Free
Education  |   March 2014
Anesthesia, Microcirculation, and Wound Repair in Aging
Author Affiliations & Notes
  • Itay Bentov, M.D., Ph.D.
    From the Department of Anesthesiology and Pain Medicine (I.B.) and Division of Gerontology and Geriatric Medicine, Department of Medicine (M.J.R.), Harborview Medical Center, University of Washington, Seattle, Washington.
  • May J. Reed, M.D.
    From the Department of Anesthesiology and Pain Medicine (I.B.) and Division of Gerontology and Geriatric Medicine, Department of Medicine (M.J.R.), Harborview Medical Center, University of Washington, Seattle, Washington.
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Submitted for publication January 18, 2013. Accepted for publication September 24, 2013.
    Submitted for publication January 18, 2013. Accepted for publication September 24, 2013.×
Article Information
Education / Review Article / Cardiovascular Anesthesia
Education   |   March 2014
Anesthesia, Microcirculation, and Wound Repair in Aging
Anesthesiology 03 2014, Vol.120, 760-772. doi:10.1097/ALN.0000000000000036
Anesthesiology 03 2014, Vol.120, 760-772. doi:10.1097/ALN.0000000000000036
Abstract

Age-related changes in skin contribute to impaired wound healing after surgical procedures. Changes in skin with age include decline in thickness and composition, a decrease in the number of most cell types, and diminished microcirculation. The microcirculation provides tissue perfusion, fluid homeostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause further disruption of the microvasculature of aged skin. Perioperative management can be modified to minimize insults to aged tissues. Judicious use of fluids, maintenance of normal body temperature, pain control, and increased tissue oxygen tension are examples of adjustable variables that support the microcirculation. Anesthetic agents influence the microcirculation of a combination of effects on cardiac output, arterial pressure, and local microvascular changes. The authors examined the role of anesthetic management in optimizing the microcirculation and potentially improving postoperative wound repair in older persons.

Aged skin is at increased risk of poor postoperative wound healing. Changes in the cutaneous microcirculation with aging contribute to this risk. This review examines the role of anesthesia management on microcirculatory function.

SURGICAL wound repair is a major problem in the older population,1  who are at increased risk of wound dehiscence and infection.2  As a specific example, surgical site infections (SSIs) are common (approximately 500,000 cases annually in the United States), lead to worse patient outcome (patients who develop SSI are twice as likely to die),3  and are an enormous economic burden (1–10 billion dollars annually).4  Many factors contribute to age-related changes in skin5  and subsequent vulnerability to impaired wound healing and infection. Changes in skin with age (fig. 1) include a decline in epidermal and dermal thickness and composition, as well as a decrease in the number of most resident cell types. The dermal–epidermal junction is flattened and the microcirculation is diminished.6  The latter is defined as blood flow through arterioles, capillaries, and venules and is the key system that affects the entire skin surface. In the aging patient, the microcirculation in the skin is reduced by 40% between the ages of 20 and 70 yr.7  The microcirculation provides tissue perfusion, fluid hemostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause disruption of the microcirculation in the skin as manifested by local edema resulting from vasodilation and increased vascular permeability.
Fig. 1.
Numerous changes in skin with age contribute to impaired wound healing.
Numerous changes in skin with age contribute to impaired wound healing.
Fig. 1.
Numerous changes in skin with age contribute to impaired wound healing.
×
Perioperative management can be modified to optimize the microcirculation. Measures that support the microcirculation include careful use of fluids, normothermia, pain control, and smoking cessation.8  Factors that can be influenced by intraoperative management (judicious use of fluids, maintenance of normal body temperature, pain control, and increased tissue oxygen tension) have been suggested to be beneficial as well. Most anesthetic agents also influence the microcirculation: a reduction in cardiac output and arterial pressure decreases flow in the microcirculation, whereas anesthetic-induced local microvascular changes and vasodilatation can increase perfusion.9  Optimization of these variables plays an important role in enhancing the microcirculation in all patients, but is especially relevant if modifications could improve postoperative wound healing in the older population.
In this review, we will use skin as a representative organ to describe age-related changes that negatively affect the microcirculation and have subsequent impacts on wound healing and the incidence of postoperative infection. We will then examine the role of anesthesia management in minimizing detrimental effects on the microcirculation. A greater understanding of these variables could promote improvements that lead to better outcomes with respect to wound repair in older patients.
Summary of Wound Repair and Aging
It has been nearly a century since it was noted that the rate of cutaneous scar formation after a wound is inversely related to the age of the patient.10  Four decades ago, it was observed that older age was associated with an increased risk of postoperative disruption of the surgical wound, leading to higher mortality.11  Recent data suggest that in patients older than 65 yr, development of SSI is associated with a two-fold increase in cost and a staggering four-fold increase in mortality.12 
Wound healing ensues via a sequential chain of events (with variable overlap) that includes inflammation, tissue formation, and remodeling13  (fig. 2). Circulating factors have a pivotal role in each of these phases. Accordingly, as we will discuss below, immediate changes in the microcirculation influence each stages of the wound-healing response in aging. As human data is lacking, we have taken data from established animal models of aging. Although animal models are not uniformly predictive of responses in human tissues,14  several animal models of wound healing are generally accepted.15 
Fig. 2.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
Fig. 2.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
×
Inflammation
Immediately after injury to the skin, local blood vessels constrict and circulating platelets attach to the endothelial wall to prevent further bleeding. The platelets aggregate and release their granules to form a fibrin clot. During this process, several mediators and cytokines that are also regulators of cell proliferation, extracellular matrix synthesis, and angiogenesis are released. As examples, transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor 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 proinflammatory molecules tumor necrosis factor-α and interleukin-1β.16 
Age-related changes in the inflammatory response (fig. 3A) result in alterations in cell adhesion, cell migration, and cytokine production. In an aged mouse model of impaired wound healing, reduced phagocytosis by macrophages and delayed T-cell infiltration into wounds were found in the aged mice relative to young mice. As expected, the production of most chemokines (as measured by messenger RNA levels) declined by 20–70% with age,17  but levels of some proinflammatory cytokines increased. Subsequent studies highlighted the critical role of macrophages: when young mice were injected at a biopsy wound site with antimacrophage serum, they exhibited delayed closure of the wounds, similar to that of aged mice.18  In contrast, aged mice wounds that were given peritoneal macrophages from young mice showed enhanced wound healing.19  Interestingly, in old female mice, healing of full-thickness dermal wounds on the upper dorsum was accelerated by treadmill exercise, potentially reflecting an exercise-induced antiinflammatory response in the wound.20  Similarly, adult men (mean age, 61 yr) who exercised before an experimental wound showed a reduction in stress-related neuroendocrine responses that was accompanied by an accelerated wound healing.21  Another therapeutic intervention is suggested by the finding that castration of male mice is associated with a reduced inflammatory response and results in acceleration of cutaneous wound healing.22  This might reflect suppression of the androgen receptor, which enhances the inflammatory response through an increase in tumor necrosis factor-α expression.23  The quantity and distribution of several growth factors are also different between aged and young mice. Expression of platelet-derived growth factor, epidermal growth factor, and their cognate receptors is delayed with increasing animal age.24  Alterations of the inflammatory response are also found in aged humans. Although total leukocyte and neutrophil counts are slightly lower in samples from older individuals,25  granulocyte adherence is greater in aged subjects especially in women.26  Phagocytosis is decreased in neutrophils from old, compared with young, healthy donors, potentially secondary to reduced neutrophil CD16 expression in the aged.27 
Fig. 3.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
Fig. 3.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
×
In summary, inflammation is an important part of the initial host response to injury and pathogens. Aging is sometimes associated with a persistent proinflammatory 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 antiinflammatory responses.
