Skin incision leads to a local response that is intended to stop the bleeding and recruit the immune system to the injured site. Blood vessels constrict, and, at the same time, platelets attach to the endothelium and aggregate and release their granules to form a fibrin clot. During this process, several mediators of cell proliferation , extracellular matrix synthesis, and angiogenesis are released. Transforming growth factor beta 1 (TGF-ß1) and platelet-derived growth factor (PDGF) elicit rapid chemotaxis of neutrophils, monocytes, and fibroblasts to the injured area, which stimulates generation of additional cytokines. The latter include the angiogenic factor vascular endothelial growth factor (VEGF) and the pro-inflammatory molecules tumor necrosis factor alpha and interleukin 1 beta [14].

Age-related changes in the inflammatory response result in alterations in cell adhesion, cell migration, and cytokine production. The production of most chemokines (measured by messenger RNA levels) declined with age by 20–70%, although levels of some pro-inflammatory cytokines are increased [15]. Total leukocyte and neutrophil counts are slightly lower in samples from older individuals [16]; however, granulocyte adherence is greater in aged subjects, especially women [17]. Phagocytosis is decreased in neutrophils from old, compared with young, healthy donors, potentially secondary to reduced neutrophil CD16 expression in the aged [18]. Aging is sometimes associated with a persistent pro-inflammatory state. At the same time, there is a reduction in the ability to generate an acute inflammatory response during injury. This paradox can result in disrupted wound healing due to lack of synchronization between pro- and anti-inflammatory responses. Interestingly, adult men (mean age 61 years) who exercised before an experimental wound showed a reduction in stress-related neuroendocrine responses that was accompanied by accelerated wound healing [19], suggesting that targeted preoperative intervention may be of benefit.

Several hours after skin closure, re-epithelization begins [20]. Epidermal cells separate from neighboring cells, move from the dermis into the margins of the incisional area, and start to degrade extracellular matrix proteins. Epidermal cells express integrin receptors, produce collagenase, and activate plasmin by plasminogen activator. The cells proliferate about 1 or 2 days after the injury and produce a scaffold of basement membrane proteins from the margins inward. During this process, mediators and cytokines (interleukins, α-, and β-chemokines) that regulate angiogenesis are released [21]. Several days after the injury, macrophages, fibroblasts, and blood vessels simultaneously invade the wound [22]. Macrophages produce growth factors, such as TGF-ß1 and PDGF. Fibroblasts synthesize a new matrix (first a provisional matrix of fibrin, collagen III, fibronectin, and hyaluronic acid; later a structural matrix of primarily collagen I replaces the provisional matrix). Blood vessels supply oxygen and nutrients, which is essential to sustain the newly formed granulation tissue. As an example, the deposition of collagen relies on proline hydroxylase, an oxygen-dependent enzyme [23].

In healthy human volunteers , superficial , split-thickness wound epithelization is delayed in subjects over 65 years old when compared to the control group (18–55 years old) [24]. Impaired endothelial cell function and reduced VEGF expression are possible mechanisms of age-related deficits in angiogenesis, which has an adverse effect on the development of an effective microcirculation [25]. In an explant model, age-related deficiencies in angiogenesis were reversed, in part, by stimulation with angiogenic growth factors [26].

During the last phase of wound healing, the extracellular matrix begins to remodel, and the incision undergoes further contraction. Fibroblasts assume a myofibroblast phenotype characterized by bundles of alpha smooth muscle actin-containing microfilaments. Synchronized collagen reorganization occurs by synthesis and catabolism (although at a much slower rate than in previous stages), which allows the granulation tissue to turn into a scar. Deposition and remodeling of collagen are slower in aged animals resulting in less scar formation [27]. Moreover, the collagen deposited has a looser, more disorganized matrix that has decreased tensile strength. The changes in aged collagen matrix reflect decreases in circulating factors, in particular reduced levels of TGF-ß1 – a potent stimulator of collagen synthesis [28]. Of note, dermal fibroblasts from aged and young donors exposed to exogenous TGF-ß1 exhibit similar biosynthetic and contractile properties [29].

