OR WAIT null SECS
Boosting a patient's oxygen intake and maintaining normal body heat during and after ob/gyn surgery may cut the postop infection rate.
|Jump to:||Choose article section... What role should oxygen play? An uphill battle to maintain alveolar immune function Atelectasis and pulmonary function Maintaining normal body temperature Loss of body heat during anesthesia Serious consequences of mild hypothermia Hypothermia and surgical site infections Techniques for maintaining normal body heat Assessing the roles of smoking and hyperglycemia Conclusions Key points|
Boosting a patient's oxygen intake and maintaining normal body heat during and after ob/gyn surgery may cut the postop infection rate.
It's now ancient historyalmost. With the advent of strict aseptic techniques during surgery, far fewer patients develop surgical wound infections. But still, some contamination during any surgery is inevitable due to the many pathogens living within the body. Ob/gyn surgical site infections (SSI) during cesarean sections and other procedures are no exception. For example, according to the CDC, the SSI rate is 6.7% following high-risk C/S deliveries and 4.1% following moderate-risk C/S deliveries.1
With these statistics in mind, ob/gyns seeking to prevent post-surgical infections must act to improve their patients' immune systems. Our purpose here is to focus on two easily controlled factors that affect a woman's immunity before, during, and after surgery: tissue oxygen concentration and core body temperature. Maintaining a patient's normal body temperature perioperatively (which although it's becoming standard of care is not widespread enough) and giving supplemental oxygen are two ways to dramatically cut postop infections. Based on prospective, randomized clinical trials, we'll examine the pros and cons of using either therapy.
Because anesthesia can compromise ventilation and oxygenation, most surgical patients are given some oxygenbut the oxygen percentage can range anywhere from 30% to 100%. Until recently, there was little basis for choosing a specific concentration. That changed, however, when researchers discovered that giving more oxygen (an inspired oxygen concentration of 80%) during and after surgery can cut postop infections rates in halfwith little, if any, risk.
Neutrophils (the larger class of infection-fighting white blood cells) engage in oxidative killing of surgical pathogens as the body's chief defense against these invaders.2 And an essential step in their attack is the transformation of oxygen molecules into a highly reactive form of oxygen known as superoxide radicals. A nicotinamide adenine dinucleotide-phosphate-linked process, it's dependent on the availability of oxygen and thus critically depends on tissue oxygen tension. With this oxygen-based defense, the risk of surgical wound infection correlates with tissue oxygen tension. For example, infection rates soar whenever tissue oxygen tension falls from 75 mm Hg to 45 mm Hg; in contrast, rates of infection drop steeply at tissue oxygen tensions near 100 mm Hg.3,4 Other factors that influence tissue oxygenationand greatly affect SSI ratesare hemoglobin concentration, cardiac output, local perfusion, smoking, anemia, perioperative fluid management, and uncontrolled surgical pain.5-10
Our research on oxygen. One way to get more oxygen to a patient's tissues is to administer higher concentrations of inspired oxygen; higher oxygen partial pressure, in turn, should reduce the risk of infection. To test this hypothesis, we undertook an outcomes study in 500 normothermic patients in which we compared 80% and 30% perioperative oxygen. While undergoing elective colon resection, these patients were randomly assigned to 80% (supplemental) or 30% (routine) perioperative oxygen administration. Anesthesia and surgical management were standardized. Tissue oxygen tension in the group given 80% oxygen averaged nearly 100 mm Hg, but in those given 30% inspired oxygen, it averaged only 50 mm Hg. We found that supplemental oxygen reduced the infection rate from 11% to 5%, a highly statistically significant reduction. Furthermore, the infected patients remained hospitalized a full week longer than the uninfected patients.4
Oxygen is inexpensive; in fact, supplemental oxygen for the entire perioperative period costs just pennies per patient. Thus, the administration of 80% oxygen during surgery would not increase overall cost.
Evaluating contradictory research. In a recent report by Pryor and colleagues, 160 patients were randomly assigned to 35% or 80% perioperative oxygen.11 Curiously, the risk of infection was greater in the patients given 80% oxygen (11% vs. 25%). This result is remarkable since there is little mechanistic basis to suggest that supplemental oxygen would reduce resistance to infection. The Pryor study not only contradicts our report,4 but also contradicts a study by Hopf and colleagues in which there was a significant inverse relationship between tissue oxygen tension and infection risk.3
The Pryor study based its sample-size estimate on an unspecified baseline risk. But assuming an 11% infection rate in patients given 35% oxygen (as reported by Greif and Pryor), an 80% power to detect a 40% reduction in the infection rate from 11% to 6.6% would have required 694 patients; to detect a 40% increase from 11% to 15.4% would require 972 patients. The study thus appears to have been underpowered from the start, a problem that was aggravated by stopping after only 160 patients were randomized.