Proliferation and Tissue Formation
Several hours after injury, reepithelization begins.28  Wounded epidermal cells express integrin receptors, produce collagenase, and activate plasmin by plasminogen activator. These changes allow them to separate from neighboring cells, interact with and degrade extracellular matrix proteins, and enable movement from the dermis into the margins of the wound area. Epidermal cells in the wound margins begin to proliferate approximately 1 or 2 days after the injury, producing a scaffold of basement membrane proteins from the margins inward. During this process, mediators and cytokines (interleukins and α- and β-chemokines) that regulate angiogenesis and influence the microcirculation are released.29  Several days after the injury, macrophages, fibroblasts, and blood vessels simultaneously invade the wound.30  Macrophages produce growth factors, such as TGF-β1 and platelet-derived growth factor. Fibroblasts synthesize a new matrix (first a provisional matrix of fibrin, collagen III, fibronectin, and hyaluronan; 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 hydroxlyase, an oxygen-dependent enzyme.31 
Studies based on animal models demonstrate that proliferation of the cell types responsible for tissue formation is reduced with aging32  (fig. 3B). As an example, punch biopsy samples obtained repeatedly over the life span of hamsters found that in vitro proliferative capacity of dermal fibroblasts mimicked in vivo dermal wound repair.33  In healthy human volunteers, superficial, split-thickness wound epithelization is delayed in older persons (older than 65 yr) when compared with the control group (18–55 yr old).34  Most studies suggest that wound angiogenesis is also decreased by approximately 70% 1 week after injury in aged animals.35,36  Others propose an altered, dysregulated response with some extracellular matrix components increased, some decreased, and many showing disrupted ultrastructure.37  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.38  In an explant model, age-related deficiencies in angiogenesis were reversed, in part, by stimulation with angiogenic growth factors.39 
Extracellular Matrix and Tissue Remodeling
During the last phase of wound healing, the extracellular matrix begins to remodel and the wound undergoes further contraction. Fibroblasts assume a myofibroblast phenotype characterized by bundles of α-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.40  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-β1—a potent stimulator of collagen synthesis.41  Of note, dermal fibroblasts from aged and young donors exposed to TGF-β1 exhibit similar biosynthetic and contractile properties.42 
Other matrix components43  that are altered with age (fig. 3C) include: decreases in osteonectin (also known as secreted protein acidic and rich in cysteine), increases in thrombospondin,44  and alterations in fibronectin and laminin.45,46  Nonprotein components of the extracellular matrix include glycosaminoglycans, such as hyaluronan, which interact with other matrix components to maintain hydration in the dermis. Hyaluronan is a linear disaccharide polymer that can range from 2 to 25,000 disaccharides with molecular masses up to 2 × 104 kDa. Hyaluronan size determines its biologic properties: high molecular-weight forms can inhibit proliferation and migration of many cell types, whereas middle and lower molecular-weight forms usually promote tissue formation.46  Hyaluronan content is maintained in aged wound dermis, but its degradation is reduced.47  Wound healing also requires matrix metalloproteinases (MMPs), which promote cell proliferation and vessel ingrowth by degrading the existing extracellular matrix. MMP activity is balanced, in part, by endogenous tissue inhibitors of metalloproteinases. Aged tissues are associated with dysregulation of MMP activity,48  with a tendency toward overexpression of MMPs49  and reduced levels of tissue inhibitors of metalloproteinases.50 
As highlighted above, alterations occur during each stage of wound repair in aging, and many of these changes negatively impact the microcirculation. Nonetheless, given sufficient time, aged animals eventually (age-related delay is approximately 30–40%) catch up to their young counterparts with respect to most aspects of tissue repair.51 
The Surgical Context of Wound Repair and Aging
Measures that support the microcirculation improve wound repair, thereby reducing the risk of postoperative dehiscence and infection.52  General preoperative measures such as smoking cessation and optimal management of comorbid medical conditions have been reviewed in other contexts.53,54  For the purpose of this review, we will focus on interventions in the perioperative setting.
Oxygen Administration
Wound healing is dependent upon adequate levels of oxygen.55  Oxygen interacts with growth factor signaling and regulates numerous transduction pathways necessary for cell proliferation and migration.56  It is also an indispensable factor for oxidative killing of microbes.57  Consequently, the effects of oxygen tension on the outcome of surgical wounds have been best studied in the context of postoperative infection. Resistance to surgical wound infection is presumed to be oxygen dependent—with low oxygen tension viewed as a predictor of the development of infection,56  particularly when subcutaneous tissue oxygenation (measured by a polarographic electrode) decreases to less than 40 mmHg.58 
In two recent meta-analyses, one found that perioperative supplemental oxygen therapy exerts a significant beneficial effect on the prevention of SSIs,59  whereas the other suggested a benefit only for specific subpopulations.60  Although most authors suggest that supplemental oxygen during surgery is associated with a reduction in infection risk,61,62  others propose it may be associated with an increased incidence of postoperative wound infection.63  Notably, in the latter report, the sample size was small and there was a difference in the baseline characteristics of the groups. 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, pulmonary complications, and wound healing.64  Of note, the administration of oxygen to aged subjects may be limited by the finding that although arterial oxygen tension did not decrease with age, there was reduced steady-state transfer of carbon monoxide in the lungs.65  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 3 decades showed impaired efficiency of maximal peripheral oxygen extraction,66  suggesting that tissue oxygen uptake is reduced in the aged subjects.67  This likely reflects a decrease in the number of capillaries as well as a reduction in mitochondrial enzyme activity.68  Animal models (rabbit69  and mouse69,70 ) have suggested that aging and ischemia have an additive effect on disruption of wound healing. Consequently, the potential benefit of increasing tissue oxygen tension during surgical wound repair in older patients should be further evaluated.
Fluid Management
Clinical signs of intravascular volume status are often difficult to evaluate in older persons.71  Moreover, the repercussions of extremes of intravascular volume have harmful sequelae. As an example, hypovolemia decreases tissue oxygen concentrations,72  whereas excessive fluid administration increases tissue edema, which can adversely affect healing.73  Numerous types of fluids74  and devices75  have been evaluated as optimizers of volume status in the general surgical population, but lack of definition of liberal versus restrictive regimens precludes evidence-based guidelines.76  When fluid administration was guided by subcutaneous oxygen tension rather than clinical criteria, patients received more fluids and accumulated more collagen in their surgical incisions.76  However, in residents of nursing homes who are at a higher risk of impaired hydration (and subsequently reduced tissue oxygenation),77  supplemental oral fluid intake neither reverses these deficits nor improves wound healing.78  The need for more accurate determination of volume status is underscored by studies which showed that judicious use of fluids improves outcomes in the older population more than in the young population.79  Goal-directed fluid therapy reduced the length of stay by an average of 2 days in general surgery cases where the mean age was 56–59 yr.80  In an older group of patients (mean age, 75 yr) undergoing repair of femoral fractures, use of goal-directed therapy shortened the length of stay by 8 days.81  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. More than 8% of men and 6% of women greater than 65 yr of age, and without severe comorbidities, have anemia as defined by hemoglobin levels less than 10 g/dl.82  Perioperative anemia in the aged population is associated with worse outcome.83  However, perioperative anemia results in an increase in erythrocyte transfusions, which are also correlated with adverse outcomes including SSI.84  Low level of hemoglobin in young healthy subjects does not reduce subcutaneous tissue oxygenation,85  suggesting that erythrocyte transfusions are not indicated to enhance wound healing. The optimal hemoglobin level to maximize wound healing in older patients remains to be elucidated.
Temperature
Mild perioperative hypothermia is common not only during general anesthesia but also during regional anesthesia.86  Age is an independent risk factor for the development of hypothermia during anesthesia.87  Mild hypothermia during the intraoperative period is associated with vasoconstriction as measured by skin temperature and subcutaneous tissue oxygen.88  This markedly increases the risk of surgical wound infection, even after clean procedures such as hernia, breast, and varicose vein surgeries.89  Thermoregulatory responses are decreased in the aged subjects,90  mostly due to altered regulation of skin blood flow in the setting of a reduced microcirculation.91  During general anesthesia with isoflurane92  and sevoflurane,93  the threshold for thermoregulatory vasoconstriction is reduced in the aged more than the young. The aged subjects are at additional risk of perioperative hypothermia because clinical signs (such as shivering) are absent at the same time thermoregulation is impaired.94  Rewarming of the older patient takes significantly longer than younger adults, reflecting the same physiology that predisposes older adults to hypothermia.95  Consequently, it is prudent to maintain euthermia for every aged patients during the intraoperative and postoperative periods, regardless of the type of anesthesia.
Strategies to maintain normothermia during anesthesia must take into account specific changes in the microcirculation. The initial decrease in core temperature results from the redistribution of heat to the peripheral microcirculation. Prewarming in the preoperative area might prevent redistribution of core heat.96  Combined strategies that use multiple modalities (prewarming with use of warmed fluids and forced-air warming devices), are more effective in prolonged surgeries and in the older population.97 
Anesthetic Management Impacts the Microcirculation and Subsequent Wound Healing
The role of anesthesia technique in postoperative wound repair is not well studied. However, several lines of retrospective data analyses of outcomes after cancer surgery suggest that anesthesia technique can influence mechanisms that are relevant to tissue repair processes.98  Wound healing and cancer progression share several pathways: cellular proliferation and migration are accelerated; the extracellular matrix undergoes greater turnover; and neovascularization is enhanced. These effects are mediated by a surge of inflammatory mediators, cytokines, and growth factors that are common to both wound repair and cancer. Although the endpoints in these studies were cancer recurrence or metastases, the subsequent changes in growth factor levels or activity of matrix-degrading MMPs99,100  are likely relevant to tissue healing. It is notable, however, that the groups studied differed not only in the use of inhalational versus IV agents but also in the use of other variables such as the amount of opiates used to control pain. Each of these components has collateral effects including changes in regional blood flow and the effective microcirculation. Nonetheless, the underlying mechanisms that influence cancer surgery outcomes should be noted when examining determinants of postoperative wound healing.
The Effect of Anesthesia Technique: General versus Regional.
