Inflammation, Wound Healing and Infection
Harriet W. Hopf
C. Richard Chapman
Michael B. Dorrough
Randal O. Dull
1. The most crucial component of infection prevention is frequent and effective hand hygiene.
2. The ideal hand hygiene agent kills a broad spectrum of microbes, has antimicrobial activity that persists for at least 6 hours after application, is simple to use, and has few side effects.
3. Wearing gloves does not reduce the need for hand hygiene.
4. Antibiotic prophylaxis has become standard for surgeries in which there is more than a minimum risk of infection. The most commonly used antibiotic for surgical prophylaxis is cefazolin, a first-generation cephalosporin, as the potential pathogens for most surgeries are Gram-positive cocci from the skin.
5. The exact timing for the administration of the antibiotic, ideally within 30 minutes to 1 hour of incision, depends on the pharmacology and half-life of the drug. Prophylactic antibiotics should be discontinued by 24 hours following surgery if postoperative dosing is selected at all. Prolonging the course of prophylactic antibiotics does not reduce the risk of infection but does increase the risk of adverse consequences of antibiotic administration, including resistance, Clostridium difficile infection, and sensitization.
6. Anesthesiologists should work in consultation with the surgeon to use guidelines determined by the local infection control committee to take initiative for administering prophylactic antibiotics because they have access to the patient during the 60 minutes prior to incision and can optimize timing of administration.
7. The standard teaching that oxygen delivery depends more on hemoglobin-bound oxygen (oxygen content) than on arterial PO2 may be true of working muscle, but it is not true of wound healing.
8. Although oxygen consumption is relatively low in wounds, it is consumed by processes that require oxygen at a high concentration.
9. High oxygen tensions (>100 mm Hg) can be reached in wounds but only if perfusion is rapid and arterial PO2 is high.
10. Peripheral vasoconstriction, which results from central sympathetic control of subcutaneous vascular tone, is probably the most frequent and clinically the most important impediment to wound oxygenation.
11. Prevention or correction of hypothermia and blood volume deficits has been shown to decrease wound infections and increase collagen deposition in patients undergoing major abdominal surgery.
12. Modifiable risks include smoking, malnutrition, hyperglycemia, hypercholesterolemia, and hypertension. These should be assessed and corrected when possible prior to surgery.
13. Maintenance of a high room temperature or forced air warming before, during, and after the operation is significantly more effective than other methods of warming, such as circulating water blankets placed under the patient and humidification of the breathing circuit.
14. Optimizing the volume of perioperative fluid administration to minimize morbidity and mortality remains a significant and controversial challenge.
15. Current best recommendations for volume management include replacing fluid losses based on standard recommendations for the type of surgery, replacement of blood loss, and replacement of other ongoing fluid losses (e.g., high urine output due to diuretic or dye administration, hyperglycemia, or thermoregulatory vasoconstriction).
16. Wounds are most vulnerable in the first few hours after surgery.
17. All vasoconstrictive stimuli must be corrected simultaneously to allow optimal healing.
18. Local perfusion is not assured until patients have a normal blood volume, are warm and pain-free, and are receiving no vasoconstrictive drugs; that is, until the sympathetic nervous system is inactivated.
19. Urine output is a poor, often misleading guide to peripheral perfusion.
20. Physical examination of the patient is a better guide to hypovolemia and vasoconstriction.
21. Administration of supplemental oxygen via face mask or nasal cannulae increases safety in patients receiving systemic opioids. As a side benefit, it may also improve wound healing, although this has not been formally studied. Pain control also appears important since it favorably influences both pulmonary function and vascular tone.
22. In patients with moderate to high risk of surgical site infection, anesthesiologists have the opportunity to enhance wound healing and reduce the incidence of wound infections by simple, inexpensive, and readily available means.
Despite major advances in the management of patients undergoing surgery—including aseptic technique, prophylactic antibiotics, and advances in surgical approaches such as laparoscopic surgery—surgical wound infection and wound failure remain common complications of surgery (Fig. 13-1). Wound complications are associated with prolonged hospitalization, increased resource consumption, and even increased mortality. More than 300,000 surgical site infections (SSIs; Table 13-1) occur each year in the United States at an estimated cost of more than $1 billion.1 A growing body of literature supports the concept that patient factors are a major determinant of wound outcome following surgery. Comorbidities such as diabetes and cardiac disease clearly contribute, but environmental stressors as well the individual response to stress may be equally important. In particular, wounds are exquisitely sensitive to hypoxia, which is both common and preventable. Perioperative management can be adapted to promote postoperative wound healing and resistance to infection. Along with aseptic technique and prophylactic antibiotics, maintaining perfusion and oxygenation of the wound is paramount. This chapter discusses how knowledge of the principles of infection control and the biology and physiology of wound repair and resistance to infection can improve outcomes.
Perhaps the most crucial component of infection prevention is frequent and effective hand hygiene. In 1847 Ignaz Semmelweis made the observation that women who delivered their babies in the First Clinic at the General Hospital of Vienna, staffed by medical students and physicians, had a mortality rate of 5 to 15%, largely the result of puerperal infections; this was substantially higher than the 2% rate of women who delivered at Clinic 2, which was staffed by midwife students and midwives.2 Students and physicians at Clinic 1 usually started the day performing autopsies (including on patients who died of puerperal fever) and then moved on to the Clinic, where they performed examinations on women in labor. Semmelweis made the connection, and although germ theory was some years off, he insisted that physicians and medical students wash their hands in a chlorinated solution when leaving the pathology laboratory. This reduced the rate of puerperal fever to the same rate as at Clinic 2. Soon, Semmelweis identified cases of transmission from an infected to an uninfected patient, and instituted the use of chlorinated solution hand washing between cases as well. He also demonstrated that the chlorinated solution was more effective than soap and water. Unfortunately, his innovation was not widely adopted, resulting from a combination of his delay in publishing his results, the reluctance of his colleagues to accept that they might be responsible for transmitting disease, and his lack of tact in trying to convince health care workers to adopt his measures. Despite our current knowledge of germ theory, hand hygiene remains an inexplicably neglected component of infection control: studies consistently demonstrate about a 40% rate of adherence (range, 5 to 81%) to hand-hygiene guidelines.3
Figure 13-1. Brennan et al.148 reviewed the records or 30,121 patients at 51 acute care hospitals in New York State in 1984 and found that surgical site infection was the most common adverse surgical event (and the second most common adverse event overall). Infect., infection; Tech. comp., technique complication; Diag., diagnosis; Therap, therapeutic; Proc., procedure. From Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study. NEJM 1991;324:370, with permission.
Bacteria are resident in the skin and can never be completely eliminated.3 Resident flora are embedded in the deeper folds of the skin and are more resistant to removal, but are also infrequently pathogenic. Coagulase-negative staphylococci and diphtheroids are the most common. Transient flora colonize the superficial layers of the skin and thus are easier to remove with hand hygiene. Transient flora are also the source of most health care-associated infections, as health care worker skin can become contaminated from patient contact or contact with contaminated surfaces. Contamination from surfaces is most commonly with organisms such as staphylococci and enterococci, which are resistant to drying. Even “clean” activities such as taking a patient's pulse or applying monitors can lead to hand contamination: 100 to 1,000 colony-forming units of Klebsiella species were measured on nurses' hands following such activities in one study.4 No studies have related hand contamination to actual transmission of infection to patients; however, numerous studies, starting with those of Semmelweis, have demonstrated a reduction in health care-associated infections following institution of hand hygiene or improved adherence to hand hygiene.3
A number of products are available for hand hygiene. The ideal agent kills a broad spectrum of microbes, has antimicrobial activity that persists for at least 6 hours after application, is simple to use, and has few side effects. The most commonly used and efficacious agents are reviewed here.
Plain (not antiseptic) soap and water are generally the least effective at reducing hand contamination.5 Although obvious dirt is removed by the detergent effect of soap and the mechanical action of washing, bacterial load is not greatly reduced. Further, soap and water hand hygiene is associated with high rates of skin irritation and drying, both of which are risk factors for an increased bacterial load. Soap and water are, however, the most effective at removing spores, and therefore should be used when contamination with Clostridium difficile or Bacillus anthracis is a concern.3
Table 13-1 Criteria for Defining a Surgical Site Infection (SSI)
Alcohol-based rinses and gels denature proteins, and this confers their antimicrobial activity.3 Ethanol is most commonly used because it has more antiviral activity than isopropanol. Antiseptics containing 60 to 95% ethanol with a water base are germicidal and effective against Gram-positive and Gram-negative bacteria, lipophilic viruses such as herpes simplex, human immunodeficiency, influenza, respiratory syncytial, and vaccinia viruses, and hepatitis B and C viruses. They have little persistent activity, although regrowth of bacteria does occur slowly after use of alcohol-based products. Combination with low doses of other agents such as chlorhexidine, quaternary ammonium compounds, or triclosan can confer persistent activity. Efficacy depends on volume applied (3 mL is superior to 1 mL) and duration of contact (ideally, 30 seconds).