It's worth noting that two of the three participating centers in the Greif study each enrolled 30% more patients than were included in their entire study. The problem with small studies is that the treatment groups may differ. There is evidence for heterogeneity in the Pryor study's treat- ment groups; for example, patients assigned to 80% oxygen weighed more and were more than twice as likely to have a body mass index exceeding 30 kg/m2. Patients assigned to 80% oxygen also had longer operations, lost significantly more blood, and required significantly more fluid replacement. Five patients given 80% oxygen required postoperative intubation compared to only one in the 35% group. An additional consideration is that factors believed to influence infection risk were uncontrolled, including anesthetic, fluid, and pain management. It thus seems likely that patients assigned to 80% oxygen were at greater underlying risk of infection and that this difference influenced the results.
Moreover, in evaluating wound infections, the Pryor study used retrospective chart evaluation although patients were prospectively assigned to 35% or 80% perioperative oxygen. The investigators thus tried to determine which patients became infected on the basis of chart reviewan insensitive way to detect infections. A further limitation is that investigators determining infection status were not blinded, since the anesthesia and postanesthesia care unit records remained "in a compartment of the medical record not used by the surgical team." In contrast, Greif and colleagues used strictly blinded observers who evaluated wounds daily throughout hospitalization. In addition, the diagnosis of infection required both expression of pus and a culture positive for pathogenic organisms.
Finally, their results contradict considerable in vitro, in vivo, and human evidence that supplemental oxygen is beneficial. Given available evidence, providing supplemental oxygen still appears to be a prudent and appropriate intervention.
In the front lines of defense against pulmonary infection are phagocytosis and oxidative killing by alveolar macrophages. Because bacteria must be ingested before killing can occur, and ingestion alone is ineffective without the oxidative killing, clearly both actions are important. It's a tug of war as pro-inflammatory cytokines act to stimulate both processes, while simultaneously the forces of anesthesia, surgery, and mechanical ventilation each independently cripple them.12 The combination of anesthesia, surgery, and mechanical ventilation, as typically occurs during surgery, markedly erodes macrophage function over time, despite the good fight put up by the proinflammatory cytokines like interleukin1ß, interleukin8, interferonß, and tumor necrosis factor.
Fortunately, supplemental oxygen may turn the tide by significantly increasing the expression of all four inflammatory cytokines. While 100% oxygen isn't a panacea and can't prevent the decline in both phagocytosis and bacterial killing during surgery, it does minimize the damage to these functions. Accordingly, phagocytosis and killing are better maintained in patients given 100% oxygen perioperatively than in those given the routine 30%.13
What this means clinically remains to be determined with controlled research. However, most likely it's helpful to maintain homeostasis (that is, keeping phagocytosis and killing at near normal levels). But that said, it's still possible that the down-regulation of proinflammatory cytokines may reduce pulmonary inflammation that could be useful in selected conditions.
Certainly, exposing a patient to oxygen concentrations near 100%for as long as several days, for examplecan cause direct pulmonary toxicity. But there's no evidence that that's the case for a patient receiving a high concentration of oxygen during a surgical procedure. While it only takes a few breaths of 100% oxygen for atelectasisor a partially collapsed lungto develop, fortunately, the condition is just as easily reversed with a single sustained positive-pressure breath.14,15 More importantly, only a small percentage of lung volume is usually atelectatic after surgery.