Although clinical and theoretical perceptions often advocate for regional anesthesia rather than general anesthesia in older patients, there is no difference in various outcome measures.101,102  Comparisons are difficult: for example, in a retrospective analysis, neuroaxial anesthesia (epidural or spinal anesthesia) for total hip or knee replacement was associated with a lower risk of SSI than general anesthesia, but the general anesthesia group was older with more comorbidities making it difficult to form definitive recommendations.103 
Effects of anesthesia on physiologic variables relevant to the microcirculation and subsequent wound repair have been examined and will be discussed here. For example, general anesthesia causes vasodilation by direct effects on the peripheral microcirculation104  and indirectly by central inhibition of vasoconstriction.105  Thoracic epidural anesthesia increases peripheral tissue oxygen tension, even outside the dermatome affected by the block.106  Core hypothermia develops equally under general and epidural anesthesia due to vasodilation in the microcirculation in the skin and loss of thermoregulation. During epidural anesthesia, skin thermoregulation in the region affected by the epidural (lower body) is reduced independent of patient age. Not surprisingly, young patients are better able than older patients to maintain skin thermoregulation in the regions not affected by epidural anesthesia.107 
Administration of typical doses of volatile or IV agents does not suppress the contribution of the endocrine response to the microcirculation.108  In contrast, regional anesthesia (most notably neuroaxial blockade) blunts the endocrine stress response to surgery.109  Continuous lumbar plexus and sciatic nerve blocks did not affect cortisol levels but attenuated the postoperative inflammatory response (lower C-reactive protein).110  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.111  Epidural anesthesia reduces the plasma levels of norepinephrine during surgery when compared with general anesthesia.112  This holds true when combined general and epidural anesthesia is compared with general anesthesia alone.113  Norepinephrine and epinephrine induce vasoconstriction in the microcirculation114  and also have effects on subsequent biological processes that influence wound repair, such as angiogenesis and inflammation. For example, norepinephrine significantly increased secretion of the angiogenic factor VEGF by ovarian cancer and melanoma cell lines.115,116  Furthermore, epinephrine suppresses phagocytosis of soluble immune complexes (aggregated γ-globulin) by macrophages in a dose-dependent manner117  (fig. 4).
Fig. 4.
The effects of local anesthetics and regional anesthesia on wound healing.
The effects of local anesthetics and regional anesthesia on wound healing.
Fig. 4.
The effects of local anesthetics and regional anesthesia on wound healing.
×
Volatile Anesthetics Agents.
Volatile anesthetic agents have several contradictory effects on microcirculatory flow. They decrease flow in the microcirculation by reducing arterial perfusion pressure and depressing myocardial contractility. At the same time, these agents can increase flow in the microcirculation by inducing a vasodilatory response.118  As a result, clinically useful concentrations of volatile agents will often produce systemic hypotension and decrease regional tissue perfusion in a tissue- and agent-specific manner.119  Muscle perfusion under anesthesia with volatile agents is better maintained in young subjects than in aged subjects.120 
Not all effects of inhalation anesthesia are detrimental to tissue repair (fig. 5). Volatile anesthetics protect against ischemia–reperfusion injury of several organs (heart,121  liver,122  kidney,123  and potentially others) by reducing necrosis and inflammation.124  Several lines of evidence suggest that inhalation anesthetics exert their effects by affecting the microcirculation and influencing subsequent angiogenesis. For example, exposure to volatile anesthetics stimulates growth and proliferation of endothelial progenitor cells.125  Conversely, volatile anesthetics, at clinically relevant doses, block transcription factor hypoxia-inducible factor-1 activity and expression of its downstream target genes. Hypoxia-inducible factor-1 is a transcriptional regulator of VEGF expression126  and mediates angiogenic responses to reduced oxygen availability.127  When renal proximal tubule cells were exposed to volatile anesthetics for 16 h, there was an increased production and release of TGF-β1, a potent stimulator of extracellular matrix synthesis, into the cell culture media. The role of TGF-β1 in the protective effect of volatile agents on ischemic injury to the kidney was specifically demonstrated in vivo—mice heterozygous for TGF-β1 (TGF-β1+/−) were not protected from ischemia–reperfusion injury by sevoflurane, and a neutralizing TGF-β1 antibody blocked renal protection with sevoflurane in TGF-β1+/+ mice.128  Despite the data above, it is worth noting that volatile anesthetic agents differ in their effects on the microcirculation with respect to specific agents (desflurane vs. isoflurane vs. sevoflurane), target organs (heart vs. kidney vs. splanchnic), and clinical states (healthy vs. sepsis vs. hemorrhagic states).129  Consequently, we cannot make meaningful recommendations regarding volatile anesthetics and wound-healing outcomes.
Fig. 5.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
Fig. 5.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
×
Opioids.
Large doses of opioids are routinely used to achieve hemodynamic stability during the intraoperative period. Compared with other commonly used IV agents, opioids have the advantage of not depressing cardiac contractility.130  Opioids have multiple effects on the microcirculation, which include inducing the release of nitric oxide131  and directly relaxing smooth muscle cells.132  Opioids can both increase and decrease body temperature. The hyperthermic response to opioids is mediated by the μ-receptor and the hypothermic response is mediated by the κ-receptor.133  Morphine has several downstream effects that can influence wound repair, such as activation of G-protein–coupled receptors to induce cellular proliferation134  and activation of the VEGF receptor.135  Activation of a receptor in a ligand-independent manner can occur through different mechanisms and includes cross-talk between signaling pathways. For example interleukin-8, an angiogenic factor, can transactivate VEGF receptor-2.136  Human endothelial cells express the opioid responsive μ-3 receptor,137  but the effect of opioids on angiogenesis itself is still under investigation. Some suggest that opioids inhibit blood vessel growth138  and that opioid antagonists promote angiogenesis,139  probably via suppression of hypoxia-inducible factor-1 α-mediated VEGF transcription.140  Others found that opioids stimulate angiogenesis and tumor growth by inhibition of apoptosis and promotion of cell cycle progression in breast cancers.141,142 
There are conflicting findings regarding the direct effect of opioids on wound repair. The expression of μ-receptors is decreased in the margins of chronic wounds.143  Some describe opioid-induced, delayed wound healing that is dose dependent.144  The latter is proposed to be mediated, in part, by the inhibition of peripheral neuropeptide release into the healing wound and reduced neurokinin receptor expression in inflammatory and parenchymal cells.145  Others suggest that topical opioids accelerate wound healing146  by up-regulating nitric oxide synthase and the VEGF receptor-2.147 
Pain148  (as well as psychological stress)149  delays wound healing. Conversely, inappropriately high doses of opioids can also impair organ function, delay mobilization, and subsequent healing after surgery.150  A recent meta-analysis that compared analgesia after surgery with opioids alone as compared with a multimodal approach (in which an epidural was used in addition to general anesthesia) did not find a difference in mortality between the groups but found a lower complication rate in the multimodal group.151  Wound-healing rates were not reported in the meta-analysis. Further studies are needed to elucidate the effects of opioids and other pain-alleviating modalities on subsequent wound repair.
Other IV Anesthetic/Sedative Agents.
It is common for combinations of different agents to be used during induction and maintenance of anesthesia.152  To our knowledge, the effects of the IV agents on the microcirculation have been best studied in different models of shock states, such as profound hemorrhage. Consequently, the observed effects are usually transient and are of uncertain relevance to wound healing.
In general, most agents either produce no change in hemodynamic parameters or cause vasodilation and cardiac depression. In normovolemic rats, regional blood flow was similar for all anesthetic agents153  although some authors have described skeletal muscle arteriolar vasodilation with propofol. In a rat model of abdominal surgery, dexmedetomidine attenuated the reduction of the microcirculatory blood flow to the intestinal mucosa.154  Ketamine is an exception as it usually induces vasoconstriction and produces an increase in blood pressure and cardiac output.155  In certain models of hemorrhagic shock, at similar systolic blood pressures, propofol produced regional vasodilation, whereas ketamine resulted in vasoconstriction.156  Of note, the potential benefit of propofol on end-organ perfusion may be offset by the finding that macromolecular leak occurred from venules during propofol/fentanyl administration, but not during ketamine anesthesia.157  Midazolam (but not ketamine or propofol) stimulated the release of VEGF by smooth muscle cell cultures, which might induce further downstream changes in the microcirculation.158  VEGF induces angiogenic responses by inducing proliferation and migration and inhibiting apoptosis of endothelial cells.159 
Intravenous agents also have numerous effects on immune responses that might be relevant to subsequent wound healing. In vitro, clinically relevant concentrations of ketamine and midazolam (but not propofol) inhibited monocyte chemotaxis.160  Thiopental and etomidate (but not ketamine, propofol, or methohexital) decreased chemotaxis by eosinophils.161  Ketamine inhibits the inflammatory response of macrophages162  and antigen-presenting cells.163  Thiopental and midazolam, but not ketamine, suppressed neutrophil function.164 
In summary, the choice of IV anesthetic agents could potentially have beneficial effects on the microcirculation and subsequent wound healing. It is premature to make any specific recommendations, as cell and animal studies are insufficient and well-designed clinical studies do not exist.
Local Anesthetics.