Chlorhexidine is a cationic bisbiguanide that disrupts cytoplasmic membranes, resulting in precipitation of cellular contents.3 It is germicidal against Gram-positive bacteria and lipophilic viruses, with somewhat less activity against Gram-negative bacteria and fungi, and minimal against tubercle bacilli. It has substantial persistence on the skin, and the Centers for Disease Control and Prevention (CDC) has identified it as the topical agent of choice for skin preparation in central venous catheter insertion. It may cause severe corneal damage
after direct contact with the eye, ototoxicity after direct contact with the inner or middle ear, and neurotoxicity after direct contact with the brain or meninges. There are reports of bacteria that have acquired reduced susceptibility to chlorhexidine, but these are of questionable clinical pertinence since the concentrations at which resistance was found were substantially lower than that of commercially available products.
Iodine and iodophors (iodine with a polymer carrier) penetrate the cell wall and impair protein synthesis and cell membrane function.3 They are bactericidal against Gram-positive, Gram-negative, and some spore-forming bacteria including clostridia and Bacillus species, although inactive against spores. They also have activity against mycobacteria, viruses, and fungi. Their persistence is generally fairly poor. They cause more contact dermatitis than other commonly used agents, and allergies to this class of topical agent are common. Iodophors generally cause fewer side effects than iodine agents.
The choice of an antiseptic depends on the expected pathogens, acceptability by health care workers, and cost. In general, antiseptics cost about $1 per patient day, far less than the cost of health care-associated infections. In nine studies that examined the effect of improved hand hygiene adherence on health care-associated infections, the majority demonstrated that as hand hygiene practices improved, infection rates decreased.3
Barriers to hand hygiene include skin irritation and fear of skin irritation, inaccessibility, time, and health care worker acceptance (largely related to the other factors mentioned). Although alcohol-based agents have long been believed to cause more skin irritation, several recent trials have demonstrated less skin irritation and better acceptance with emollient-containing, alcohol-based hand rubs compared with either antimicrobial or nonantimicrobial soap. The use of appropriate (glove-compatible) lotions twice a day also reduces skin irritation—as well as leading to a 50% increase in hand hygiene frequency in one study.3 Alcohol-based gels are also generally more accessible than antiseptic soap and water, as the dispenser may be pocket-sized or placed conveniently near sites of patient care. It has been estimated that alcohol-based gels require only about 25% of the time of going to a sink to wash one's hands. However, soap and water should be used to remove particulate matter including blood and other body fluids or after five to ten applications of alcohol-based agent.
Adherence to hand hygiene guidelines (Tables 13-2, 13-3 and 13-4) generally decreases as the frequency of indicated hand washing increases, as the workload increases, and as staffing decreases. In an intensive care unit (ICU), hand hygiene for nurses is generally indicated about 20 times per hour, as compared with a normal ward where this number decreases to 8 per hour.3 In the operating room (OR), frequent patient contact by the anesthesiologist requires frequent hand hygiene, probably at about the level of nurses in the ICU, while accessibility is often quite limited. Sinks are available only outside the OR. Therefore, alcohol-based agents should be available within hand's reach of the anesthesia machine. Loftus et al.6 studied bacterial contamination of the anesthesia work area (adjustable pressure limiting valve complex and agent flowmeter) and cross-contamination of the sterile anesthesia stopcock during 61 first cases in their operating room. They found an average increase in bacterial contamination of the work area of 115 colonies per surface area sampled during cases (95% confidence interval: 62–169; p <0.001). Transmission of bacteria from the work area to the sterile stopcock in the patients' intravenous tubing occurred in 32% of cases, including transmission of methicillin-resistant Staphylococcus aureus (MRSA) in two cases and vancomycin-resistant Enterococcus in one case. A high level of contamination of the work area (>100 colonies per surface area sampled) increased the risk of stopcock contamination 4.7 fold (95% confidence interval: 1.42–15.42; p = 0.011). Thus, transmission of bacterial con-tamination by the anesthesia provider appears to be common,
a potential source of nosocomial infections, and largely preventable.6
Table 13-2 Indications for Hand Hygiene
Table 13-3 Hand Hygiene Technique
Wearing gloves does not reduce the need for hand hygiene. Although gloves provide protection, bacterial flora from patients may be cultured from up to 30% of health care workers who wear gloves during patient contact.3 Therefore, hand hygiene should be practiced both before putting on gloves and immediately after removal. Moreover, gloves should be removed or changed immediately after each procedure, including vascular access, intubation, and neuraxial anesthesia, because gloves become contaminated by patient contact just as hands do.
Artificial and long fingernails, as well as chipped fingernail polish, are associated with higher concentrations of bacteria on the hands of health care workers. Artificial nails have been identified as a source in several hospital-associated outbreaks of infection with Gram-negative bacilli and yeast, and CDC guidelines discourage wearing of artificial nails by health care workers in high-risk settings; many hospitals have banned wearing of artificial nails by any employee who has direct patient contact.3 It may also be appropriate to counsel patients scheduled for surgery that artificial nails may increase their risk of infection, although this has not been investigated. Large quantities of bacteria are typically trapped under the fingernails, and 2002 CDC guidelines recommend that health care workers keep their nail tips trimmed to less than ¼ inch.3
Bacteria may be cultured at higher concentrations from the skin beneath a ring. On the other hand, wearing a ring does not increase overall bacterial levels measured on the hands of health care workers. Therefore, it remains unclear whether transmission of infection could be reduced by prohibiting health care workers from wearing rings.3
Table 13-4 Skin Care
Masks have long been advocated as preventing surgical site infection, and are used almost universally in U.S. operating rooms. Tunevall7 studied the rate of wound infections in 3,088 patients over 115 weeks. In alternating weeks, OR personnel either wore masks or did not (personnel with active respiratory infections continued to wear masks). There was no difference in the rate of surgical wound infections (4.7 vs. 3.5%, respectively) in the two groups, nor in bacterial species cultured from the wounds. Friberg et al.8 demonstrated comparable air and surface contamination during sham surgery in a horizontal laminar air flow unit whether OR personnel wore a nonsterile hood and mask or a sterilized helmet aspirator system. When the head covering but not the mask was omitted, however, contamination increased three- to fivefold. These data suggest that wearing a head cover is useful for preventing SSI, while wearing a mask is not. Nonetheless, the study by Tunevall is a small one, and most hospital personnel continue to require a mask in the OR while surgical instruments are open. Moreover, the mask does serve the purpose of protecting the health care provider, particularly when combined with eye protection, and thus should most likely be used during tracheal intubation and at other times when protection from body fluids is appropriate.
Although the preponderance of postoperative surgical infections is caused by flora that are endogenous to the patient, environmental and airborne contaminants may also play a causative role. An important, but frequently overlooked, consideration is the role that traffic patterns into an OR can play in patient exposure to airborne organisms. A recent Israeli study of risk factors for surgical infection after total knee replacement demonstrated a trend toward increased infection rates with in increased number of orthopaedic surgeons or anesthetists present in the OR.9 This study reconfirmed a prior study showing a trend toward increased incidence of surgical site infection as the number of people in the operating suite increases.10 However, it has been noted in one audit that physicians and nurses did little to limit the number of people through ORs during procedures.11 Current recommended practices are that traffic patterns should limit the flow of people through an OR that is in use, and that no more people than necessary should be in an OR during a procedure.12 The anesthesiologist is clearly in a position to play a leadership role in controlling human traffic through the OR.
Mermel et al.13 in 1991 demonstrated that central venous lines placed by the anesthesiologist in the OR became infected more often (relative risk [RR], 2.1; p = 0.03) than those placed by surgeons or other providers, whether in or out of the OR. Contributing factors appeared to be site of placement and the stringency of aseptic technique. Internal jugular vein insertion has a greater risk of infection (RR, 4.3; p <0.01) compared with subclavian vein, although its other benefits may outweigh this risk. Raad et al.14 demonstrated that use of a maximal sterile barrier
technique versus sterile gloves and small sterile drapes led to a significant reduction in central venous catheter-related infection from 7.2 to 2.2% (p = 0.03). Therefore, gowning and gloving, careful aseptic technique, and use of a wide sterile field should be routine.15 In anesthetized patients, the central line is ideally placed before the surgical site is draped in order to avoid contamination of the wire on the underside of the surgical drape.