Smoking can accelerate aging by promoting oxidative stress [32] and telomere shortening [33]. Clinical assessment of skin wrinkling/aging in an aged cohort revealed that smoking one pack/day is equivalent to a decade of chronological aging [34]. It is disappointing that the aged are less likely to receive smoking cessation advice and support than younger adults [35]. Smoking decreases endothelial-dependent vasodilation and reduced blood flow to the skin due to activation of circulating leukocytes and platelet aggregation [36]. Smoking cessation for at least 4 weeks before surgery reduces the incidence of surgical site infection [37].

Despite the documented reduction in mortality and improvement of quality of life produced by physical activity, the molecular and cellular changes that occur during physical activity are still being elucidated [38]. Regular physical activity can, in part, abrogate age-induced endothelial dysfunction [39]. Increased blood flow to the skin was observed in aged male individuals who exercised regularly for a decade when compared to sedentary matched controls [40]. In a nonsurgical group, a short training schedule (three times per week for 1 month) was shown to improve wound healing [41].

Patients with diabetes mellitus are at increased risk of SSI , and perioperative hyperglycemia is a risk factor for postoperative infection, even in nondiabetics [42]. An intensive perioperative glycemic control with insulin has been recommended in high-risk surgical patients as it decreases mortality [43] and wound infections [44]. It is reasonable to assume that tight blood sugar control may be beneficial for wound healing in the aged population because it affects many pathways that regulate wound healing [45]. Several lines of evidence suggest that this line of reasoning is not straightforward. A trial of long-term intensive therapy of hyperglycemia in diabetic patients in the community reduced the risk of developing microvascular complications; however, the benefit was mainly in younger patients at early stages of diabetic complications, and the trial was stopped due to increased mortality in the intensive treatment group [46]. Intensive perioperative glycemic control did not demonstrate significant outcome differences compared with conventional glycemic control and resulted in an increase in hypoglycemic episodes [47]. Concerns regarding hypoglycemia are important because the aged are less likely to manifest clinical signs of severe hypoglycemia than the young [48]. Current recommendations suggest that perioperative insulin treatment of patients suffering from diabetes who are older than 70 years old should be more careful (similar to patients suffering from renal disease with a GFR < 45 ml/min) [49]. The role of glycemic control , blood sugar targets, and the duration of perioperative treatment that is required to reduce SSI (and other complications) still needs to be elucidated for the general surgical population. The results should be interpreted with caution in the aged population.

The Centers for Medicare and Medicaid Services implemented a project of prophylactic antimicrobials to decrease the morbidity and mortality associated with SSI . An agreement exists regarding the need for antibiotics in several types of surgeries (coronary artery bypass grafting, vascular, colorectal, hip/knee arthroplasty, and hysterectomy [50]) that are commonly performed on older adults. Underscoring the importance of antibiotic prophylaxis for the older population is data demonstrating that preoperative antibiotics administration is associated with reduced 60-day mortality in aged patients undergoing general surgery [51]. In carriers of nasal Staphylococcus aureus, decolonization with a topical application of an antibiotic that is effective against Gram-positive bacteria reduced any healthcare-associated wound infection [52] and SSIs [53].

Wound healing is dependent upon adequate levels of oxygen [54]. Oxygen interacts with growth factor signaling and regulates numerous transduction pathways necessary for cell proliferation and migration [55]. It is also an indispensable factor for oxidative killing of microbes [56]. Low oxygen tension in the wound bed is considered to be a predictor of the development of infection [55], particularly when subcutaneous tissue oxygenation (measured by a polarographic electrode) falls below 40 mmHg [57]. Meta-analyses of supplemental oxygen therapy to reduce SSI suggest a beneficial effect [58], although not for all types of surgeries [59]. While most authors suggest that supplemental oxygen during surgery is associated with a reduction in infection risk [60, 61], others propose it may be associated with an increased incidence of postoperative wound infection [62]. A prospective trial randomizing patients to either 30% or 80% supplemental oxygen during and 2 h after surgery did not find any difference in several outcome measures including death and wound healing [63]. Of note, the administration of oxygen to the aged may be limited by the finding that although arterial oxygen tension does not decrease with age, there is a reduced steady-state transfer of carbon monoxide in the lungs [64]. This indicates that oxygen transport could be diffusion-limited in older subjects, especially when oxygen consumption is increased. Furthermore, longitudinal studies of five healthy men over three decades showed impaired efficiency of maximal peripheral oxygen extraction [65], suggesting that tissue oxygen uptake is reduced in the aged [66]. Consequently, the potential benefit of increasing tissue oxygen tension during surgical wound repair in older patients should be further evaluated.