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.165  Local anesthetics may positively influence wound healing by reducing the stress response and alleviating pain.166  Intraarticular lidocaine, used to achieve pain management after knee surgery, increased oxygen tension in the subcutaneous tissue.167  Local anesthetics can be detrimental by delaying the synthesis of collagen168  and by an antiproliferative effect on mesenchymal cells.169 
The response of the microcirculation to local anesthetics is not consistent. The first-known local anesthetic, cocaine,170  induces vasoconstriction, even at small doses, by inhibition of norepinephrine uptake.171  Modern local anesthetics (lidocaine172  and bupivacaine173 ) have a dose-dependent effect: low concentrations cause vasoconstriction of arterioles, whereas high concentrations cause vasodilation. Human studies suggest that dose-dependent properties of lidocaine may be pronounced in aged tissues. This likely reflects a longer drug half-life in older individuals, as a result of age-related decreases in hepatic blood flow and clearance.174 
Summary
Nearly every anesthesiologist who provides care to adults will participate in the care of geriatric patients.175  A growing older population is undergoing surgical procedures that are increasing in number and complexity.176  Poor healing of surgical wounds is a major cause of morbidity, mortality, and substantial economic burden. Wound healing is dependent on the microcirculation that supplies the incision area. Measures that support the microcirculation during the perioperative period have a profound effect on wound healing. Some measures such as maintenance of normal body temperature and control of postoperative pain are supported by ample evidence and have been implemented in routine clinical care. Other measures, for example, the choice of anesthesia technique and use of opioids are supported by basic research but need further clinical studies. A better understanding of the effect of aging and anesthesia on the microcirculation can potentially assist in improving postoperative wound repair, thereby benefiting a growing older population.
References
McGarry, SA, Engemann, JJ, Schmader, K, Sexton, DJ, Kaye, KS Surgical-site infection due to Staphylococcus aureus among elderly patients: Mortality, duration of hospitalization, and cost.. Infect Control Hosp Epidemiol. (2004). 25 461–7 [Article] [PubMed]
Lober, CW, Fenske, NA Cutaneous aging: Effect of intrinsic changes on surgical considerations.. South Med J. (1991). 84 1444–6 [Article] [PubMed]
Kirkland, KB, Briggs, JP, Trivette, SL, Wilkinson, WE, Sexton, DJ The impact of surgical-site infections in the 1990s: Attributable mortality, excess length of hospitalization, and extra costs.. Infect Control Hosp Epidemiol. (1999). 20 725–30 [Article] [PubMed]
Perencevich, EN, Sands, KE, Cosgrove, SE, Guadagnoli, E, Meara, E, Platt, R Health and economic impact of surgical site infections diagnosed after hospital discharge.. Emerg Infect Dis. (2003). 9 196–3 [Article] [PubMed]
Zouboulis, CC, Makrantonaki, E Clinical aspects and molecular diagnostics of skin aging.. Clin Dermatol. (2011). 29 3–14 [Article] [PubMed]
Montagna, W, Carlisle, K Structural changes in ageing skin.. Br J Dermatol. (1990). 122suppl 35 61–70 [Article] [PubMed]
Tsuchida, Y The effect of aging and arteriosclerosis on human skin blood flow.. J Dermatol Sci. (1993). 5 175–81 [Article] [PubMed]
Sørensen, LT Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: A systematic review and meta-analysis.. Arch Surg. (2012). 147 373–83 [Article] [PubMed]
Longnecker, DE Effects of general anesthetics on the microcirculation.. Microcirc Endothelium Lymphatics. (1984). 1 129–50 [PubMed]
Du Noüy, PL Cicatrization of wounds: III. The relation between the age of the patient, the area of the wound, and the index of cicatrization.. J Exp Med. (1916). 24 461–70 [Article] [PubMed]
Mendoza, CBJr, Postlethwait, RW, Johnson, WD Veterans Administration cooperative study of surgery for duodenal ulcer. II. Incidence of wound disruption following operation.. Arch Surg. (1970). 101 396–8 [Article] [PubMed]
Kaye, KS, Anderson, DJ, Sloane, R, Chen, LF, Choi, Y, Link, K, Sexton, DJ, Schmader, KE The effect of surgical site infection on older operative patients.. J Am Geriatr Soc. (2009). 57 46–54 [Article] [PubMed]
Singer, AJ, Clark, RA Cutaneous wound healing.. N Engl J Med. (1999). 341 738–46 [Article] [PubMed]
Seok, J, Warren, HS, Cuenca, AG, Mindrinos, MN, Baker, HV, Xu, W, Richards, DR, McDonald-Smith, GP, Gao, H, Hennessy, L, Finnerty, CC, López, CM, Honari, S, Moore, EE, Minei, JP, Cuschieri, J, Bankey, PE, Johnson, JL, Sperry, J, Nathens, AB, Billiar, TR, West, MA, Jeschke, MG, Klein, MB, Gamelli, RL, Gibran, NS, Brownstein, BH, Miller-Graziano, C, Calvano, SE, Mason, PH, Cobb, JP, Rahme, LG, Lowry, SF, Maier, RV, Moldawer, LL, Herndon, DN, Davis, RW, Xiao, W, Tompkins, RG Inflammation and Host Response to Injury, Large Scale Collaborative Research Program, Genomic responses in mouse models poorly mimic human inflammatory diseases.. Proc Natl Acad Sci U S A. (2013). 110 3507–12 [Article] [PubMed]
Gottrup, F, Agren, MS, Karlsmark, T Models for use in wound healing research: A survey focusing on in vitro and in vivo adult soft tissue.. Wound Repair Regen. (2000). 8 83–96 [Article] [PubMed]
Tarnuzzer, RW, Schultz, GS Biochemical analysis of acute and chronic wound environments.. Wound Repair Regen. (1996). 4 321–5 [Article] [PubMed]
Swift, ME, Burns, AL, Gray, KL, DiPietro, LA Age-related alterations in the inflammatory response to dermal injury.. J Invest Dermatol. (2001). 117 1027–35 [Article] [PubMed]
Cohen, BJ, Danon, D, Roth, GS Wound repair in mice as influenced by age and antimacrophage serum.. J Gerontol. (1987). 42 295–301 [Article] [PubMed]
Danon, D, Kowatch, MA, Roth, GS Promotion of wound repair in old mice by local injection of macrophages.. Proc Natl Acad Sci U S A. (1989). 86 2018–20 [Article] [PubMed]
Keylock, KT, Vieira, VJ, Wallig, MA, DiPietro, LA, Schrementi, M, Woods, JA Exercise accelerates cutaneous wound healing and decreases wound inflammation in aged mice.. Am J Physiol Regul Integr Comp Physiol. (2008). 294 R179–84 [Article] [PubMed]
Emery, CF, Kiecolt-Glaser, JK, Glaser, R, Malarkey, WB, Frid, DJ Exercise accelerates wound healing among healthy older adults: A preliminary investigation.. J Gerontol A Biol Sci Med Sci. (2005). 60 1432–6 [Article] [PubMed]
Ashcroft, GS, Mills, SJ Androgen receptor-mediated inhibition of cutaneous wound healing.. J Clin Invest. (2002). 110 615–24 [Article] [PubMed]
Lai, JJ, Lai, KP, Chuang, KH, Chang, P, Yu, IC, Lin, WJ, Chang, C Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression.. J Clin Invest. (2009). 119 3739–51 [Article] [PubMed]
Ashcroft, GS, Horan, MA, Ferguson, MW The effects of ageing on wound healing: Immunolocalisation of growth factors and their receptors in a murine incisional model.. J Anat. (1997). 190Pt 3 351–65 [Article] [PubMed]
Hsieh, MM, Everhart, JE, Byrd-Holt, DD, Tisdale, JF, Rodgers, GP Prevalence of neutropenia in the U.S. population: Age, sex, smoking status, and ethnic differences.. Ann Intern Med. (2007). 146 486–92 [Article] [PubMed]
Silverman, EM, Silverman, AG Granulocyte adherence in the elderly.. Am J Clin Pathol. (1977). 67 49–52 [PubMed]
Butcher, SK, Chahal, H, Nayak, L, Sinclair, A, Henriquez, NV, Sapey, E, O’Mahony, D, Lord, JM Senescence in innate immune responses: Reduced neutrophil phagocytic capacity and CD16 expression in elderly humans.. J Leukoc Biol. (2001). 70 881–6 [PubMed]
Clark, RA Basics of cutaneous wound repair.. J Dermatol Surg Oncol. (1993). 19 693–706 [Article] [PubMed]
Gillitzer, R, Goebeler, M Chemokines in cutaneous wound healing.. J Leukoc Biol. (2001). 69 513–21 [PubMed]