Epidural abscess formation is an extremely rare but potentially catastrophic complication of neuraxial anesthesia and epidural catheter placement. Therefore, careful attention to aseptic technique and infection control is required. The most important consideration is to prevent contamination of the needle and catheter. Thus, hand washing, skin preparation, draping, and maintenance of a sterile field should be carefully observed. Gowning and wearing a mask, however, are unlikely to reduce the risk of infection. Finally, epidurals should probably be avoided in patients known or suspected to have bacteremia or deferred until after appropriate antibiotics are administered.
After antibiotics came into widespread use in the 1940s and 1950s, there was much debate over the possibility that antibiotic prophylaxis might prevent SSI. In 1957 Miles et al.16 used a guinea pig model for the proof of principle that administration of an antibiotic prior to contamination (incision) could reduce the risk of surgical site infection. When appropriate antibiotics were given within 2 hours before or after intradermal injection of bacteria they were effective in preventing invasive infection and necrosis. When given outside this window, they were not effective. This gave rise to the concept of a “decisive period” in which antibiotics will be effective, which remains a guiding principle of antibiotic prophylaxis. Miles et al. also demonstrated that injection of epinephrine intradermally prior to administration of antibiotics led to antibiotic failure, as demonstrated in an increased wound infection rate. This demonstrated the crucial role of local perfusion in delivering antibiotics to the site. Knighton et al.,17 using the same model, demonstrated that increased inspired oxygen was equally as effective as antibiotics in preventing infection, and that the two effects were additive (Fig. 13-2). Knighton et al.18 also delayed the administration of oxygen for up to 6 hours after inoculation and demonstrated no reduction in effect. Thus, the decisive period for oxygen is considerably longer than that of antibiotics.
Two surgeons at Washington University in St. Louis, Harvey Bernard and William Cole,19 reported on the first controlled clinical trial of the efficacy of antibiotic prophylaxis in 1964 and demonstrated a benefit in abdominal operations. Thereafter, numerous clinical trials were performed with somewhat variable results. Eventually these served to define the timing and population in which prophylactic antibiotics work. By the 1970s antibiotic prophylaxis for high-risk surgery—meaning clean-contaminated and contaminated cases—was becoming well accepted and widely used, although some skeptics remained. In 1992, Classen et al.20 published their prospective series including 2,847 patients undergoing clean or clean-contaminated surgical procedures at LDS Hospital in Salt Lake City, UT (Fig. 13-3). They demonstrated that the decisive period for SSI in humans undergoing surgery was essentially the same as for experimental infections in guinea pigs. That is, they found the lowest infection rate when antibiotics were given within 2 hours before or after incision and a rapid increase in SSI rate when they were given outside that range. The best results, though only by a small margin and not statistically significant, were within 0 to 60 minutes of surgery, and this subsequently became the clinical standard.
Figure 13-2. The effect of oxygen and/or antibiotics on lesion diameter after intradermal injection of bacteria into guinea pigs. Note that at every level, oxygen adds to the effect of antibiotics and that increasing oxygen in the breathing mixture from 12 to 20% or from 20 to 45% exerts an effect comparable to that of appropriately timed antibiotics. (From Rabkin J, Hunt TK: Infection and oxygen, Problem wounds: The Role of Oxygen. Edited by Davis J, Hunt TK. New York, Elsevier, 1988, pp 1, with permission.)
Figure 13-3. The figure demonstrates rates of surgical wound infection corresponding to the temporal relation between antibiotic administration and the start of surgery. The number of infections and the number of patients for each hourly interval appear as the numerator and denominator, respectively, of the fraction for that interval. The trend toward higher rates of infection for each hour that antibiotic administration was delayed after the surgical incision was significant (z score = 2.00; p <0.05 by the Wilcoxon test). (From Classen D, Evans R, Pestotni KS, et al: The timing of prophylactic administration of antibiotics and the risk of surgical wound infection. NEJM 1992:326;281, with permission.)
Antibiotic prophylaxis has now become standard for surgeries in which there is more than a minimum risk of infection. Although not every surgery and situation has been studied, a strong rationale for the approach to prophylactic antibiotics has emerged. Several groups separately developed guidelines for use, culminating in recommendations published in 2004 by the National Surgical Infection Prevention Project.21 These guidelines emphasize timing and choice of appropriate agents. Guidelines generally do not specify antibiotic agents, although they give rationales for various choices.21 The agent for antibiotic prophylaxis must cover the most likely spectrum of bacteria presented in the surgical field (see Table 13-5). The most commonly used antibiotic for surgical prophylaxis is cefazolin, a first-generation cephalosporin, as the potential pathogens for most surgeries are Gram-positive cocci from the skin.21,22
By definition, prophylactic antibiotics are given pre- or intraoperatively. The exact timing for the administration of the antibiotic depends on the pharmacology and half-life of the drug. Ideally, administration of the prophylaxis should be within 30 minutes to 1 hour of incision.16,20,22,23 This is uncomplicated for antibiotics that can be given as a bolus dose (e.g., cephalosporins) or as an infusion over a few minutes (e.g., clindamycin) and thus provide tissue levels within minutes. For drugs like vancomycin that require infusion over an hour, coordination of administration is more complex. In general, it is considered acceptable if the infusion is started prior to incision. When a tourniquet is used, the infusion must be complete prior to inflation of the tourniquet. An appropriate dose based on body weight and volume of distribution should be given. Depending on the half-life, antibiotics should be repeated during long operations or operations with large blood loss.24 For example, cefazolin is normally dosed every 8 hours but the dose should be repeated every 4 hours intraoperatively.24 Finally, prophylactic antibiotics should be discontinued by 24 hours following surgery if postoperative dosing is selected at all. Prolonging the course of prophylactic antibiotics does not reduce the risk of infection but does increase the risk of adverse consequences of antibiotic administration,21 including resistance, Clostridium difficile infection, and sensitization.
Unfortunately, MRSA is becoming a more common pathogen. Although it varies by country, region, and hospital, about 60% of S. aureus are MRSA. Independent risk factors identified for MRSA infection include prolonged use of prophylaxis, use of drains for more than 24 hours, and increasing number of procedures performed on the patient. Hand hygiene is among the most effective means of preventing development of MRSA since alcohol-based gel used properly kills over 99.9% of all transient pathogens including MRSA. There does not appear to be a justification for using antibiotics effective against MRSA for prophylaxis in most clinical settings.
Because they have access to the patient during the 60 minutes prior to incision and can optimize timing of administration, anesthesiologists should work in consultation with the surgeon to use guidelines determined by the local infection control committee to take initiative for administering prophylactic antibiotics. In this way, anesthesiologists can make a major contribution to preventing surgical site infection. The Centers for Medicare and Medicaid Services has identified timely and appropriate antibiotic prophylaxis administration as a cornerstone of surgical site infection prevention. Physician and hospital reimbursements are increasingly tied to such performance measures, meaning anesthesiologists also have an economic interest in ensuring adherence to guidelines.
Mechanisms of Wound Repair
Wound healing is a complex process, requiring a coordinated repair response including inflammation, matrix production, angiogenesis, epithelization, and remodeling (Fig. 13-4). Many factors may impair wound healing. Systemic factors such as medical comorbidities, nutrition,25,26 sympathetic nervous system activation,27 and age28,29,30 have a substantial effect on the repair process. Local environmental factors in and around the wound including bacterial load,31 degree of inflammation, moisture content,32 oxygen tension,33 and vascular perfusion34 also have a profound effect on healing. Although all of these factors are important, perhaps the most critical element is oxygen supply to the wound. Wound hypoxia impairs each of the components of healing.35
Although the role of oxygen is usually thought of in terms of aerobic respiration and energy production via oxidative phosphorylation, in wound healing oxygen is required as a cofactor for enzymatic processes and for cell-signaling mechanisms. Oxygen is a rate-limiting component in leukocyte-mediated bacterial killing and collagen formation because specific enzymes require oxygen at a partial pressure of at least 40 mm Hg.36,37 The mechanisms by which the other processes are oxygen-dependent are less clear, but these processes also require oxygen at a concentration much above that required for cellular respiration.38,39,40,41
The Initial Response to Injury
A surgical incision disrupts the skin barrier, creating an acute wound, and an effective initial response to injury depends on the ability to clean foreign material and to resist infection. This response initiates a sequence of events that starts with any source of injury that disrupts homeostasis in the local environment and eventually leads to healing.