Clinical signs of intravascular volume status are often difficult to evaluate in older persons [67]. Moreover, the repercussions of extremes of intravascular volume have harmful sequelae. As an example, hypovolemia decreases tissue oxygen concentrations [68], while excessive fluid administration increases tissue edema, which can adversely affect healing [69]. In residents of nursing homes who are at a higher risk of impaired hydration (and subsequently reduced tissue oxygenation) [70], supplemental oral fluid intake did not reverse these deficits nor improve wound healing [71]. The need for more accurate determination of volume status is underscored by studies that show judicious use of fluids improves outcomes in the older population more than in the young population [72]. In a group of patients undergoing repair of femoral fractures (mean age 75 years old), using goal directed therapy shortened the hospital length of stay [73]. Consequently, a strategy of administering fluids in a manner that maintains optimal hemodynamics and end-organ perfusion is recommended.

Anemia is common in the older population. Over 8% of men and 6% of women greater than 65 years of age, and without severe comorbidities, have anemia as defined by hemoglobin levels below 10 g/dl [74]. Perioperative anemia in the aged population is associated with worse outcome [75]. However, an increase in red blood cell transfusions is correlated with increased SSI [76]. The optimal strategies to treat anemia preoperatively and to appropriately transfuse during surgery and postoperatively in order to maximize surgical wound healing in older adults have yet to be elucidated.

Mild perioperative hypothermia is common not only during general anesthesia but also during regional anesthesia [77]. Age is an independent risk factor for development of hypothermia during anesthesia [78]. Mild hypothermia during the intraoperative period increases the risk of surgical wound infection, even after clean procedures such as hernia, breast, and varicose vein surgeries [79]. Thermoregulatory responses are decreased in the aged [80], mostly due to altered regulation of skin blood flow in the setting of a reduced microcirculation [81]. During general anesthesia with isoflurane [82] and sevoflurane [83], the threshold for thermoregulatory vasoconstriction is reduced in the aged more than the young. The aged are at additional risk of perioperative hypothermia because clinical signs (such as shivering) are absent at the same time thermoregulation is impaired [84]. Rewarming of the older patient takes significantly longer than younger adults, reflecting the same physiology that predisposes older adults to hypothermia [85]. Consequently, it is prudent to maintain euthermia for every aged patient during the intraoperative and postoperative period, regardless of the type of anesthesia. Strategies that use multiple modalities, for example, prewarming with the use of warmed fluids and forced-air warming devices, are more effective in maintaining euthermia, specifically in prolonged surgeries and in the older population [86].

It is often assumed that the best anesthetic technique for older adults will result in reduction of the stress response while maintaining other compensatory responses. Numerous studies have evaluated the effects of different anesthetic techniques on markers of stress, metabolism, and inflammation . Administration of typical doses of volatile or intravenous agents does not suppress the endocrine response [87]. In contrast, regional anesthesia (most notably neuraxial blockade) blunts the endocrine stress response to surgery [88]. Thoracic epidural anesthesia increases peripheral tissue oxygen tension, even outside the dermatomes affected by the block [89]. Continuous lumbar plexus and sciatic nerve blocks did not affect cortisol levels but attenuated the postoperative inflammatory response (lower C-reactive protein) [90]. In a study of regional block after knee arthroplasty, clinical signs of inflammation were reduced although there were no detectable changes in levels of measured cytokines [91]. Although these clinical and theoretical perceptions often advocate for regional anesthesia rather than general anesthesia in older patients, there is no difference in various outcome measures [92, 93]. Studies that document a lower risk of SSI after neuraxial anesthesia than after general anesthesia (e.g., in a retrospective analysis of total hip or knee replacement [94]) are often lacking methodologically (e.g., the groups are dissimilar; the general anesthesia group was older with more comorbidities than those who received neuraxial anesthesia). Future studies will need to elucidate the effect of anesthetic technique (as well as the effects of different anesthetic medications such as opioids) on postoperative wound healing.