We recently compared two groups of patients: one group received 30% oxygen and the other 80% oxygen during and for 2 hours after surgery. On the first postoperative day, pulmonary function, assessed as oxygen saturation and alveolar-arterial differences in oxygen, was identical in the two groups and the amount of atelectasis was also similar. We found that 80% oxygen given during and for a short period after surgery does not cause atelectasis or impair pulmonary function.16 Recently, Edmark and colleagues confirmed these results by showing that 80% inspired oxygen caused minimal atelectasis whereas a 100% dose provoked atelectasis.17
Tightly controlled, body temperature is normally maintained within a very narrow range. Even minor deviations in core temperature spur aggressive thermoregulatory defenses. Sweating, vasoconstriction, and shivering are the three major autonomic thermoregulatory defenses that control human body temperature. Each response has a threshold, gain, and maximum response intensity. The threshold is the core temperature that triggers a given response. The gain of a thermoregulatory response is defined by the incremental intensity of the response once it is triggered. Most commonly, this is the slope of a regression between response intensity and change in core temperature. The maximum response intensity is simply the greatest response that the body can mobilize, even during extreme thermal perturbations. The thresholds for sweating and vasoconstriction (both near 37ºC) are separated by only a few tenths of a degree centigrade. In contrast, the shivering response isn't triggered until core temperature falls nearly a full degree below the vasoconstriction threshold.18 The difference between the sweating and vasoconstriction thresholds is the interthreshold range, which defines the normal body temperature range.
Unless an anesthetized patient's body is warmed, it will lose too much body heat during surgery. The cool operating theater itself is one reason, of course, but anesthesia also can wreck havoc with normal thermoregulation. For example, volatile anesthetics and the IV anesthetic propofol increase the interthreshold range almost twentyfoldas do opioids and most sedatives, but to a lesser extent.19-21
Hypothermia during anesthesia develops in three phases: (1) During the first hour, core temperature drops by 1.0 to 1.5ºC as body heat shifts from the core to the cooler peripheryand in so doing, reduces core temperature.22 Anesthetics inhibit thermoregulatory control and, therefore, disrupt the tonic vasoconstriction that normally maintains a core-to-peripheral temperature gradient. (2) Phase 2, which typically lasts 2 to 3 hours, is a slow, linear drop in core temperature during which the rate of heat loss exceeds heat production. (3) Finally, a plateau occurs (usually at a core body temperature of about 34ºC) when patients become so cold that thermoregulatory vasoconstriction reemerges, which confines metabolic heat to the core and prevents further hypothermia.23
Mild hypothermia (a drop in core body temperature of only 1.5°C) triples the risk of morbid myocardial events, the leading cause of unexpected mortality after otherwise routine surgery.24 This below normal temperature sabotages platelet function by slowing the release of thromboxane A3, a key component in thrombus development after injury, and impairing enzymes of the coagulation cascade.25 These observations probably explain why mild hypothermia increases blood loss and increases the need for allogeneic blood transfusions.
Three randomized trials looked at how hypothermia affects coagulation in patients undergoing hip arthroplasty.26 In the first, a drop of just 1.5ºC (35.0ºC; a typical temperature in unwarmed surgical patients) increased blood loss by 500 mL and significantly increased the requirement for allogeneic blood transfusion. In the second trial, during which a perioperative core temperature of 36.0ºC was maintained, hypothermia also slightly increased blood loss (but only by about 200 mL).27 In the last study, in contrast, blood loss was not altered in unwarmed patients whose core body temperature was 0.8ºC lower than warmed patients.28 There's no known reason why results of the last trial differ from the first two.
Mild hypothermia slows the metabolism of many drugs commonly used during surgery. Examples are the IV anesthetic propofol and the muscle relaxant vecuronium, which acts twice as long in patients cooled to a core temperature of 34.5ºC.29 Inevitably, this lengthens a patient's recovery time from general anesthesia, which adds to the overall cost of surgical care.30
An often-overlooked drawback of hypothermia is thermal discomfort, which many times bothers patients more than actual pain. Physicians should remember that thermal discomfort is nearly as serious to patients as pain itself and, therefore, merits similar attention. Hypothermia appears to aggravate pain perception, so maintaining a normal body temperature both improves thermal comfort and reduces pain perception. 31
SSIs, which are established during the first 2 hours after surgery (the "decisive period"), cause significant morbidity and typically add about a week to the hospital stay. Events like hypovolemia and local administration of epinephrine raise the risk of infection when they occur during the decisive periodbut not later on.32 Conversely, antibiotics given during the decisive period are effective; while those given later are not.32 We noted earlier that the primary defense against surgical pathogens is oxidative killing by neutrophils. On the plus side, local hyperthermia causes hyperemia, which increases tissue oxygenation.7 Hypothermia, in contrast, triggers thermoregulatory vasoconstriction, which then diminishes tissue perfusion and oxygenation. And hypothermia compounds the damage by slowing down production of superoxide radicals and other oxygen intermediates at any tissue oxygen concentration.33 In this way, hypothermia hampers neutrophil oxidative killing by making less oxygen available to the tissues and by impairing the production of superoxide radicals. Subnormal body temperature may also raise the risk of infection by exacerbating blood loss and transfusion requirement.