Wound healing has traditionally been described in four separate phases: hemostasis, inflammation, proliferation, and remodeling.42 Considerable overlap exists between each of these phases, and differentiating precisely when one phase ends and the next begins is virtually impossible. Each phase is composed of complex interactions between host cells, contaminants, cytokines and other chemical mediators that, when functioning properly, lead to repair of injury. These processes are highly conserved across species,43 indicating the critical importance of the inflammatory response that directs the process of cellular/tissue repair. When any component of healing is disturbed and interrupts the orderly progression of repair, wound failure may result.44
Injury damages the local circulation and causes platelets to aggregate and release a variety of substances, including chemoattractants and growth factors.42 The initial result is coagulation, which prevents exsanguination but also widens the area that is no longer perfused. Platelet degranulation releases platelet-derived growth factor, transforming growth factorbeta (TGF-β), epidermal growth factor, and insulinlike growth factor-1 (IGF-1), which conjointly initiate the inflammatory process.42 Bradykinin, complement, and histamine released by mast cells cause vasodilation and increased vascular permeability. Polymorphonuclear leukocytes arrive at the wound almost immediately and are followed by macrophages at 24 to 48 hours. These inflammatory cells activate in response to endothelial integrins, selectins, cell adhesion molecules, cadherins, fibrin, lactate, hypoxia, foreign bodies, infectious agents, and growth factors.42 In turn, macrophages and lymphocytes produce more lactate45 and growth factors, including IGF-1, leukocyte growth factor, interleukins (ILs) 1 and 2, TGF-β, and vascular endothelial growth factor (VEGF).46 This early inflammatory phase
is characterized by erythema and edema of the wound edges.
Table 13-5 UCSF Guidelines for Prophylactic Antibiotics in Adult Patients to Reduce Surgical Site Infection
Figure 13-4. Schematic of the processes of wound healing. (From Hunt T: Fundamentals of wound management in surgery, Wound Healing: Disorders of Repair. South Plainfield, NJ, Chirugecom, Inc, 1976, with permission.)
Activated neutrophils and macrophages also release proteases, including neutrophil elastase, neutrophil collagenase, matrix metalloproteinase, and macrophage metalloelastase.42These proteases degrade damaged extracellular matrix components to allow their replacement. Proteases also degrade the basement membrane of capillaries to enable inflammatory cells to migrate into the wound.
In wounds, local blood supply is compromised at the same time that metabolic demand is increased. As a result, the wound environment becomes hypoxic and acidotic with high lactate levels.47,48 This represents the sum of three effects: (1) decreased oxygen supply due to vascular damage and coagulation, (2) increased metabolic demand due to the heightened cellular response (anaerobic glycolysis), and (3) aerobic glycolysis by inflammatory cells.49,50 Leukocytes contain few mitochondria and therefore acquire energy from glucose, primarily by production of lactate and even in the presence of adequate oxygen supply.50 In activated neutrophils, the respiratory burst, in which oxygen and glucose are converted to superoxide, hydrogen ion, and lactate, accounts for up to 98% of oxygen consumption; in the setting of injury, this activity increases by up to 50-fold over baseline.51,52
Local hypoxia is a normal and inevitable result of tissue injury.53,54 Hypoxia acts as a stimulus to repair,55 but also leads to poor healing33 and increased susceptibility to infection.56,57Numerous experimental models16,56,57,58,59 as well as human clinical experience60,61,62 have led to the conclusion that wound healing is delayed in hypoxic wounds. The partial pressure of oxygen in dermal wounds is heterogeneous, ranging from 0 to 10 mm Hg in the central (“dead space”) portion of the wound, to 80 to 100 mm Hg (near arterial) adjacent to perfused arterioles and capillaries53 (Fig. 13-5). The PO2 of a given area depends on diffusion of oxygen from perfused capillaries, and thus wound PO2 depends on capillary density, arterial PO2, and the metabolic activity of the cells, with some contribution from shifts in the oxyhemoglobin dissociation curve associated with wound pH and temperature.
Resistance to Infection
After a disruption of the normal skin barrier, successful wound healing requires the ability to clear foreign material and resist infection. Neutrophils provide nonspecific immunity and prevent infection. Leukocytes migrate in tissue toward the site of injury via chemotaxis, defined as locomotion oriented along a chemical gradient.42 Chemical gradients can be produced both exogenously and endogenously. Exogenous gradients result from bacterial products present in contaminated tissues. Endogenous mediators include components of the complement system (C5a), products of lipoxygenase pathway (leukotriene B4), and cytokines (IL-1, 8), along with lactate.63
Together, these chemical mediators help to organize and control leukocyte invasion, bacterial killing, necrotic tissue removal, and the initiation of angiogenesis and matrix production. In the absence of infection, neutrophils disappear by about 48 hours. Nonspecific phagocytosis and intracellular killing are the major immune pathways activated in wounds.64
Figure 13-5. The varying oxygen tension in the wound module. Cross-section of the wound module in a rabbit ear chamber is in left upper corner of figure. Note that PO2, depicted graphically above the cross-section, is highest next to the vessels, with a gradient down to zero at the wound edge. Note also the lactate gradient, high in the dead space and lower (but still above plasma) toward the vasculature. Hydrogen peroxide is present at fairly high concentrations and is also a major stimulus to wound repair.73VEGF, vascular endothelial growth factor. (Modified version reprinted from IA Silver: The physiology of wound healing, Fundamentals of Wound Management. Edited by TK Hunt, JE Dunphy. New York, Appleton-Century-Crofts, 1980, p 30, with permission.)
Neutrophils are the primary cell responsible for nonspecific immunity, and their function depends on a high partial pressure of oxygen.36,65 This is because reactive oxygen species are the major component of the bactericidal defense against wound pathogens.64 Phagocytosis of the pathogen activates the phagosomal oxidase (also known as the primary oxidase or nicotinamide adenine dinucleotide phosphate-oxidase [NADPH]-linked oxygenase), present in the phagocytic membrane, which uses oxygen as the substrate to catalyze the formation of superoxide. Superoxide itself is bactericidal, but more importantly it initiates a series of cascades that produce other oxidants within the phagosome that increase bacterial-killing capacity (Fig. 13-6). For example, in the presence of superoxide dismutase, superoxide is reduced to hydrogen peroxide (H2O2). H2O2 combines with chloride and in the presence of myeloperoxidase forms the bactericidal hypochlorous acid, more commonly recognized as the active ingredient in bleach.65,66. Because intraphagosomal oxidant production depends on conversion of oxygen to superoxide, the process is exquisitely sensitive to the partial pressure of oxygen in the tissue. The Km (half-maximal velocity) for the phagosomal oxidase using oxygen as a substrate is 40 to 80 mm Hg.36 This means that resistance to infection is critically impaired by wound hypoxia and becomes more efficient as PO2 increases even to very high levels (500 to 1,000 mm Hg).36 Such levels do not occur naturally in tissue, but can be achieved by the administration of hyperbaric oxygen.67,68,69,70 This is one mechanism for the proposed benefit of hyperbaric oxygen therapy as an adjunctive treatment for necrotizing infections and chronic refractory osteomyelitis.71,72
Figure 13-6. Schematic of superoxide and other oxidant production within the phagosome. NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NADP, nicotinamide adenine dinucleotide phosphate; SOD, superoxide dismutase; MP, myeloperoxidase. (From Hunt TK, Hopf HW: Wound healing and wound infection. What surgeons and anesthesiologists can do. Surg Clin North Am 1997; 77(3): 587, with permission.)
Oxidants produced by inflammatory cells have a dual role in wound repair. Not only are they central to resistance to infection, but they also play a major role in initiating and directing the healing process. Oxidants, and in particular
hydrogen peroxide produced via the respiratory burst, increase neovascularization and collagen deposition in vitro and in vivo.73
The proliferative phase normally begins approximately 4 days after injury, concurrent with a waning of the inflammatory phase. It consists of granulation tissue formation and epithelization. Granulation involves neovascularization and synthesis of collagen and connective tissue proteins.