McClain, SA, Simon, M, Jones, E, Nandi, A, Gailit, JO, Tonnesen, MG, Newman, D, Clark, RA Mesenchymal cell activation is the rate-limiting step of granulation tissue induction.. Am J Pathol. (1996). 149 1257–70 [PubMed]
Mussini, E, Hutton, JJJr, Udenfriend, S Collagen proline hydroxylase in wound healing, granuloma formation, scurvy, and growth.. Science. (1967). 157 927–9 [Article] [PubMed]
Reed, MJ, Koike, T, Puolakkainen, P Wound repair in aging. A review.. Methods Mol Med. (2003). 78 217–37 [PubMed]
Bruce, SA, Deamond, SF Longitudinal study of in vivo wound repair and in vitro cellular senescence of dermal fibroblasts.. Exp Gerontol. (1991). 26 17–27 [Article] [PubMed]
Holt, DR, Kirk, SJ, Regan, MC, Hurson, M, Lindblad, WJ, Barbul, A Effect of age on wound healing in healthy human beings.. Surgery. (1992). 112 293–7; discussion 297–8 [PubMed]
Swift, ME, Kleinman, HK, DiPietro, LA Impaired wound repair and delayed angiogenesis in aged mice.. Lab Invest. (1999). 79 1479–87 [PubMed]
Reed, MJ, Corsa, A, Pendergrass, W, Penn, P, Sage, EH, Abrass, IB Neovascularization in aged mice: Delayed angiogenesis is coincident with decreased levels of transforming growth factor beta1 and type I collagen.. Am J Pathol. (1998). 152 113–23 [PubMed]
Ashcroft, GS, Horan, MA, Ferguson, MW Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model.. J Invest Dermatol. (1997). 108 430–7 [Article] [PubMed]
Rivard, A, Fabre, JE, Silver, M, Chen, D, Murohara, T, Kearney, M, Magner, M, Asahara, T, Isner, JM Age-dependent impairment of angiogenesis.. Circulation. (1999). 99 111–20 [Article] [PubMed]
Arthur, WT, Vernon, RB, Sage, EH, Reed, MJ Growth factors reverse the impaired sprouting of microvessels from aged mice.. Microvasc Res. (1998). 55 260–70 [Article] [PubMed]
Reiser, K, McGee, C, Rucker, R, McDonald, R Effects of aging and caloric restriction on extracellular matrix biosynthesis in a model of injury repair in rats.. J Gerontol A Biol Sci Med Sci. (1995). 50A B40–7 [Article] [PubMed]
Ashcroft, GS, Dodsworth, J, van Boxtel, E, Tarnuzzer, RW, Horan, MA, Schultz, GS, Ferguson, MW Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels.. Nat Med. (1997). 3 1209–15 [Article] [PubMed]
Reed, MJ, Vernon, RB, Abrass, IB, Sage, EH TGF-beta 1 induces the expression of type I collagen and SPARC, and enhances contraction of collagen gels, by fibroblasts from young and aged donors.. J Cell Physiol. (1994). 158 169–79 [Article] [PubMed]
Trombetta-Esilva, J, Bradshaw, AD The function of SPARC as a mediator of fibrosis.. Open Rheumatol J. (2012). 6 146–55 [Article] [PubMed]
Agah, A, Kyriakides, TR, Letrondo, N, Björkblom, B, Bornstein, P Thrombospondin 2 levels are increased in aged mice: Consequences for cutaneous wound healing and angiogenesis.. Matrix Biol. (2004). 22 539–47 [Article] [PubMed]
Kyriakides, TR, Bornstein, P Matricellular proteins as modulators of wound healing and the foreign body response.. Thromb Haemost. (2003). 90 986–92 [PubMed]
Sprenger, CC, Plymate, SR, Reed, MJ Aging-related alterations in the extracellular matrix modulate the microenvironment and influence tumor progression.. Int J Cancer. (2010). 127 2739–48 [Article] [PubMed]
Reed, MJ, Damodarasamy, M, Chan, CK, Johnson, MN, Wight, TN, Vernon, RB Cleavage of hyaluronan is impaired in aged dermal wounds.. Matrix Biol. (2013). 32 45–51 [Article] [PubMed]
Parrinello, S, Coppe, JP, Krtolica, A, Campisi, J Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation.. J Cell Sci. (2005). 118Pt 3 485–96 [Article] [PubMed]
Ashcroft, GS, Horan, MA, Herrick, SE, Tarnuzzer, RW, Schultz, GS, Ferguson, MW Age-related differences in the temporal and spatial regulation of matrix metalloproteinases (MMPs) in normal skin and acute cutaneous wounds of healthy humans.. Cell Tissue Res. (1997). 290 581–91 [Article] [PubMed]
Ashcroft, GS, Herrick, SE, Tarnuzzer, RW, Horan, MA, Schultz, GS, Ferguson, MW Human ageing impairs injury-induced in vivo expression of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and -2 proteins and mRNA.. J Pathol. (1997). 183 169–76 [Article] [PubMed]
Reed, MJ, Karres, N, Eyman, D, Vernon, RB, Edelberg, JM Age-related differences in repair of dermal wounds and myocardial infarcts attenuate during the later stages of healing.. In Vivo. (2006). 206B 801–6 [PubMed]
Hunt, TK, Hopf, HW Wound healing and wound infection. What surgeons and anesthesiologists can do.. Surg Clin North Am. (1997). 77 587–6 [Article] [PubMed]
Leaper, DJ Risk factors for and epidemiology of surgical site infections.. Surg Infect (Larchmt). (2010). 11 283–7 [Article] [PubMed]
Davis, GB, Peric, M, Chan, LS, Wong, AK, Sener, SF Identifying risk factors for surgical site infections in mastectomy patients using the National Surgical Quality Improvement Program database.. Am J Surg. (2013). 205 194–9 [Article] [PubMed]
Tandara, AA, Mustoe, TA Oxygen in wound healing—More than a nutrient.. World J Surg. (2004). 28 294–300 [Article] [PubMed]
Sundaresan, M, Yu, ZX, Ferrans, VJ, Sulciner, DJ, Gutkind, JS, Irani, K, Goldschmidt-Clermont, PJ, Finkel, T Regulation of reactive-oxygen-species generation in fibroblasts by Rac1.. Biochem J. (1996). 318Pt 2 379–82 [PubMed]
Babior, BM Oxygen-dependent microbial killing by phagocytes (first of two parts).. N Engl J Med. (1978). 298 659–68 [Article] [PubMed]
Hopf, HW, Hunt, TK, West, JM, Blomquist, P, Goodson, WHIII, Jensen, JA, Jonsson, K, Paty, PB, Rabkin, JM, Upton, RA, von Smitten, K, Whitney, JD Wound tissue oxygen tension predicts the risk of wound infection in surgical patients.. Arch Surg. (1997). 132 997–4; discussion 1005 [Article] [PubMed]
Qadan, M, Akça, O, Mahid, SS, Hornung, CA, Polk, HCJr Perioperative supplemental oxygen therapy and surgical site infection: A meta-analysis of randomized controlled trials.. Arch Surg. (2009). 144 359–66; discussion 366–7 [Article] [PubMed]
Togioka, B, Galvagno, S, Sumida, S, Murphy, J, Ouanes, JP, Wu, C The role of perioperative high inspired oxygen therapy in reducing surgical site infection: A meta-analysis.. Anesth Analg. (2012). 114 334–42 [Article] [PubMed]
Greif, R, Akça, O, Horn, EP, Kurz, A, Sessler, DI Outcomes Research Group, Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection.. N Engl J Med. (2000). 342 161–7 [Article] [PubMed]
Belda, FJ, Aguilera, L, García de la Asunción, J, Alberti, J, Vicente, R, Ferrándiz, L, Rodríguez, R, Company, R, Sessler, DI, Aguilar, G, Botello, SG, Ortí, R Spanish Reduccion de la Tasa de Infeccion Quirurgica Group, Supplemental perioperative oxygen and the risk of surgical wound infection: A randomized controlled trial.. JAMA. (2005). 294 2035–42 [Article] [PubMed]
Pryor, KO, Fahey, TJIII, Lien, CA, Goldstein, PA Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: A randomized controlled trial.. JAMA. (2004). 291 79–7 [Article] [PubMed]
Meyhoff, CS, Wetterslev, J, Jorgensen, LN, Henneberg, SW, Høgdall, C, Lundvall, L, Svendsen, PE, Mollerup, H, Lunn, TH, Simonsen, I, Martinsen, KR, Pulawska, T, Bundgaard, L, Bugge, L, Hansen, EG, Riber, C, Gocht-Jensen, P, Walker, LR, Bendtsen, A, Johansson, G, Skovgaard, N, Heltø, K, Poukinski, A, Korshin, A, Walli, A, Bulut, M, Carlsson, PS, Rodt, SA, Lundbech, LB, Rask, H, Buch, N, Perdawid, SK, Reza, J, Jensen, KV, Carlsen, CG, Jensen, FS, Rasmussen, LS PROXI Trial Group, Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: The PROXI randomized clinical trial.. JAMA. (2009). 302 1543–50 [Article] [PubMed]
Guénard, H, Marthan, R Pulmonary gas exchange in elderly subjects.. Eur Respir J. (1996). 9 2573–7 [Article] [PubMed]
McGuire, DK, Levine, BD, Williamson, JW, Snell, PG, Blomqvist, CG, Saltin, B, Mitchell, JH A 30-year follow-up of the Dallas Bedrest and Training Study: I. Effect of age on the cardiovascular response to exercise.. Circulation. (2001). 104 1350–7 [Article] [PubMed]