One RCT clearly demonstrated the effects of mild hypothermia on infection. Patients with a drop in average core temperature of only 1.9ºC were three times more likely to develop SSIs than those kept normothermic.34 The infected patients stayed a week longer in the hospital. An even more surprising finding was that hypothermic patients' average hospital stays were 20% longer than those of normothermic patients. Even when only uninfected patients were compared, the hypothermic group stayed significantly longer in the hospital. In addition, hypothermic patients formed significantly fewer scars. It thus appears that mild hypothermia not only triples the risk of SSI but also prolongs hospital stays, even in uninfected patients. Investigators haven't specifically evaluated the effects of combining normothermia with supplemental oxygen; but benefits are likely additive.
Although mostly unconfirmed in humans, therapeutic hypothermia does seem to benefit some groups of patients, specifically, those recovering from cerebral ischemia. In contrast, numerous prospective, randomized outcome data indicate that mild hypothermia causes numerous severe adverse reactions in many patient populations. Given this evidence, it seems apparent that body temperature should be monitored during nearly every surgical procedure and that patients should be kept normothermic unless hypothermia is induced for a specific therapeutic indication. Although maintaining normothermia is becoming the standard of care, too many patients are still allowed to become hypothermic during surgery. Inadequate intraoperative core temperature monitoring in many patients contributes to the problem.
Several techniques are used to maintain perioperative normothermia. The easiest and most popular method is to cover patients with one of the passive insulators available in every operating room: cotton blankets, surgical drapes, plastic bags, and "space blankets." Each of these covers cuts cutaneous heat loss by about one third, a clinically important amount.35 Unfortunately, adding additional insulatorstwo extra blankets, for examplecannot stop cutaneous heat loss.36 If covering the patient with a single layer of insulation maintains normothermia, then you needn't take further action. But if the patient's core body temperature continues to decrease with a single layer of insulation, adding additional layers is unlikely to stop the developing hypothermia. When this happens, the physician must institute active warming measures.
What doesn't work. Unfortunately, many active warming systems are ineffective, notably, airway heating and humidification.37 This is not surprising since simple heat transfer through a patient's airway is trivial.38 While circulating-water mattress systems are attractive because they're easy to use and inexpensive, unfortunately, they are nearly ineffective as well.39
IV fluid warming is yet another commonly advocated warming method. But warming IV fluids won't warm patients because warmed fluid temperature only slightly exceeds body temperature. Fluid warming also cannot compensate for heat loss from the skin or incisions. But it is true that patients given large volumes of cold fluids can become hypothermic. Each liter of fluid administered at ambient temperature or unit of blood from the refrigerator decreases an adult's mean body temperature by 0.25ºC.38 It's prudent to warm fluids if large volumes are to be administered; however, it is usually unnecessary to warm fluids for small or medium-sized operations.
What does work. Anesthetized patients lose almost 90% of metabolic heat through their anterior skin surface.22 To be effective, therefore, patient-warming systems must warm the anterior skin surface. Forced-air convection is probably the most commonly used system used for warming surgical patients.40 Such a system consists of a blower that delivers electrically heated air into a quilt-like disposable cover. The cover disperses the air over the top of the body, producing a warm microenvironment around the patient. Forced-air warming is the most effective commonly available, noninvasive method that is competitively priced.
Smoking and diabetes each independently increase the risk of SSIs and perioperative cardiopulmonary complications.
Smoking. Generally, smokers are at higher risk for perioperative wound and cardiopulmonary complications. Wound healing is impaired in smokers, primarily because they produce less collagen than nonsmokers.41 Not surprisingly, a greater proportion of smokers versus nonsmokers are admitted to the intensive care unit postoperatively.42
A smoker's greater risk of infection may be the result of a change in pulmonary mechanics (increased closing capacity, reduced clearance of pulmonary secretions, and chronic obstructive lung disease). Impaired immune function43,44 and collagen production39 may also contribute. Research in rats exposed to smoke shows that gene expression and production of all pro-inflammatory cytokines (except IL-6) increase during anesthesia. Exposure to smoke markedly suppresses the clearance and inflammatory responses of alveolar macrophages during anesthesia at both the cellular and histologic levels.44 Therefore, one may expect the SSI rate to increase in smokers.