New blood vessels must replace the injured microcirculation. Neovascularization in wounds proceeds both by angiogenesis and vasculogenesis. Angiogenesis is the phenomenon of new vessel growth via budding from existing vessels. In the setting of wounds, new vessels grow from mature vessels, usually intact, postcapillary venules in the undamaged tissue immediately adjacent to the site of injury. Normally, the oxygen tension in adjacent tissue is sufficient to support this process. The new vessel growth extends and enters into the damaged areas that are typically high in lactate and have a low partial pressure of oxygen. Mature extracellular matrix is required for ingrowth of mature vessels.74
In vasculogenesis, bone marrow-derived endothelial precursor cells (EPCs) populate the tissue and differentiate and grow into new vessel tubules. In wounds, these tubules appear in the damaged area before any direct anastomosis with pre-existing vessels is made. These tubules must connect with existing vasculature to establish an intact blood supply in the wound. Angiogenesis has long been held to be the primary mechanism for new blood vessel growth in granulation tissue. Recent research, however, has demonstrated that as many as 15 to 20% of new blood vessels in wounds are derived from hematopoietic stem cells.74,75,76
Angiogenesis and vasculogenesis both occur in response to similar stimuli, consisting of some combination of redox stress, hypoxia, and lactate. However, the specific mechanisms by which they proceed appear to differ somewhat. Angiogenesis involves the movement of endothelial cells in response to three waves of growth factors. The first wave of growth factors comes with the release by platelets of platelet-derived growth factor, TGF-β, IGF-1, and others during the inflammatory phase. The second wave comes from fibroblast growth factor released from normal binding sites on connective tissue molecules. The third and dominant wave comes from VEGF, delivered largely by macrophages stimulated by fibrinopeptides, hypoxia, and lactate.77 Although it is usually present, hypoxia is not required for granulation because of constitutive (aerobic) lactate production by inflammatory cells and fibro-blasts. Too little lactate leads to inadequate granulation, while levels in excess of about 15 mM—usually associated with inflammation or infection—delay granulation.78The capillary endothelial response to angiogenic agents requires oxygen so that angiogenesis progresses in proportion to blood perfusion and arterial PO2.79
Vasculogenesis occurs in response to similar stressors as angiogenesis. EPCs are mobilized from the bone marrow into the circulation via a nitric oxide-mediated mechanism. Tissue hypoxia induces release of VEGF-A, which activates bone marrow stromal nitric oxide synthase. Increased bone mar-row nitric oxide leads to release of EPCs into the circulation. These circulating EPCs home to the wound via tissue-hypoxia–induced up-regulation of stromal cell-derived factor 1-α. Within the wound, EPCs undergo differentiation and participate in the formation of new blood vessels.75
Collagen and Extracellular Matrix Deposition
New blood vessels grow into the matrix that is produced by fibroblasts. Although fibroblasts replicate and migrate mainly in response to growth factors and chemoattractants, production of mature collagen requires oxygen.37,80,81 Lactate, hypoxia, and some growth factors induce collagen mRNA synthesis and procollagen production. Posttranslational modification by prolyl and lysyl hydroxylases is required to allow collagen peptides to aggregate into triple helices. Collagen can only be exported from the cell when it is in this triple helical structure. The helical configuration is also primarily responsible for tissue strength. The activity of the hydroxylases is critically dependent on vitamin C and tissue oxygen tension, with a Km for oxygen of about 25 mm Hg.37,80,81,82 Wound strength, which results from collagen deposition, is therefore highly vulnerable to wound hypoxia.33
Neovascularization and extracellular matrix (primarily collagen) production are closely linked. Fibroblasts cannot produce mature collagen in the absence of mature blood vessels that deliver oxygen to the site. New blood vessels cannot mature without a strong collagen matrix. Mice kept in a hypoxic environment of 13% inspired oxygen develop some new blood vessels in a test wound with the addition of exogenous VEGF or lactate, but these vessels are immature with little surrounding matrix and demonstrate frequent areas of hemorrhage.41
Epithelization is characterized by replication and migration of epithelial cells across the skin edges in response to growth factors. Cell migration may begin from any site that contains living keratinocytes, including remnants of hair follicles, sebaceous glands, islands of living epidermis, or the normal wound edge. In acute wounds that are primarily closed, epithelization is normally completed in 1 to 3 days. In open wounds healing by secondary intention, epithelization is the final phase of healing and cannot progress until the wound bed is fully granulated. Like immunity and granulation, epithelization depends on growth factors and oxygen. Silver83 and Medawar40 demonstrated in vivo that the rate of epithelization depends on local oxygen. Topical oxygen applied in a manner that does not dry out epithelial cells has been advocated as a method to increase the rate of epithelization.84 Ngo et al.85 demonstrated oxygen-dependent differentiation and cell growth in human keratinocyte culture. In contrast, O'Toole et al.86 demonstrated that hypoxia increases epithelial migration in vitro. This may be explained, at least in part, by the dependence of epithelization on the presence of a bed of healthy granulation tissue, which is known to be oxygen-dependent.
Maturation and Remodeling
The final phase of wound repair is maturation, which involves ongoing remodeling of the granulation tissue and increasing wound tensile strength. As the matrix becomes denser with thicker, stronger collagen fibrils, it becomes stiffer and less compliant. Fibroblasts are capable of adapting to changing mechanical stress and loading. Fibroblasts migrate throughout the matrix to help mold the wound to new stresses. Matrix metalloproteinases and other proteases help with fibroblast migration and continued matrix remodeling in response to mechanical stress. Some fibroblasts differentiate into myofibroblasts under the influence of TGF-β, resulting in contractile cells. As the myofibroblasts contract, the collagenous matrix cross-links in the shortened position. This helps to strengthen the matrix and minimize scar size. Contraction is inhibited by the use of high doses of corticosteroids.87 Even steroids given
several days after injury have this effect. In those wounds where contraction is detrimental, this effect can be used for benefit.
Net collagen synthesis continues for at least 6 weeks and up to 6 months after wounding. Over time, the initial collagen threads are reabsorbed and deposited along stress lines, conferring greater tensile strength. Collagen found in granulation tissue is biochemically different from collagen of uninjured skin, and a scar never achieves the tensile strength of uninjured skin. Hydroxylation and glycosylation of lysine residues in granulation tissue collagen lead to thinner collagen fibers. At 1 week, a wound closed by primary intention has only reached 3% of the tensile strength of normal skin. By 3 weeks it is at 30%, and it only reaches 80% after 3 to 6 months.
Some wounds heal to excess. Hypertrophic scar and keloid are common forms of abnormal scar due to abnormal responses to healing. Hypertrophic scarring may be thought of as “exuberant” scarring in which the inflammatory process that allows wound healing remains excessively active, resulting in stiff, rubbery, nonmobile scar tissue. Hypertrophic scars are most commonly seen following burns and are thought to correlate with the length of time required to close the wound, although other factors are also believed to play a role and are being actively explored. Keloids are scars that outgrow the boundaries of the initial scar, and are most typically seen following surgical incisions. Keloid formation is most likely due to a genetic predisposition, although exogenous inflammatory factors may also play a role.
Wound Perfusion and Oxygenation
Complications of wounds include failure to heal, infection, and excessive scarring or contracture. Rapid repair has the least potential for infection and excess scarring. The perioperative physician's goals, therefore, are to avoid contamination, ensure rapid tissue synthesis, and optimize the immune response. All surgical procedures lead to some degree of contamination that must be controlled by local host defenses. The initial hours after contamination represent a decisive period during which inadequate local defenses may allow an infection to become established.
Normally, wounds on the extremities and trunk heal more slowly than those on the face. The major difference in these wounds is the degree of tissue perfusion and thus the wound tissue oxygen tension. As a rule, repair proceeds most rapidly and immunity is strongest when wound oxygen levels are high, and this is only achieved by maintaining perfusion of injured tissue.88 Ischemic or hypoxic tissue, on the other hand, is highly susceptible to infection and heals poorly, if at all. Wound tissue oxygenation is complex and depends on the interaction of blood perfusion, arterial oxygen tension, hemoglobin dissociation conditions, carrying capacity, mass transfer resistances, and local oxygen consumption. Wound oxygen delivery depends on vascular anatomy, the degree of vasoconstriction, and arterial PO2.
The standard teaching that oxygen delivery depends more on hemoglobin-bound oxygen (oxygen content) than on arterial PO2 may be true of working muscle, but it is not true of wound healing. In muscle, intercapillary distances are small and oxygen consumption is high. In contrast, intercapillary distances are large and oxygen consumption is relatively low in subcutaneous tissue.38 In wounds, where the microvasculature is damaged, diffusion distances are substantially increased. Peripheral vasoconstriction further increases diffusion distance.53 The driving force of diffusion is partial pressure. Hence, a high PO2 is needed to force oxygen into injured and healing tissues, particularly in subcutaneous tissue, fascia, tendon, and bone, the tissues most at risk for poor healing.