The effect of local anesthetic infiltration on wound healing has been studied in numerous models with conflicting results. Some suggest that exposure to local anesthetics enhances wound repair, others propose no effect or a negative impact [95]. Local anesthetics may positively influence wound healing by reducing the stress response and alleviating pain [96]. Intra-articular lidocaine, used to achieve pain management after knee surgery, increased oxygen tension in the subcutaneous tissue [97]. Conversely, local anesthetics can be detrimental by delaying the synthesis of collagen [98], by an antiproliferative effect on mesenchymal cells [99], and, specifically in the aged, by regulation of growth factors [100]. Dose-dependent properties of lidocaine may be pronounced in aged tissues; a longer drug half-life in older individuals is probably the result of age-related decreases in hepatic blood flow and clearance [101].

In a retrospective observational study of pressure ulcers that developed in the operating room, age was an independent risk factor, but there was no association with the duration of surgery, hypotension, or vasopressor use [104]. Current evidence in the general nonsurgical population supports the use of strategies to prevent pressure ulcers (use of support surfaces, repositioning the patient, optimizing nutritional status, and moisturizing sacral skin [105]). It is reasonable to apply these interventions in the operating room, although the efficacy of specific measures is still under investigation [106].

A closed claim analysis found that age is a risk factor for ulnar neuropathy after anesthesia [107]. The median age of individuals who experience postoperative ulnar and peroneal postoperative neuropathy is 50 years [108]. Potential mechanisms include age-related vulnerability of nerves (e.g., a deceleration of the ulnar nerve conduction velocity with age [109]), but global age-related microvascular and musculoskeletal changes probably play an important role. Aging is associated with sarcopenia (loss of skeletal muscle mass and function). Loss of muscle fiber begins at approximately 50 years of age, and by age 80, healthy individuals have lost about 30–50% of their muscle mass [110]. There is substantial variability between individuals in rates of sarcopenia that can be explained by gender, genetics, and lifestyle; however, much of the variability among individuals remains unexplained. The loss of muscle is accompanied by an increase in adipose tissue that results in a reduction of total body water [111]. These changes may predispose the nerve to compression from pressure against hard surfaces or bone, because there is a reduction in cushioning around the nerve. Sarcopenia leads to reduced mobility and is an important factor in the development of frailty, a state of extreme vulnerability to adverse events [112]. Results of trials that examined the benefits of exercise and dietary supplementation to improve muscle mass and physical performance in the aged are inconsistent [113]. Over 15 years ago, the ASA published a practice guideline aimed “to prevent or reduce the frequency of occurrence or minimize the severity of peripheral neuropathies that may be related to perioperative positioning of patients” [114]. While age is identified as one of the specific preexisting conditions that may predispose a patient to develop peripheral neuropathies (other predisposing factors that were identified are smoking, diabetes, vascular disease, and extremes of body weight), no age-specific preventive strategies were offered. At the minimum, strategies used in the operating room for the general population (support surfaces, repositioning) should be applied to older patients as well.

Age-related osteopenia (bone mass loss that is less severe than osteoporosis) is considered a condition primarily affecting postmenopausal females; however, older males (as well as those treated by glucocorticoids or with androgen deprivation therapy for prostate cancer) are also at increased risk for osteopenia. Sarcopenia and osteopenia may also contribute to the development of osteoarthritis [115]. About one third to half of adults older than 65 years suffers from osteoarthritis. Osteoarthritis is a degenerative process of joint cartilage and the underlying bone [116]. Aging makes the joint more susceptible to the effects of abnormal biomechanics, joint injury, genetics, and obesity. Clinically, osteoarthritis usually presents as pain and stiffness of joints. The most commonly involved joints are in the bones of the hand, but involvement of joints in the neck, lower back, knees, and hips can have ramifications for surgical positioning. Induction in a supine position with the head elevated may need to be modified in a patient with severe osteoarthritis of the neck, not only because of potential for a difficult airway but also because it may be difficult for the patient to lie supine with the head elevated on a pillow. Placing a patient in lithotomy position may be impossible in patients with severe hip and knee arthritis.