Poole, D, Behnke, B, Musch, T Capillary hemodynamics and oxygen pressures in the aging microcirculation.. Microcirculation. (2006). 13 289–99 [Article] [PubMed]
Coggan, AR, Spina, RJ, King, DS, Rogers, MA, Brown, M, Nemeth, PM, Holloszy, JO Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women.. J Gerontol. (1992). 47 B71–6 [Article] [PubMed]
Wu, L, Xia, YP, Roth, SI, Gruskin, E, Mustoe, TA Transforming growth factor-beta1 fails to stimulate wound healing and impairs its signal transduction in an aged ischemic ulcer model: Importance of oxygen and age.. Am J Pathol. (1999). 154 301–9 [Article] [PubMed]
Quirinia, A, Viidik, A The impact of ischemia on wound healing is increased in old age but can be countered by hyperbaric oxygen therapy.. Mech Ageing Dev. (1996). 91 131–44 [Article] [PubMed]
McGee, S, Abernethy, WBIII, Simel, DL The rational clinical examination. Is this patient hypovolemic?. JAMA. (1999). 281 1022–9 [Article] [PubMed]
Arkiliç, CF, Taguchi, A, Sharma, N, Ratnaraj, J, Sessler, DI, Read, TE, Fleshman, JW, Kurz, A Supplemental perioperative fluid administration increases tissue oxygen pressure.. Surgery. (2003). 133 49–55 [Article] [PubMed]
Brandstrup, B, Tønnesen, H, Beier-Holgersen, R, Hjortsø, E, Ørding, H, Lindorff-Larsen, K, Rasmussen, MS, Lanng, C, Wallin, L, Iversen, LH, Gramkow, CS, Okholm, M, Blemmer, T, Svendsen, PE, Rottensten, HH, Thage, B, Riis, J, Jeppesen, IS, Teilum, D, Christensen, AM, Graungaard, B, Pott, F Danish Study Group on Perioperative Fluid Therapy, Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens: A randomized assessor-blinded multicenter trial.. Ann Surg. (2003). 238 641–8 [Article] [PubMed]
Grocott, MP, Mythen, MG, Gan, TJ Perioperative fluid management and clinical outcomes in adults.. Anesth Analg. (2005). 100 1093–106 [Article] [PubMed]
Green, D, Paklet, L Latest developments in peri-operative monitoring of the high-risk major surgery patient.. Int J Surg. (2010). 8 90–9 [Article] [PubMed]
Bundgaard-Nielsen, M, Secher, NH, Kehlet, H ‘Liberal’ vs. ‘restrictive’ perioperative fluid therapy—A critical assessment of the evidence.. Acta Anaesthesiol Scand. (2009). 53 843–51 [Article] [PubMed]
Stotts, NA, Hopf, HW The link between tissue oxygen and hydration in nursing home residents with pressure ulcers: Preliminary data.. J Wound Ostomy Continence Nurs. (2003). 30 184–90 [PubMed]
Stotts, NA, Hopf, HW, Kayser-Jones, J, Chertow, GM, Cooper, BA, Wu, HS Increased fluid intake does not augment capacity to lay down new collagen in nursing home residents at risk for pressure ulcers: A randomized, controlled clinical trial.. Wound Repair Regen. (2009). 17 780–8 [Article] [PubMed]
Spahn, DR, Chassot, PG CON: Fluid restriction for cardiac patients during major noncardiac surgery should be replaced by goal-directed intravascular fluid administration.. Anesth Analg. (2006). 102 344–6 [Article] [PubMed]
Gan, TJ, Soppitt, A, Maroof, M, el-Moalem, H, Robertson, KM, Moretti, E, Dwane, P, Glass, PS Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery.. Anesthesiology. (2002). 97 820–6 [Article] [PubMed]
Sinclair, S, James, S, Singer, M Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture: Randomised controlled trial.. BMJ. (1997). 315 909–12 [Article] [PubMed]
Endres, HG, Wedding, U, Pittrow, D, Thiem, U, Trampisch, HJ, Diehm, C Prevalence of anemia in elderly patients in primary care: Impact on 5-year mortality risk and differences between men and women.. Curr Med Res Opin. (2009). 25 1143–58 [Article] [PubMed]
Wu, WC, Schifftner, TL, Henderson, WG, Eaton, CB, Poses, RM, Uttley, G, Sharma, SC, Vezeridis, M, Khuri, SF, Friedmann, PD Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.. JAMA. (2007). 297 2481–8 [Article] [PubMed]
Dunne, JR, Malone, D, Tracy, JK, Gannon, C, Napolitano, LM Perioperative anemia: An independent risk factor for infection, mortality, and resource utilization in surgery.. J Surg Res. (2002). 102 237–44 [Article] [PubMed]
Hopf, HW, Viele, M, Watson, JJ, Feiner, J, Weiskopf, R, Hunt, TK, Noorani, M, Yeap, H, Ho, R, Toy, P Subcutaneous perfusion and oxygen during acute severe isovolemic hemodilution in healthy volunteers.. Arch Surg. (2000). 135 1443–9 [Article] [PubMed]
Sessler, DI Mild perioperative hypothermia.. N Engl J Med. (1997). 336 1730–7 [Article] [PubMed]
Frank, SM, Beattie, C, Christopherson, R, Norris, EJ, Rock, P, Parker, S, Kimball, AWJr Epidural versus general anesthesia, ambient operating room temperature, and patient age as predictors of inadvertent hypothermia.. Anesthesiology. (1992). 77 252–7 [Article] [PubMed]
Sheffield, CW, Sessler, DI, Hopf, HW, Schroeder, M, Moayeri, A, Hunt, TK, West, JM Centrally and locally mediated thermoregulatory responses alter subcutaneous oxygen tension.. Wound Repair Regen. (1996). 4 339–45 [Article] [PubMed]
Melling, AC, Ali, B, Scott, EM, Leaper, DJ Effects of preoperative warming on the incidence of wound infection after clean surgery: A randomised controlled trial.. Lancet. (2001). 358 876–80 [Article] [PubMed]
Hajat, S, Kovats, RS, Lachowycz, K Heat-related and cold-related deaths in England and Wales: Who is at risk?. Occup Environ Med. (2007). 64 93–100 [Article] [PubMed]
Holowatz, LA, Thompson-Torgerson, C, Kenney, WL Aging and the control of human skin blood flow.. Front Biosci (Landmark Ed). (2010). 15 718–39 [Article] [PubMed]
Kurz, A, Plattner, O, Sessler, DI, Huemer, G, Redl, G, Lackner, F The threshold for thermoregulatory vasoconstriction during nitrous oxide/isoflurane anesthesia is lower in elderly than in young patients.. Anesthesiology. (1993). 79 465–9 [Article] [PubMed]
Ozaki, M, Sessler, DI, Matsukawa, T, Ozaki, K, Atarashi, K, Negishi, C, Suzuki, H The threshold for thermoregulatory vasoconstriction during nitrous oxide/sevoflurane anesthesia is reduced in the elderly.. Anesth Analg. (1997). 84 1029–33 [PubMed]
Vassilieff, N, Rosencher, N, Sessler, DI, Conseiller, C Shivering threshold during spinal anesthesia is reduced in elderly patients.. Anesthesiology. (1995). 83 1162–6 [Article] [PubMed]
Carli, F, Gabrielczyk, M, Clark, MM, Aber, VR An investigation of factors affecting postoperative rewarming of adult patients.. Anaesthesia. (1986). 41 363–9 [Article] [PubMed]
de Brito Poveda, V, Clark, AM, Galvão, CM A systematic review on the effectiveness of prewarming to prevent perioperative hypothermia.. J Clin Nurs. (2013). 22 906–18 [Article] [PubMed]
Moola, S, Lockwood, C Effectiveness of strategies for the management and/or prevention of hypothermia within the adult perioperative environment.. Int J Evid Based Healthc. (2011). 9 337–45 [Article] [PubMed]
Snyder, GL, Greenberg, S Effect of anaesthetic technique and other perioperative factors on cancer recurrence.. Br J Anaesth. (2010). 105 106–15 [Article] [PubMed]
Looney, M, Doran, P, Buggy, DJ Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor β in women undergoing anesthesia and surgery for breast cancer.. Anesthesiology. (2010). 113 1118–25 [Article] [PubMed]
Deegan, CA, Murray, D, Doran, P, Moriarty, DC, Sessler, DI, Mascha, E, Kavanagh, BP, Buggy, DJ Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery.. Reg Anesth Pain Med. (2010). 35 490–5 [Article] [PubMed]
O’Hara, DA, Duff, A, Berlin, JA, Poses, RM, Lawrence, VA, Huber, EC, Noveck, H, Strom, BL, Carson, JL The effect of anesthetic technique on postoperative outcomes in hip fracture repair.. Anesthesiology. (2000). 92 947–57 [Article] [PubMed]
Roy, RC Choosing general versus regional anesthesia for the elderly.. Anesthesiol Clin North America. (2000). 18 91–104, vii [Article] [PubMed]
Chang, CC, Lin, HC, Lin, HW, Lin, HC Anesthetic management and surgical site infections in total hip or knee replacement: A population-based study.. Anesthesiology. (2010). 113 279–84 [Article] [PubMed]
Kobayashi, Y, Yoshida, K, Noguchi, M, Wakasugi, Y, Ito, H, Okabe, E Effect of enflurane on contractile reactivity in isolated canine mesenteric arteries and veins.. Anesth Analg. (1990). 70 530–6 [Article] [PubMed]
Xiong, J, Kurz, A, Sessler, DI, Plattner, O, Christensen, R, Dechert, M, Ikeda, T Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds.. Anesthesiology. (1996). 85 240–5 [Article] [PubMed]
Treschan, TA, Taguchi, A, Ali, SZ, Sharma, N, Kabon, B, Sessler, DI, Kurz, A The effects of epidural and general anesthesia on tissue oxygenation.. Anesth Analg. (2003). 96 1553–7 [Article] [PubMed]
Frank, SM, Shir, Y, Raja, SN, Fleisher, LA, Beattie, C Core hypothermia and skin-surface temperature gradients. Epidural versus general anesthesia and the effects of age.. Anesthesiology. (1994). 80 502–8 [Article] [PubMed]
Kehlet, H Manipulation of the metabolic response in clinical practice.. World J Surg. (2000). 24 690–5 [Article] [PubMed]
Moraca, RJ, Sheldon, DG, Thirlby, RC The role of epidural anesthesia and analgesia in surgical practice.. Ann Surg. (2003). 238 663–73 [Article] [PubMed]
Bagry, H, de la Cuadra Fontaine, JC, Asenjo, JF, Bracco, D, Carli, F Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty.. Reg Anesth Pain Med. (2008). 33 17–3 [Article] [PubMed]
Martin, F, Martinez, V, Mazoit, JX, Bouhassira, D, Cherif, K, Gentili, ME, Piriou, P, Chauvin, M, Fletcher, D Antiinflammatory effect of peripheral nerve blocks after knee surgery: Clinical and biologic evaluation.. Anesthesiology. (2008). 109 484–90 [Article] [PubMed]
Breslow, MJ, Parker, SD, Frank, SM, Norris, EJ, Yates, H, Raff, H, Rock, P, Christopherson, R, Rosenfeld, BA, Beattie, C Determinants of catecholamine and cortisol responses to lower extremity revascularization. The PIRAT Study Group.. Anesthesiology. (1993). 79 1202–9 [Article] [PubMed]
Yokoyama, M, Itano, Y, Katayama, H, Morimatsu, H, Takeda, Y, Takahashi, T, Nagano, O, Morita, K The effects of continuous epidural anesthesia and analgesia on stress response and immune function in patients undergoing radical esophagectomy.. Anesth Analg. (2005). 101 1521–7 [Article] [PubMed]
Jensen, JA, Jonsson, K, Goodson, WHIII, Hunt, TK, Roizen, MF Epinephrine lowers subcutaneous wound oxygen tension.. Curr Surg. (1985). 42 472–4 [PubMed]
Lutgendorf, SK, Cole, S, Costanzo, E, Bradley, S, Coffin, J, Jabbari, S, Rainwater, K, Ritchie, JM, Yang, M, Sood, AK Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.. Clin Cancer Res. (2003). 9 4514–21 [PubMed]
Yang, EV, Kim, SJ, Donovan, EL, Chen, M, Gross, AC, Webster Marketon, JI, Barsky, SH, Glaser, R Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: Implications for stress-related enhancement of tumor progression.. Brain Behav Immun. (2009). 23 267–75 [Article] [PubMed]
Abrass, CK, O’Connor, SW, Scarpace, PJ, Abrass, IB Characterization of the beta-adrenergic receptor of the rat peritoneal macrophage.. J Immunol. (1985). 135 1338–41 [PubMed]
Kawano, T, Oshita, S, Takahashi, A, Tsutsumi, Y, Tanaka, K, Tomiyama, Y, Kitahata, H, Nakaya, Y Molecular mechanisms underlying ketamine-mediated inhibition of sarcolemmal adenosine triphosphate-sensitive potassium channels.. Anesthesiology. (2005). 102 93–101 [Article] [PubMed]
Hartman, JC, Pagel, PS, Proctor, LT, Kampine, JP, Schmeling, WT, Warltier, DC Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs.. Can J Anaesth. (1992). 39 877–87 [Article] [PubMed]
Dwyer, R, Howe, J Peripheral blood flow in the elderly during inhalational anaesthesia.. Acta Anaesthesiol Scand. (1995). 39 939–44 [Article] [PubMed]
De Hert, SG, Turani, F, Mathur, S, Stowe, DF Cardioprotection with volatile anesthetics: Mechanisms and clinical implications.. Anesth Analg. (2005). 100 1584–93 [Article] [PubMed]
Beck-Schimmer, B, Breitenstein, S, Urech, S, De Conno, E, Wittlinger, M, Puhan, M, Jochum, W, Spahn, DR, Graf, R, Clavien, PA A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic.. Ann Surg. (2008). 248 909–18 [Article] [PubMed]
Lee, HT, Ota-Setlik, A, Fu, Y, Nasr, SH, Emala, CW Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo.. Anesthesiology. (2004). 101 1313–24 [Article] [PubMed]
Raphael, J Physiology and pharmacology of myocardial preconditioning.. Semin Cardiothorac Vasc Anesth. (2010). 14 54–9 [Article] [PubMed]
Lucchinetti, E, Zeisberger, SM, Baruscotti, I, Wacker, J, Feng, J, Zaugg, K, Dubey, R, Zisch, AH, Zaugg, M Stem cell-like human endothelial progenitors show enhanced colony-forming capacity after brief sevoflurane exposure: Preconditioning of angiogenic cells by volatile anesthetics.. Anesth Analg. (2009). 109 1117–26 [Article] [PubMed]
Puppo, M, Battaglia, F, Ottaviano, C, Delfino, S, Ribatti, D, Varesio, L, Bosco, MC Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha.. Mol Cancer Ther. (2008). 7 1974–84 [Article] [PubMed]
Itoh, T, Namba, T, Fukuda, K, Semenza, GL, Hirota, K Reversible inhibition of hypoxia-inducible factor 1 activation by exposure of hypoxic cells to the volatile anesthetic halothane.. FEBS Lett. (2001). 509 225–9 [Article] [PubMed]
Lee, HT, Kim, M, Kim, J, Kim, N, Emala, CW TGF-beta1 release by volatile anesthetics mediates protection against renal proximal tubule cell necrosis.. Am J Nephrol. (2007). 27 416–24 [Article] [PubMed]
Turek, Z, Sykora, R, Matejovic, M, Cerny, V Anesthesia and the microcirculation.. Semin Cardiothorac Vasc Anesth. (2009). 13 249–58 [Article] [PubMed]
Kawakubo, A, Fujigaki, T, Uresino, H, Zang, S, Sumikawa, K Comparative effects of etomidate, ketamine, propofol, and fentanyl on myocardial contractility in dogs.. J Anesth. (1999). 13 77–2 [Article] [PubMed]
Stefano, GB, Salzet, M, Magazine, HI, Bilfinger, TV Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase.. J Cardiovasc Pharmacol. (1998). 31 813–20 [Article] [PubMed]
White, DA, Reitan, JA, Kien, ND, Thorup, SJ Decrease in vascular resistance in the isolated canine hindlimb after graded doses of alfentanil, fentanyl, and sufentanil.. Anesth Analg. (1990). 71 29–4 [Article] [PubMed]
Xin, L, Geller, EB, Adler, MW Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain.. J Pharmacol Exp Ther. (1997). 281 499–7 [PubMed]
Law, PY, Loh, HH Regulation of opioid receptor activities.. J Pharmacol Exp Ther. (1999). 289 607–24 [PubMed]
Singleton, PA, Lingen, MW, Fekete, MJ, Garcia, JG, Moss, J Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation.. Microvasc Res. (2006). 72 3–11 [Article] [PubMed]
Petreaca, ML, Yao, M, Liu, Y, Defea, K, Martins-Green, M Transactivation of vascular endothelial growth factor receptor-2 by interleukin-8 (IL-8/CXCL8) is required for IL-8/CXCL8-induced endothelial permeability.. Mol Biol Cell. (2007). 18 5014–23 [Article] [PubMed]
Cadet, P, Mantione, KJ, Bilfinger, TV, Stefano, GB Differential expression of the human mu opiate receptor from different primary vascular endothelial cells.. Med Sci Monit. (2004). 10 BR351–5 [PubMed]
Pasi, A, Qu, BX, Steiner, R, Senn, HJ, Bär, W, Messiha, FS Angiogenesis: Modulation with opioids.. Gen Pharmacol. (1991). 22 1077–9 [Article] [PubMed]
Faramarzi, N, Abbasi, A, Tavangar, SM, Mazouchi, M, Dehpour, AR Opioid receptor antagonist promotes angiogenesis in bile duct ligated rats.. J Gastroenterol Hepatol. (2009). 24 1226–9 [Article] [PubMed]
Roy, S, Balasubramanian, S, Wang, J, Chandrashekhar, Y, Charboneau, R, Barke, R Morphine inhibits VEGF expression in myocardial ischemia.. Surgery. (2003). 134 336–44 [Article] [PubMed]
Gupta, K, Kshirsagar, S, Chang, L, Schwartz, R, Law, PY, Yee, D, Hebbel, RP Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.. Cancer Res. (2002). 62 4491–8 [PubMed]
Farooqui, M, Li, Y, Rogers, T, Poonawala, T, Griffin, RJ, Song, CW, Gupta, K COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia.. Br J Cancer. (2007). 97 1523–31 [Article] [PubMed]
Bigliardi, PL, Sumanovski, LT, Büchner, S, Rufli, T, Bigliardi-Qi, M Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression.. J Invest Dermatol. (2003). 120 145–52 [Article] [PubMed]