Although oxygen consumption is relatively low in wounds, it is consumed by processes that require oxygen at a high concentration. Inflammatory cells use little oxygen for respiration, producing energy largely via the hexose-monophosphate shunt.36 Most of the oxygen consumed in wounds is used for oxidant production (bacterial killing), with a significant contribution as well for collagen synthesis, angiogenesis, and epithelization. The rate constants (Km) for oxygen for these components of repair all fall within the physiologic range of 25 to 100 mm Hg.36,37,40,65,80,89
Because of the high rate constants for oxygen substrate for the components of repair, the rate at which repair proceeds varies according to tissue PO2 from zero to at least 250 mm Hg. In vitro fibroblast replication is optimal at a PO2 of about 40 to 60 mm Hg. Neutrophils lose their ability to kill bacteria in vitro below a PO2 of about 40 mm Hg.90,91 These in vitro observations are clinically relevant. “Normal” subcutaneous PO2, measured in test wounds in uninjured, euthermic, euvolemic volunteers breathing room air, is 65 ± 7 mm Hg.92 Thus, any reduction in wound PO2 may impair immunity and repair. In surgical patients, the rate of wound infections is inversely proportional56 and collagen deposition is directly proportional33 to postoperative subcutaneous wound tissue oxygen tension.
High oxygen tensions (>100 mm Hg) can be reached in wounds but only if perfusion is rapid and arterial PO2 is high.33,88 This is because subcutaneous tissue serves a reservoir function, so there is normally flow in excess of nutritional needs and wound cells consume relatively little oxygen, about 0.7 mL/100 mL of blood flow at a normal perfusion rate.38,39When arterial oxygen tension (Pao2) is high, this small volume can be carried by plasma alone. Contrary to popular belief, therefore, oxygen-carrying capacity, that is, hemoglobin concentration, is not particularly important to wound healing, provided that perfusion is normal.93,94 Wound PO2 and collagen synthesis remain normal in individuals who have hematocrit levels as low as 15 to 18% provided they can appropriately increase cardiac output and vasoconstriction is prevented.94,95
Peripheral vasoconstriction, which results from central sympathetic control of subcutaneous vascular tone, is probably the most frequent and clinically the most important impediment to wound oxygenation. Subcutaneous tissue is both a reservoir to maintain central volume and a major site of thermoregulation. There is little local regulation of blood flow, except by local heating.96,97 Therefore, subcutaneous tissue is particularly vulnerable to vasoconstriction. Sympathetically induced peripheral vasoconstriction is stimulated by cold, pain, fear, and blood volume deficit,98,99 and by various pharmacologic agents including nicotine,92 β-adrenergic antagonists, and α1-agonists, all commonly present in the perioperative environment. Perioperative hypothermia is common and results from anesthetic drugs, exposure to cold, and redistri-bution of body heat from the core to the periphery.100 Blood loss and increases in insensible losses increase fluid requirements in the perioperative period, thereby leaving the patient vulnerable to inadequate fluid replacement. Thus, vasomotor tone is, to a large degree, under the perioperative physician's control.98,99
Prevention or correction of hypothermia101 and blood volume deficits102 have been shown to decrease wound infections and increase collagen deposition in patients undergoing major abdominal surgery. Preoperative systemic (forced air warmer) or local (warming bandage) warming have also been shown to decrease wound infections, even in clean, low-risk surgeries such as breast surgery and inguinal hernia repair.103 Subcutaneous tissue oxygen tension is significantly higher in patients with good pain control than those with poor pain control after
arthroscopic knee surgery.104 Stress also causes wound hypoxia and significantly impairs wound healing and resistance to infection.105,106 These effects are clearly mediated, in large part, by changes in the partial pressure of oxygen in the injured tissue.
Greif et al.107 demonstrated in a randomized, controlled, double-blind trial including 500 patients that in warm, volume-replete patients with good pain control undergoing major colon surgery, administration of 80% versus 30% oxygen intraoperatively and for the first 2 postoperative hours significantly reduced the wound infection rate by 50%. Belda et al.108replicated these results (significant 40% reduction in surgical site infection) in a randomized, controlled, double-blind trial in 300 colon surgery patients randomized to 80% versus 30% oxygen intraoperatively and during the first 6 postoperative hours. Surgical and anesthetic management were standardized and intended to support optimal perfusion. Myles et al.109demonstrated a significant reduction in major postoperative complications, as well as specifically wound infections in 2,050 major surgery patients randomized to 80% oxygen versus 30% oxygen in 70% nitrous oxide intraoperatively. A smaller (n = 165) randomized, controlled study by Pryor et al.,110 demonstrated a doubling of surgical site infection in patients randomized to 80% versus 35% oxygen intraoperatively. There were a number of methodologic flaws in the study, but, more importantly, the two groups of patients were not equivalent, which likely explained the increase in infections seen in the 80% oxygen group. Thus, the preponderance of evidence indicates that use of high inspired oxygen intraoperatively and providing supplemental oxygen postoperatively in well-perfused patients undergoing major abdominal surgery will reduce the risk of wound infection.
Delivery of antibiotics also depends on perfusion. Parenteral antibiotics given so that high levels are present in the blood at the time of wounding clearly diminish but do not eliminate wound infections.20 In about one third of all wound infections, the bacteria cultured from the wound are sensitive to the prophylactic antibiotic given to the patient, even when the antibiotics were given according to standard procedure.20 The vulnerable third of patients appear to be the hypoxic and vasoconstricted group. When antibiotics are present in the wound at the time of injury, they are trapped in the fibrin clot at the wound site where they may have efficacy against con-taminating organisms. Antibiotics diffuse poorly into the fibrin clot, however, so that later administration, whether more than 2 hours after injury or in response to wound infection, will have little effect. On the other hand, oxygen diffuses easily through the fibrin clots and is effective even 6 hours after contamination.18
Role of Dysregulation in Impaired Wound Healing
Human beings challenged by adverse physical or psychosocial events mount a coordinated, adaptive reaction characterized by physiological arousal. This response is often associated psychologically with the experience of threat or other negative affect. The term for such an arousal reaction is stress response, and any event that triggers such a response is a stressor. The major mechanisms of the stress response are the hypothalamo-pituitary-adrenocortical (HPA) axis and the sympatho-adrenomedullary (SAM) axis.111 Psychosocial stressors evoke cognitive responses such as appraisal, memory, expectation, and the attribution of meaning. These endogenous processes heavily involve the prefrontal and frontal cortices of the brain, and these cortices exert control over aspects of the hypothalamus, including the periventricular nucleus (PVN). The PVN initiates the HPA stress response and controls it through negative feedback mechanisms. The PVN triggers further stress response in the SAM axis by recruiting catecholaminergic cells in the rostral ventrolateral medulla. This structure is a cardiovascular regulatory area involved, together with the solitary nucleus, in the control of blood pressure. The rostral ventrolateral medulla activates the solitary nucleus and, together with it, provides tonic excitatory drive to sympathetic vasoconstrictor nerves that maintain resting blood pressure levels. A normal stress response involves a complex pattern of autonomic arousal that includes increased blood pressure followed by a period of recovery when blood pressure and other aspects of arousal return to normal.
Human life is complex and often involves repetitive stressors or a series of stressors. When the HPA axis must mount a new stress response before the previous stress response has fully recovered, it incurs risk of system dysregulation. That is, processes normally self-regulating through negative feedback become unregulated and dysfunctional, with maladaptive consequences. SAM dysregulation, which may involve altered medullary GABAergic neurotransmission,112 can result in abnormal blood flow of indefinite duration. This, in turn, can compromise oxygenation of the healing wound.
Given knowledge of the physiology of wound healing, what are the best strategies to ensure optimal healing? Wound infection, healing failure, and dehiscence are dreaded complications of surgery. To the degree they are predictable, interventions can be targeted at those patients most at risk (Table 13-6).
The CDC, in the “Study of the Effect of Nosocomial Infection Control” (SENIC),113 developed a remarkably useful and simple predictive tool based on a score of 0 or 1 for each of the following four patient factors: an abdominal operation, an operation that lasts 2 hours or more, a surgical site that is contaminated or infected, and a patient who will have three or more diagnoses at discharge, exclusive of wound infection. The risk of infection with a score of 0 is 1%, with a score of 1 is 3.6%, with a score of 2 is 9%, with a score of 3 is 17%, and with a score of 4 is 27%. These percentages may seem high, but this index was constructed on 3% of the American surgical patients in 1975–1976 and 1983, and the overall results are
consistent with numerous other studies. More recent risk analyses by the same group, based on simpler predictors (e.g., American Society of Anesthesiologists Physical Status Classification) have yielded less sensitivity, but about the same overall infection rate.114
Table 13-6 Preoperative Checklist
Modifiable risks include smoking, malnutrition, hyperglycemia, hypercholesterolemia, and hypertension. These should be assessed and corrected when possible prior to surgery. The decision to delay surgery must take into account both the urgency of the surgery and the severity of the risk.