In a prospective cohort study, smoking was found to be an independent risk factor for predicting SSI in postmastectomy breast cancer patients.45 In another recent study in ambulatory surgery patients, smoking increased the risk of surgical wound infections sixfold,46 whereas a threefold increase was observed in a study of colectomy patients.34
Fortunately, smoking-induced changes appear to be reversible to some extent, with about 4 to 8 weeks needed for substantial improvement. Researchers have shown that patients who stopped smoking 8 weeks before cardiac surgery had fewer pulmonary complications than smokers.47 In addition, a smoking cessation program begun 6 to 8 weeks before elective hip or knee arthroplasty surgery reduced the wound-related complications sixfold and cardiovascular complications about tenfold. Even better news is that recently investigators found that staying away from tobacco for even 4 weeks reduced the infection rate in experimental incisional wounds in healthy humans.48
Hyperglycemia. Most clinicians know that wound healing is usually delayed in patients with diabetes. Hyperglycemia leads to osmotic diuresis, which might eventually decrease tissue perfusion and oxygenation. More importantly, hyperglycemia damages macrophages and neutrophils. Furthermore, plasma glucose concentration modulates hemodynamic, metabolic, and inflammatory responses to lipopolysaccharide in rabbits.49
While high blood sugar levels alter the functions of polymorphonuclear neutrophils, in vitro evidence shows that tight control of glucose concentration improves various immune functions.50,51 Similar results were obtained in coronary artery bypass graft surgery patients. In this study, neutrophil phagocytic activity was better preserved in patients who received aggressive insulin therapy (i.e., tighter glucose control) than in patients given standard insulin therapy.52 These findings support the hypothesis that hyperglycemia impairs phagocytosis and tighter glucose control improves it.
Nonetheless, controversy remains on whether insulin offers any direct protection for the immune system. A detailed discussion of this debate appears in a recent outcome study wherein critically ill patients who received intensive insulin therapy lived longer.53,54 In a prospective cohort and casecontrol study, Latham and colleagues assessed the significance of diabetes and hyperglycemia independently in the wound infections of cardiothoracic surgery patients. Both diabetes and hyperglycemia were found to independently increase SSIs.55 Similarly, another group of investigators also showed that poorly managed diabetes (preoperative blood glucose levels >200 mg/dL) independently increased deep sternal site infections tenfold.56
Available data suggest that boosting a patient's oxygen intake improves surgical outcome with little or no risk. Moreover, supplemental perioperative oxygen is inexpensive and easy to provide. Administering 80% perioperative oxygen has no downsideit does not cause atelectasis or compromise pulmonary function, for example. Giving more oxygen, however, can make a dramatic difference, by activating alveolar immune defenses and cutting the risk of surgical wound infection in half.
Anesthetics, unfortunately, impair the body's tightly regulated temperature control, so virtually all surgical patients become hypothermic if not warmed. Hypothermia begins with a core-to-peripheral redistribution of body heat, followed by a linear decrease in core temperature as the patient's heat loss exceeds heat production. Among the possible major adverse effects linked to mild perioperative hypothermia are a tripling in the rate of myocardial complications, an increased need for transfusions, and a tripling in the risk of surgical wound infections. Mild hypothermia also prolongs the duration of hospitalization, even in uninfected patients.
Given the adverse effects of hypothermia, surgical patients should be kept normothermic. They can be covered with passive insulation, but that alone is insufficient. Fluids should be warmed when large volumes are administered. Forced air is by far the most commonly used active patient warming system.
Smoking increases the risk of surgical wound infections; having patients quit smoking for about 4 to 8 weeks before surgery appears to significantly reduce this risk. Hyperglycemia and diabetes each independently increase the risk of surgical wound infections and perioperative cardiopulmonary complications. Tighter control of blood glucose and aggressive insulin therapy appear to decrease the incidence of these complications.
Supported by NIH Grants GM 58273, GM 061655, and DE 014879-01A1 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, CA), the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY). Dr. Akça is the recipient of a Research Training Grant from the Foundation for Anesthesia Education and Research. Mallinckrodt Anesthesiology Products, Inc. (St. Louis, MO) donated the thermocouples we used. Dr. Sessler has a personal financial interest in Radiant Medical, Inc. Informed consent was obtained from all participants, and all protocols were approved by the Institutional Review Board of the institution where the research was conducted.
1. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 to June 2002, Issued August 2002. Am J Infect Control. 2002;30:458-475.
2. Babior BM. Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med. 1978;298:659-668.
3. Hopf HW, Hunt TK, West JM, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg. 1997;132:997-1005
4. Greif R, Akça O, Horn EP, et al. Supplemental perioperative oxygen to reduce the incidence of surgical wound infection. Outcomes Research Group. N Engl J Med. 2000;342:161-167.
5. Gosain A, Rabkin J, Reymond JP, et al. Tissue oxygen tension and other indicators of blood loss or organ perfusion during graded hemorrhage. Surgery. 1991;109:523-532.
6. Shoemaker WC, Appel PL, Kram HB. Oxygen transport measurements to evaluate tissue perfusion and titrate therapy: dobutamine and dopamine effects. Crit Care Med. 1991;19:672-688.
7. Plattner O, Akça O, Herbst F, et al. The influence of two surgical bandage systems on wound tissue oxygen tension. Arch Surg. 2000;135:818-822.
8. Jensen JA, Goodson WH, Hopf HW, et al. Cigarette smoking decreases tissue oxygen. Arch Surg. 1991;126:1131-1134.
9. Arkilic CF, Taguchi A, Sharma N, et al. Supplemental perioperative fluid administration increases tissue oxygen pressure. Surgery. 2003;133:49-55.
10. Akça O, Melischek M, Scheck T, et al. Postoperative pain and subcutaneous oxygen tension. Lancet. 1999;354:41-42.
11. Pryor KO, Fahey TJ 3rd, 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;291:79-87.
12. Kotani N, Takahashi S, Hashimoto H, et al. Inhalation of volatile anesthetics under mechanical ventilation augment expression of pro-inflammatory cytokines in alveolar macrophages (abstract). Anesthesiology. 1999;91:A1396.
13. Kotani N, Hashimoto H, Sessler DI, et al. Supplemental intraoperative oxygen augments antimicrobial and proinflammatory responses of alveolar macrophages. Anesthesiology. 2000;93:15-25.
14. Rothen HU, Sporre B, Engberg G, et al. Prevention of atelectasis during general anaesthesia. Lancet. 1995;345:1387-1391.
15. Rothen HU, Sporre B, Engberg G, et al. Influence of gas composition on recurrence of atelectasis after a reexpansion maneuver during general anesthesia. Anesthesiology. 1995;82:832-842.
16. Akça O, Podolsky A, Eisenhuber E, et al. Comparable postoperative pulmonary atelectasis in patients given 30% or 80% oxygen during and for 2 hours after colon resection. Anesthesiology. 1999;91:991-998.
17. Edmark L, Kostova-Aherdan K, Enlund M, et al. Optimal oxygen concentration during induction of general anesthesia. Anesthesiology. 2003;98:28-33.
18. Sessler DI. Mild perioperative hypothermia. N Engl J Med. 1997;336:1730-1737.
19. Annadata RS, Sessler DI, Tayefeh F, et al. Desflurane slightly increases the sweating threshold but produces marked, nonlinear decreases in the vasoconstriction and shivering thresholds. Anesthesiology. 1995;83:1205-1211.
20. Matsukawa T, Kurz A, Sessler DI, et al. Propofol linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology. 1995;82:1169-1180.
21. Kurz A, Go JC, Sessler DI, et al. Alfentanil slightly increases the sweating threshold and markedly reduces the vasoconstriction and shivering thresholds. Anesthesiology. 1995;83:293-299.
22. Matsukawa T, Sessler DI, Sessler AM, et al. Heat flow and distribution during induction of general anesthesia. Anesthesiology. 1995; 82: 662-673.
23. Kurz A, Sessler DI, Christensen R, et al. Heat balance and distribution during the core-temperature plateau in anesthetized humans. Anesthesiology. 1995;83:491-499.
24. Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA. 1997;277:1127-1134.
25. Valeri CR, Feingold H, Cassidy G, et al. Hypothermia-induced reversible platelet dysfunction. Ann Surg. 1987;205:175-181.
26. Schmied H, Kurz A, Sessler DI, et al. Mild intraoperative hypothermia increases blood loss and allogeneic transfusion requirements during total hip arthroplasty. Lancet. 1996;347:289-292.
27. Winkler M, Akça O, Birkenberg B, et al. Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg. 2000;91:978-984.
28. Johansson T, Lisander B, Ivarsson I. Mild hypothermia does not increase blood loss during total hip arthroplasty. Acta Anaesthesiol Scand. 1999;43:1005-1010.
