar to that seen in chronic inflammatory responses that precede and constitute the hallmark of cancer-related inflammation.

Cancer and inflammation are connected by two pathways: an intrinsic one and an extrinsic one.⁷¹ The intrinsic pathway is activated by genetic events such as mutations, chromosomal rearrangements, and so on that affect oncogenes. Cells that are transformed by these events produce inflammatory mediators, thereby generating an inflammatory microenviroment in the tumor area. By contrast, in the extrinsic pathway it is the inflammatory or infectious condition that is responsible for the risk of developing cancer at certain sites, such as colon, prostate, and pancreas. The two pathways lead to a common one and follow the activation of the nuclear transcription factor NF-κB and other transcription factors.

These factors regulate the production of inflammatory mediators such as cytokines and chemokines, which in turn recruit and activate various leukocytes. The cytokines activate the same key transcription factors in inflammatory cells, stromal cells, and tumor cells. This results in the subsequent release of more inflammatory mediators and the formation of a cancer-related inflammatory milieu (Figure 17–1).⁷¹

Role of the ICAM-1 and Src Protein Tyrosine Kinase on Inflammation and Metastasis

The role of cell adhesion molecules (CAMs) such as ICAM-1, VCAM-1, E-selectin, and P-selectin has been studied extensively in the process of inflammation.⁷² Similarly, CAMs have been implicated in tumor progression.⁷³ Some circulating cancer cells have been shown to extravasate to a secondary site using a process similar to inflammatory cells.⁷⁴ This process shared by inflammatory and cancer cells may partially explain the link between inflammation and the occurrence of metastasis. Furthermore, it may help to understand the therapeutic benefit of anti-inflammatory drugs in cancer treatment.

Scientific evidence has implicated a role of ICAM-1 in tumor invasion in vitro and in metastasis in vivo and hence in the malignant potential of various types of cancer. Kageshita et al⁷⁵ have demonstrated that ICAM-1 expression in primary lesions and the serum of patients with malignant melanoma was associated with a reduction in the disease-free interval and survival. Also, a significantly higher level of serum ICAM-1 (sICAM-1) was detected in the patients with liver metastasis, and its levels were increased in serial blood samples obtained from patients with progressing disease. Similar results were reported in a study that examined the role of ICAM-1 in the invasion of human breast cancer cells.⁷⁴

Maurer et al⁷⁶ determined that overexpression of ICAM-1, V-CAM-1, and endothelial leukocyte adhesion molecule 1 (ELAM-1) influenced the tumor progression in colorectal cancer. High expression of ICAM-1 in tumors was an indicator of metastatic potential and poor prognosis.⁷⁷ Because ICAM-1 is associated with a variety of cancer types and has a role in cancer metastasis, it can be also used as a biomarker for tumor prognosis as well as a target for therapeutic interventions.^78,79,80

Current evidence has shown that the binding of apical cell surface associated mucin (MUC-1) on circulating tumor cells to the ICAM-1 on the endothelial cells could represent one of the first crucial steps in metastasis. This molecule is a mucin-glycosylated phosphoprotein that lines the apical surface of epithelial cells in the lung and several other organs. Roland et al⁸¹ proposed that this binding results in a release of cytokines and chemokines that attract macrophages and upregulate tumor production of ICAM-1. Macrophages produce more cytokines that attract neutrophils (polymorphonuclear neutrophils, PMNs), which adhere to the ICAM-1 of the tumor cell surface. This interaction causes degranulation of the PMNs, releasing proteases, with subsequent deterioration of the endothelial barrier promoting extravasation of the tumor cells and formation of metastatic sites.^82,83,84,85

Another potent regulator of endothelial permeability and the inflammatory responses in tissue cells is Src kinase.⁸⁶ Src protein tyrosine kinase (PTK) family members have been identified as essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells.⁸⁷ The Src family of nonreceptor protein tyrosine kinases plays a critical role in a variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility adhesion, angiogenesis, and survival. Activation of Src family kinases is common in a variety of human cancers, may occur through different mechanisms, and is frequently a critical event in tumor progression. Src kinases appear to be important in the proliferation of the tumor, disruption of cell/cell contacts, migration, invasiveness, and resistance to apoptosis. Src family kinases are thus attractive targets for use as anticancer theurapeutics.⁸⁸

It has been demonstrated that once tumor cells leave their primary site, they enter the blood vessels and again they extravasate to form satellite lesions. It was shown in mice that endothelial barrier disruption by VEGF-mediated Src activation potentiated tumor cell extravasation and metastasis. Some of the metastatic tumor cells secrete VEGF, which subsequently activates Src and compromises the endothelial barrier by disrupting a VE-/-β-catenin complex in lung endothelial cell-cell junctions. This is supported by the findings that mice genetically deficient in the c-Src are resistant to tumor cell metastasis.⁸⁹ Src is also an upstream regulator of Rho family GTPases (guanosine triphosphatases) such as Rac and Rho, which together regulate dynamic changes in the cytoskeleton and control the disassembly of actin-based cytoskeletal structures and cell-matrix adhesions.⁹⁰

Finally, another protein that plays a role in inflammation by attracting monocytes and macrophages to the site is the monocyte chemoattractant protein 1 (MCP-1). This is a chemokine that exerts strong chemoattractant activities on monocytes, T cells, and NK cells.⁹¹ In addition to promoting the transmigration of circulating monocytes into tissues, MCP-1 exerts various other effects on these cells, including superoxide anion induction chemotaxis and calcium flux.⁹² Its production is also associated with angiogenesis and tumor invasion. Goede et al⁹³ analyzed the angiogenesis-inducing capability of MCP-1 and found it was a potent angiogenic factor when implanted into the rabbit cornea, with an effect similar to the specific angiogenic VEGF. Moreover, serum levels of MCP-1 have been found to be elevated in lung cancer patients with bone metastases.⁹⁴

Evidence of Antimetastatic Effect of Local Anesthetics

Anti-inflammatory properties of ropivacaine have been demonstrated in different experimental models of lung injury.⁹⁵ Lidocaine also has well-documented anti-inflammatory properties and a safer profile for systemic toxicity. As mentioned, inflammatory processes involving Src tyrosine protein kinase and ICAM-1 play a role in cancer metastasis. It could be hypothesized that the amide LAs might attenuate the metastatic process of cancer cells in a similar manner to the inflammatory one.

In a recent study, we showed that lidocaine and ropivacaine may inhibit inflammatory cytokine signaling, proliferation, and migration of lung adenocarcinoma cells.⁹⁶ The following in vitro study was performed: NCI-H838 lung cancer cells were incubated with TNF-α in the absence/presence of ropivacaine or lidocaine (1 nM, 1 μM, 10 μM, 100 μM). Cell lysates were analyzed for Src activation (phosphor-Y419 Src) and ICAM-1 phosphorylation (phosphor-Y512 ICAM-1) via Western blot. MCP-1 production, cell proliferation, and migration were also evaluated. The results of this work showed that both lidocaine and ropivacaine inhibited Src activation induced by inflammatory mediators TNF-α (Figures 17–2 and 17–3). We also showed that both lidocaine and ropivacaine attenuated TNF-α-induced MCP-1 production in H838 cancer cells, and that they inhibited their proliferation and migration as well (Figure 17–4). Interestingly, the ester LA chloroprocaine did not demonstrate these properties, suggesting these effects were specific to the amide type of LAs.

To support the direct inhibition of Src tyrosine protein kinase by the amide LAs, the cells were treated with veratridine, a sodium channel activator and tetrodotoxin (TTX), a non-LA sodium channel inhibitor. We did not observe any alteration in the phosphorylation status of Src and ICAM-1 after treatment with veratridine compared to untreated cells, indicating that the phosphorylation of these two proteins was independent from sodium channel activation. The application of TTX had no effect on the phosphorylation status of these proteins, neither after treatment with TTX alone compared to untreated cells nor after coincubation with TNF-α compared to TNF-α alone. Taken together with the results obtained in the experiments with veratridine, we postulated that the observed effects of the inhibition of Src and ICAM-1 phosphorylation were independent of sodium channel inhibition.

Metastatic disease after cancer surgery remains a crucial issue. Cancer dissemination is a multistep process in which many cellular and molecular regulatory mechanisms may be involved and are targets for therapeutic interventions.

Traditional systemic therapy is delayed for weeks after major surgery to allow wound healing and thus avoiding the risks of immunosuppression and postoperative infections. However, recent studies demonstrated that cellular and molecular events that are critical to the metastatic process may be significantly influenced during and immediately after surgery.⁹⁷ The perioperative period may be a window of therapeutic opportunity because metastasis may be initiated during this period. Preliminary studies using LAs have shown encouraging results for cancer outcomes. So far, the potential beneficial effect of regional anesthesia to improve long-term outcome after cancer surgery has contributed mainly to the inhibition of the neuroendocrine stress response to surgery and to the reduction in the requirements of the volatile anesthetics and opioids.

CONCLUSION

The amide LAs block TNF-α-induced Src activation and ICAM-1 phosphorylation in vitro. Both of these processes may favor the extravasation of tumor cancer cells and metastasis. Cytokines such as TNF-α increase the expression of ICAM-1 in the H838 NSCLC. Src protein tyrosine kinase, which lies both upstream and downstream of activated ICAM-1, functions as a regulator of endothelial permeability and is also involved in signaling epithelial-to-mesenchymal transformation and extravasation of cancer cells, a process necessary for tumor metastasis. The activity of these two systems is significantly inhibited in vitro by the application of amide-type LAs. The immediate postoperative period is a crucial time in surgical oncology because no treatment will be started for a few weeks. The application of amide-type LAs in the perioperative period may be beneficial in preventing metastasis. However, the current preliminary data require further studies before any clinical recommendations can be made.

REFERENCES