Stress dysregulation also predisposes to poor wound healing. Human and murine studies are consistent in showing that exposing a subject to a stressor delays wound repair. Animal stress models typically involve restraint or social disruption, while human models usually employ a public speaking challenge.115 Laboratory stress is short term and associated with increased cortisol and corticosterone levels that down-regulate the early inflammatory response. This directly implicates the HPA axis, but the background processes are more extensive. Human studies can also take advantage of naturally occurring stressors such as academic examination or marital discord. Such studies compare stressed and nonstressed populations in rate of healing following a punch biopsy or induced blister. This approach allows investigators to study chronic conditions associated with dysregulation such as depression.
The mechanisms behind wound healing are more extensive than altered HPA axis function alone, and so negative clinical outcomes can take multiple forms. The nervous, endocrine, and immune systems operate interdependently through a common chemical language composed of neurotransmitters, hormones, cytokines, peptides, and endocannabinoids.111Simple stress can slow wound healing, but stress-induced dysregulation can lead to enduring dysfunction in autonomic nervous system, endocrine function, and/or immune function. Immune complications include impaired bacterial clearance at the wound,105 the sickness responses associated with proinflammatory cytokines,116 and systemic imbalance in the T-helper 1/T-helper 2 (Th1/Th2) cytokine profile. This profile represents balance in the contributions of helper T-cell subsets: Th1 is proinflammatory and Th2 anti-inflammatory. Th1-dominant imbalance indicates excessive inflammation with resultant fatigue, aching joints, and loss of appetite. Surgery sometimes creates a Th2 imbalance, which puts the patient at risk for sepsis, edema, and other complications such as poor sleep. Th1/Th2 balance normally recovers after surgery, but some patients come to surgery already chronically dysregulated in cytokine profile, which may predispose them to poor wound healing and other negative outcomes.
Adverse psychosocial circumstances at the time of surgery may put patients at risk for poor wound healing. Kiecolt-Glaser et al.117 studied the impact of hostile marital interactions on the healing of experimental blister wounds. High-hostile couples produced more proinflammatory cytokines and healed more slowly than low-hostile couples. Using a tape-stripping model, Muizzuddin et al.118 investigated the effect of marital dissolution on skin barrier recovery and found that high stress was associated with slower recovery. Bosch and colleagues119 studied the healing of a circular wound on the oral hard palate in subjects who varied in depression and/or dysphoria. High-dysphoric individuals had higher wound sizes from day 2 onward and depressive symptoms predicted slower wound healing. Collectively, these studies point to links between psychosocial distress, dysregulation at the system level, and impaired capacity for wound healing. It seems likely that stress-reduction techniques will reduce wound complications, and well-designed clinical trials are needed in this area.
Careful surgical technique is fundamental to optimal wound healing (Table 13-7). Delicate handling of the tissue, adequate hemostasis, and surgeon experience lead to healthier wounds. Incisions should be planned with regard to blood supply, particularly when operating near or in old incisions. Mechanical retractors should be released from time to time to allow perfusion to the wound edges. Judicious antibiotic irrigation of contaminated areas may be effective. Because dried wounds lose perfusion, wounds should be kept moist, especially during long operations. Not all wounds can be anatomically closed. Edema, obesity, the possibility of unacceptable respiratory compromise, or need to debride grossly contaminated or necrotic soft tissues can all interfere with closure of the wound.
As the operation proceeds, new wounds are made and contamination continues. All anesthetic agents tend to cause hypothermia—first, by causing vasodilation, which redistributes heat from core to periphery in previously vasoconstricted patients, and secondly by increasing heat loss and decreasing heat production.100 Vasoconstriction is uncommon intraoperatively, as the threshold for thermoregulatory vasoconstriction is decreased, but is often severe in the immediate postoperative period when anesthesia is discontinued and the thermoregulatory threshold returns to normal in the face of core hypothermia. The onset of pain with emergence from anesthesia adds to this vasoconstriction because of the associated catecholamine release.104 Rapid rewarming using a forced air warmer for hypothermic patients in the postanesthesia care unit (PACU) does appear to be effective,120although prevention of hypothermia is clearly the goal.101 Maintenance of a high room temperature or forced air warming before, during, and after the operation is significantly more effective than other methods of warming such as circulating water blankets placed under the patient and humidification of the breathing circuit.121
Surgical stress results in increased intravenous fluid requirements. The increased fluid requirement may be partly due to substances like IL-6, TNF, substance-P, and bradykinin, which are released in response to, and in proportion to, surgical stress.122 These inflammatory mediators cause both vasodilation and an
increase in vascular permeability.123 This loss of functional intravascular volume is in addition to other known causes of perioperative hypovolemia or fluid loss. These include preoperative mechanical bowel preparation, lack of oral intake, fever, pre-existing medical conditions, and medications such as diuretics, as well surgical fluid losses, which include evaporation and blood loss.
Table 13-7 Intraoperative Management
There are known serious complications of both hyper-volemia and hypovolemia, particularly in the perioperative period. The major complications associated with hyper-volemia include pulmonary edema, congestive heart failure, edema of gut with prolonged ileus, and possibly an increase in cardiac arrhythmias.124 The major complications of hypo-volemia, aside from hemodynamic instability, include decreased oxygenation of surgical wounds (which predisposes to wound infection),33,56,88,125,126,127 decreased collagen formation,33,102impaired wound healing, and increased wound breakdown.
Optimizing the volume of perioperative fluid administration to minimize morbidity and mortality remains a significant and controversial challenge. Estimates of blood loss, third-space fluid losses, and maintenance requirements are notoriously inaccurate and may lead to either over- or underreplacement if used as guides. Currently, most practitioners rely on clinical acumen, vital signs such as heart rate and blood pressure, and urine output to manage perioperative fluids. Surgical patients can be markedly hypovolemic without a change in any one of these variables because of the compensatory action of peripheral vasoconstriction,33,88,127 Unfortunately, this shunts blood away from skin, increases wound hypoxemia, and increases the risk of surgical wound infection.56 Kabon et al.128 performed a randomized, controlled trial to compare standard (8 mL/kg/hr) versus high (16 to 18 mL/kg/hr) volume administration in 253 patients undergoing elective colon resection. They found a trend toward reduced wound infections in the group that received high volume (8.5 vs. 11.3%), which would be a clinically significant reduction. Unfortunately, the study was terminated early, so it had inadequate power. Patients at high risk for heart failure or with end-stage renal disease were excluded, so the study also has limited generalizability.
A number of methods, both invasive and minimally invasive, have been investigated as more sensitive measures of volume status. Hartmann et al.102 used subcutaneous PO2 to guide perioperative volume management in a randomized controlled trial in abdominal surgery patients. Patients randomized to the intervention group (vs. usual management) received more fluid, had significantly higher wound oxygen tension, and deposited more collagen in a test wound.
Pulmonary arterial catheters have also been used in an attempt to optimize volume management, generally with little success. Most of these studies were performed in an ICU setting, rather than during surgery. In one study in 4,059 patients undergoing abdominal surgery,123 those who received a pulmonary artery (PA) catheter had worse outcomes than those who did not. In fact, the rate of major postoperative cardiac events was 15.4% in the PA catheter group versus 3.6% in the control group. This could be partly due to the observation that many clinicians misinterpret PA data.129 With recent studies demonstrating a lack of patient benefit with PA catheters and the increase in use and availability of less invasive monitors like echocardiography, the future of these catheters is uncertain.130
Intraoperative transesophageal echocardiography (TEE) has been advocated as a more useful monitor of intraoperative volume status. Mythen and Webb131 used TEE to optimize intraoperative volume management in 60 cardiac patients and demonstrated that the patients with TEE management received more intravenous (IV) fluid and had decreased gut hypoperfusion (7 vs. 56%) compared with traditional management. There were also fewer “major complications” (0 vs. 6), although the study was too small to achieve statistical significance. Sinclair et al.132 randomized 40 patients undergoing surgical repair of proximal femoral fractures to TEE-guided volume management or traditional management. The patients with the TEE management had faster recoveries and more rapid hospital discharge. Thus, TEE shows promise for guiding volume management in both cardiac and noncardiac surgeries. Identification of the appropriate markers and interventions, however, remains inadequately studied.