29. Heier T, Caldwell JE, Sessler DI, et al. Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology. 1991;74:815-819.
30. Lenhardt R, Marker E, Goll V, et al. Mild intraoperative hypothermia prolongs postanesthetic recovery. Anesthesiology. 1997;87:1318-1323.
31. Kober A, Scheck T, Fulesdi B, et al. Effectiveness of resistive heating compared with passive warming in treating hypothermia associated with minor trauma: a randomized trial. Mayo Clin Proc. 2001;76:369-375.
32. Miles AA, Miles EM, Burke J. The value and duration of defence reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol. 1957;38:79-96.
33. Wenisch C, Narzt E, Sessler DI, et al. Mild intraoperative hypothermia reduces production of reactive oxygen intermediates by polymorphonuclear leukocytes. Anesth Analg. 1996;82:810-816.
34. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med. 1996;334:1209-1215.
35. Sessler DI, McGuire J, Sessler AM. Perioperative thermal insulation. Anesthesiology. 1991;74:875-879.
36. Sessler DI, Schroeder M. Heat loss in humans covered with cotton hospital blankets. Anesth Analg. 1993;77:73-77.
37. Deriaz H, Fiez N, Lienhart A. [Effect of hygrophobic filter or heated humidifier on preoperative hypothermia] Ann Fr Anesth Réanim. 1992;11:145-149.
38. Sessler DI. Consequences and treatment of perioperative hypothermia. Anesth Clin North Am. 1994;12:425-456.
39. Hynson JM, Sessler DI. Intraoperative warming therapies: a comparison of three devices. J Clin Anesth. 1992;4:194-199.
40. Kurz A, Kurz M, Poeschl G, et al. Forced-air warming maintains intraoperative normothermia better than circulating-water mattresses. Anesth Analg. 1993;77:89-95.
41. Jorgensen LN, Kallehave F, Christensen E, et al. Less collagen production in smokers. Surgery. 1998;123:450-455.
42. Moller AM, Maaloe R, Pedersen T. Postoperative intensive care admittance: the role of tobacco smoking. Acta Anaesthesiol Scand. 2001;45:345-348.
43. Ferson M, Edwards A, Lind A, et al. Low natural killer-cell activity and immunoglobulin levels associated with smoking in human subjects. Int J Cancer. 1979;23:603-609.
44. Kotani N, Hashimoto H, Sessler DI, et al. Exposure to cigarette smoke impairs alveolar macrophage functions during halothane and isoflurane anesthesia in rats. Anesthesiology. 1999;91:1823-1833.
45. Sorensen LT, Horby J, Friis E, et al. Smoking as a risk factor for wound healing and infection in breast cancer surgery. Eur J Surg Oncol. 2002;28:815-820.
46. Myles PS, Iacono GA, Hunt JO, et al. Risk of respiratory complications and wound infection in patients undergoing ambulatory surgery: smokers versus nonsmokers. Anesthesiology. 2002;97:842-847.
47. Warner MA, Divertie MB, Tinker JH. Preoperative cessation of smoking and pulmonary complications in coronary artery bypass patients. Anesthesiology. 1984;60:380-383.
48. Sorensen LT, Karlsmark T, Gottrup F. Abstinence from smoking reduces incisional wound infection: a randomized controlled trial. Ann Surg. 2003;238:1-5.
49. Losser MR, Bernard C, Beaudeux JL, et al. Glucose modulates hemodynamic, metabolic, and inflammatory responses to lipopolysaccharide in rabbits. J Appl Physiol. 1997;83:1566-1574.
50. Gallacher SJ, Thomson G, Fraser WD, et al. Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabet Med. 1995; 12: 916-920.
51. Nielson CP, Hindson DA. Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro. Diabetes. 1989;38:1031-1035.
52. Rassias AJ, Marrin CA, Arruda J, et al. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg.1999; 88: 1011-1016.
53. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-1367.
54. Dellinger EP. Preventing surgical-site infections: the importance of timing and glucose control. Infect Control Hosp Epidemiol. 2001;22:604-606.
55. Latham R, Lancaster AD, Covington JF, et al. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol. 2001;22:607-612.
56. Trick WE, Scheckler WE, Tokars JI, et al. Modifiable risk factors associated with deep sternal site infection after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2000;119:108-114.
Daniel Sessler, Oxan Akca. Preventing surgical site infections--without drugs.
Feb. 1, 2004;49:78-87.