Rook, JM, McCarson, KE Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release.. Biochem Pharmacol. (2007). 74 752–7 [Article] [PubMed]
Rook, JM, Hasan, W, McCarson, KE Morphine-induced early delays in wound closure: Involvement of sensory neuropeptides and modification of neurokinin receptor expression.. Biochem Pharmacol. (2009). 77 1747–55 [Article] [PubMed]
Küchler, S, Wolf, NB, Heilmann, S, Weindl, G, Helfmann, J, Yahya, MM, Stein, C, Schäfer-Korting, M 3D-wound healing model: Influence of morphine and solid lipid nanoparticles.. J Biotechnol. (2010). 148 24–30 [Article] [PubMed]
Poonawala, T, Levay-Young, BK, Hebbel, RP, Gupta, K Opioids heal ischemic wounds in the rat.. Wound Repair Regen. (2005). 13 165–74 [Article] [PubMed]
McGuire, L, Heffner, K, Glaser, R, Needleman, B, Malarkey, W, Dickinson, S, Lemeshow, S, Cook, C, Muscarella, P, Melvin, WS, Ellison, EC, Kiecolt-Glaser, JK Pain and wound healing in surgical patients.. Ann Behav Med. (2006). 31 165–72 [Article] [PubMed]
Kiecolt-Glaser, JK, Marucha, PT, Malarkey, WB, Mercado, AM, Glaser, R Slowing of wound healing by psychological stress.. Lancet. (1995). 346 1194–6 [Article] [PubMed]
Kehlet, H Multimodal approach to control postoperative pathophysiology and rehabilitation.. Br J Anaesth. (1997). 78 606–17 [Article] [PubMed]
Nishimori, M, Low, JH, Zheng, H, Ballantyne, JC Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery.. Cochrane Database Syst Rev. (2012). 7 CD005059 [PubMed]
Eger, EIII Characteristics of anesthetic agents used for induction and maintenance of general anesthesia.. Am J Health Syst Pharm. (2004). 61suppl 4 S3–10 [PubMed]
Seyde, WC, McGowan, L, Lund, N, Duling, B, Longnecker, DE Effects of anesthetics on regional hemodynamics in normovolemic and hemorrhaged rats.. Am J Physiol. (1985). 2491 Pt 2 H164–73 [PubMed]
Yeh, YC, Sun, WZ, Ko, WJ, Chan, WS, Fan, SZ, Tsai, JC, Lin, TY Dexmedetomidine prevents alterations of intestinal microcirculation that are induced by surgical stress and pain in a novel rat model.. Anesth Analg. (2012). 115 46–3 [Article] [PubMed]
Brookes, ZL, Brown, NJ, Reilly, CS Intravenous anaesthesia and the rat microcirculation: The dorsal microcirculatory chamber.. Br J Anaesth. (2000). 85 901–3 [Article] [PubMed]
Brookes, ZL, Brown, NJ, Reilly, CS Response of the rat cremaster microcirculation to hemorrhage in vivo: Differential effects of intravenous anesthetic agents.. Shock. (2002). 18 542–8 [Article] [PubMed]
Brookes, ZL, Brown, NJ, Reilly, CS Differential effects of intravenous anaesthetic agents on the response of rat mesenteric microcirculation in vivo after haemorrhage.. Br J Anaesth. (2002). 88 255–63 [Article] [PubMed]
Tanabe, K, Dohi, S, Matsuno, H, Hirade, K, Kozawa, O Midazolam stimulates vascular endothelial growth factor release in aortic smooth muscle cells: Role of the mitogen-activated protein kinase superfamily.. Anesthesiology. (2003). 98 1147–54 [Article] [PubMed]
Ferrara, N, Gerber, HP, LeCouter, J The biology of VEGF and its receptors.. Nat Med. (2003). 9 669–76 [Article] [PubMed]
Krumholz, W, Reussner, D, Hempelmann, G The influence of several intravenous anaesthetics on the chemotaxis of human monocytes in vitro.. Eur J Anaesthesiol. (1999). 16 547–9 [Article] [PubMed]
Krumholz, W, Abdulle, O, Knecht, J, Hempelmann, G Effects of i.v. anaesthetic agents on the chemotaxis of eosinophils in vitro.. Br J Anaesth. (1999). 83 333–5 [Article] [PubMed]
Li, CY, Chou, TC, Wong, CS, Ho, ST, Wu, CC, Yen, MH, Ding, YA Ketamine inhibits nitric oxide synthase in lipopolysaccharide-treated rat alveolar macrophages.. Can J Anaesth. (1997). 44 989–95 [Article] [PubMed]
Ohta, N, Ohashi, Y, Fujino, Y Ketamine inhibits maturation of bone marrow-derived dendritic cells and priming of the Th1-type immune response.. Anesth Analg. (2009). 109 793–800 [Article] [PubMed]
Nishina, K, Akamatsu, H, Mikawa, K, Shiga, M, Maekawa, N, Obara, H, Niwa, Y The inhibitory effects of thiopental, midazolam, and ketamine on human neutrophil functions.. Anesth Analg. (1998). 86 159–65 [PubMed]
Brower, MC, Johnson, ME Adverse effects of local anesthetic infiltration on wound healing.. Reg Anesth Pain Med. (2003). 28 233–40 [Article] [PubMed]
Bamigboye, AA, Hofmeyr, GJ Local anaesthetic wound infiltration and abdominal nerves block during caesarean section for postoperative pain relief.. Cochrane Database Syst Rev. (2009).  CD006954
Akça, O, Melischek, M, Scheck, T, Hellwagner, K, Arkiliç, CF, Kurz, A, Kapral, S, Heinz, T, Lackner, FX, Sessler, DI Postoperative pain and subcutaneous oxygen tension.. Lancet. (1999). 354 41–2 [Article] [PubMed]
Chvapil, M, Hameroff, SR, O’Dea, K, Peacock, EEJr Local anesthetics and wound healing.. J Surg Res. (1979). 27 367–71 [Article] [PubMed]
Lucchinetti, E, Awad, AE, Rahman, M, Feng, J, Lou, PH, Zhang, L, Ionescu, L, Lemieux, H, Thébaud, B, Zaugg, M Antiproliferative effects of local anesthetics on mesenchymal stem cells: Potential implications for tumor spreading and wound healing.. Anesthesiology. (2012). 116 841–56 [Article] [PubMed]
Calatayud, J, González, A History of the development and evolution of local anesthesia since the coca leaf.. Anesthesiology. (2003). 98 1503–8 [Article] [PubMed]
Lange, RA, Cigarroa, RG, Yancy, CWJr, Willard, JE, Popma, JJ, Sills, MN, McBride, W, Kim, AS, Hillis, LD Cocaine-induced coronary-artery vasoconstriction.. N Engl J Med. (1989). 321 1557–62 [Article] [PubMed]
Johns, RA, DiFazio, CA, Longnecker, DE Lidocaine constricts or dilates rat arterioles in a dose-dependent manner.. Anesthesiology. (1985). 62 141–4 [Article] [PubMed]
Johns, RA, Seyde, WC, DiFazio, CA, Longnecker, DE Dose-dependent effects of bupivacaine on rat muscle arterioles.. Anesthesiology. (1986). 65 186–91 [Article] [PubMed]
Nation, RL, Triggs, EJ, Selig, M Lignocaine kinetics in cardiac patients and aged subjects.. Br J Clin Pharmacol. (1977). 4 439–48 [Article] [PubMed]
Prough, DS Anesthetic pitfalls in the elderly patient.. J Am Coll Surg. (2005). 200 784–94 [Article] [PubMed]
Etzioni, DA, Liu, JH, O’Connell, JB, Maggard, MA, Ko, CY Elderly patients in surgical workloads: A population-based analysis.. Am Surg. (2003). 69 961–5 [PubMed]
Fig. 1.
Numerous changes in skin with age contribute to impaired wound healing.
Numerous changes in skin with age contribute to impaired wound healing.
Fig. 1.
Numerous changes in skin with age contribute to impaired wound healing.
×
Fig. 2.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
Fig. 2.
The stages of wound healing are a sequential chain of events that include: (A) inflammation, (B) proliferation and granulation tissue formation, and (C) extracellular matrix (ECM) deposition and tissue remodeling. PDGF = platelet-derived growth factor; TGF-β1 = transforming growth factor-β1; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.
×
Fig. 3.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
Fig. 3.
Age-related changes in every stage of the wound-healing process may delay and impair surgical wound repair in older patients. ECM = extracellular matrix; HA = hyaluronan; MMP = matrix metalloproteinases; SPARC = secreted protein acidic and rich in cysteine; TGF-β = transforming growth factor-β; TIMP = tissue inhibitor of matrix metalloproteinases; VEGF = vascular endothelial growth factor.
×
Fig. 4.
The effects of local anesthetics and regional anesthesia on wound healing.
The effects of local anesthetics and regional anesthesia on wound healing.
Fig. 4.
The effects of local anesthetics and regional anesthesia on wound healing.
×
Fig. 5.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
Fig. 5.
The effects of volatile anesthetics on wound healing. ECM = extracellular matrix; HIF-1 = hypoxia-inducible factor-1; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor.
×