A final topic of debate is whether colloids or crystalloids are preferable for intraoperative fluid administration. Synthetic colloids have been associated with coagulopathy when large volumes are delivered, which appears to be in large part mediated by dilution of coagulation factors.133 Crystalloids, on the other hand, may cause a hypercoagulable state.134 The intravascular half-life of colloids, either albumin or synthetic colloids, is much longer than that of crystalloids, allowing the total volume of fluid administered to be reduced by including colloids in surgical fluid resuscitation.135 Edema formation may also be decreased. A number of studies124,135,136 purport to evaluate intraoperative or postoperative fluid administration in terms of restrictive versus traditional fluid management. Virtually all have compared colloid (“restrictive” group) with crystalloid (“traditional” group) administration. Thus, the “restricted” volume group likely received a larger amount of effective intravascular volume than the traditional or “liberal” group. In general, these studies have demonstrated improved outcomes (reduction in SSI, earlier return of bowel function) for the colloid group. The mechanism for the benefit is unclear, however, as on the basis of effective intravascular volume delivered, the crystalloid groups might actually have been less well volume replaced than the colloid groups.
Current best recommendations include replacing fluid losses based on standard recommendations (Table 13-8) for the type of surgery, replacement of blood loss, and replacement of other ongoing fluid losses (e.g., high urine output due to diuretic or dye administration, hyperglycemia, or thermoregulatory vasoconstriction). Maintenance of normothermia is
also critical to optimal volume management. Warm patients are unlikely to develop pulmonary edema with a high rate of fluid administration because they have excess capacitance due to vasodilation. Cold patients, on the other hand, are highly susceptible to pulmonary edema even after relatively small fluid boluses. Thermoregulatory vasoconstriction increases afterload, causing increased cardiac work. Moreover, administered fluid cannot open up constricted vessels until the hypothermic stimulus is removed; thus, there is virtually no excess capacitance in the system.
Table 13-8 Standard Volume Management Guidelines for Surgical Patients
Pain control should be addressed intraoperatively so that patients do not have severe pain on emergence. Achieving the goal is more important than the technique used to do so. Although regional anesthesia and analgesia may provide superior pain relief, the effects of specific analgesic regimens on wound outcome have not yet been adequately studied.
Wounds are most vulnerable in the first few hours after surgery (Table 13-9). Although antibiotics lose their effectiveness after the first hours, oxygen-mediated natural wound immunity lasts longer.17 Even a short period of vasoconstriction during the first day is sufficient to reduce oxygen supply and increase infection risk.56 Correction and prevention of vasoconstriction in the first 24 to 48 hours after surgery will have significant beneficial effects.56 Strict glycemic control is also important,137 although the best method to achieve this in the non-ICU setting has not yet been established.
All vasoconstrictive stimuli must be corrected simultaneously to allow optimal healing. Volume is the last to be corrected because vasoconstriction for other reasons induces diuresis and renders the patient relatively hypovolemic (peripherally, not centrally). These measures are particularly important in any patients at high risk for wound complications for other reasons (e.g., malnutrition, steroid use, diabetes), or when vasoconstrictive drugs such as beta-blockers and α-agonists are required for other reasons.
Local perfusion is not assured until patients have a normal blood volume, are warm and pain-free, and are receiving no vasoconstrictive drugs; that is, until the sympathetic nervous system is inactivated. Warming should continue until patients are thoroughly awake and active and can maintain their own thermal balance. After major operations, warming may be useful for many hours or even days. The goal is to achieve warmth at the skin; wound vasoconstriction due to cold surroundings often coexists with core hyperthermia. Moderate hyperthermia is not, itself, a problem. When extensive wounds are left open, warmth should be continued, and heat losses due to evaporation should be prevented to avoid vasoconstriction and to minimize caloric losses.
Table 13-9 Postoperative Management
Assessing perfusion, especially in the PACU, is critical. Unfortunately, urine output is a poor, often misleading guide to peripheral perfusion.126 Markedly low output may indicate decreased renal perfusion, but normal or even high urine output has little correlation to wound or tissue PO2. Many factors commonly present in the perioperative period, including hyperglycemia, dye administration, thermoregulatory vasoconstriction, adrenal insufficiency, and various drugs, may cause inappropriate diuresis in the face of mild hypovolemia.
Physical examination of the patient is a better guide to hypovolemia and vasoconstriction. Assess vasoconstriction by a capillary return time of >2 to 3 seconds at the forehead and >5 seconds over the patella. Eye turgor is another good measure of volume status. Finally, patients can usually distinguish thirst from a dry mouth. Skin should be warm and dry.
After major abdominal surgery, third-space losses continue for about 12 to 24 hours, so that increased fluid requirements continue. In general, for large abdominal cases, 2 to 3 mL/kg/hr of IV fluids is sufficient for the first 12 to 24 postoperative hours. After that period, the IV rate should be decreased below calculated maintenance levels because edema fluid begins to be mobilized, thus increasing circulating intravascular volume.
When excessive tissue fluids have accumulated, diuresis should be undertaken gently so that transcapillary refill can maintain blood volume. This applies to patients who need renal dialysis as well. The average dialysis patient vasoconstricts sufficiently to lower tissue PO2 by 30% or more during dialysis and needs about 24 hours to return vasomotor tone and wound and tissue PO2 to normal.138 Fluid losses from the vascular system are not necessarily replaced from the tissues as rapidly as they are sustained. Tissue edema may be the price paid for adequate intravascular volume. Edema increases intracapillary distance, so that there may be a delicate balance between excessive edema and peripheral vasoconstriction (which worsens the hypoxia caused by edema).
Vasoconstrictive drugs should be avoided. The most common and most avoidable is nicotine in the form of cigarettes. Beta-blockers should be used only when clearly medically indicated.139 Both are known to reduce wound and tissue PO2. Clonidine is an alternative drug for heart rate control140,141,142 that also induces vasodilation and may increase wound PO2.143 High-dose α-adrenergic agonists or other vasopressors may cause harm by decreasing tissue PO2, but in a limited experience we have found that lower doses have little or no effect on wound/tissue PO2. It is important to remember that decreasing cardiac output may also reduce wound perfusion. Thus, a balance must be maintained between minimizing use of vasopressors and maintaining adequate cardiac output.
Maintenance of tissue PO2 requires attention to pulmonary function postoperatively. Administration of supplemental oxygen via face mask or nasal cannulae increases safety in patients receiving systemic opioids.144 As a side benefit it may also improve wound healing, although this has not been formally studied. Pain control also appears important since it favorably influences both pulmonary function and vascular tone. This is particularly true in patients at high risk for pulmonary complications postoperatively, such as morbidly obese patients and those with pulmonary disease.145 Epidural analgesia may
be the route of choice in these patients. It has several advantages over parenterally administered opioids in that it generally achieves lower pain scores with less sedation. Nonetheless, opioid-induced pruritus is more common with epidural administration, and in some patients may be severe enough to counteract the benefits of pain control.
Patient-controlled analgesia is also quite effective at achieving low pain scores. It also has the benefit of giving control to the patient, leading to patient satisfaction as high as with epidural analgesia in many cases.146 Nurse-administered, as-needed doses of IV or intramuscular opioids should be avoided as inadequate pain control often exceeds 50% using this approach.147 The key to pain control is recognition of the need for analgesia and attention to the patient's complaints of pain. Opioid requirements vary enormously and are not always predictable, but even tolerant patients (IV drug abusers or those with cancer pain) can be given adequate pain relief with sufficient attention.
In patients with moderate to high risk of surgical site infection, anesthesiologists have the opportunity to enhance wound healing and reduce the incidence of wound infections by simple, inexpensive, and readily available means. Intraoperatively, appropriate antibiotic use, prevention of vasoconstriction through volume and warming, and maintenance of a high PaO2 (300 to 500 mm Hg) are key. Postoperatively, the focus should remain on prevention of vasoconstriction through pain relief, warming, and adequate volume administration in the PACU. The addition of measures to reduce and prevent the stress response is likely to be effective as well, although further study is required.
Areas for Future Research
§ When and why should a mask be worn in the OR?
§ Should IVs be placed using sterile technique? A-lines?
§ Is delay of antibiotics for culture justified?
§ Can you modulate more than the sympathetic nervous system?
§ Psychological preparation and intervention can modulate both HPA axis and SAM axis aspects of the stress response. Will this reduce wound complications?
§ Do nonsteroidal anti-inflammatory agents increase risk of wound complications?
§ Does dexamethasone for postoperative nausea and vomiting prophylaxis increase the risk of wound complications?
§ Do epidurals reduce the risk of SSI? Are they cost-effective (vs. time and risk)?
§ Who should get a high FIO2? Is there potential toxicity?
§ Does postoperative oxygen reduce wound complications? How long should patients receive supplemental oxygen postoperatively?
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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine