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Diabetes, Hyperglycemia, and Infections*

Ashley M. Shilling* MD

Assistant Professor of Anesthesiology

Jacob Raphael MD

Assistant Professor of Anesthesiology

University of Virginia Medical Center, PO Box 800710, Charlottesville, VA 22908, USA

Postoperative infection is not only a major source of morbidity and mortality in patients under-going surgery, but also an important cause of increased hospital stay and resource utilization.Diabetes has been shown in multiple studies to increase the risk of post-surgical infection.More recently, hyperglycemia has been investigated as an independent risk factor for postoper-ative infection. This paper will review the effects of intra-operative, postoperative, and long-term glycemic control on postoperative infection rates. The mechanisms by which surgerycauses hyperglycemia will be reviewed, as well as the immunologic and humeral effects ofhyperglycemia.

Key words: diabetes; hyperglycemia; surgical infection; anesthesia; infectious complications.

Postoperative infections are a devastating complication for patients undergoing surgery.They are the second most common cause of nosocomial infection and account for ap-proximately 17% of all hospital-acquired infections.1 These infections lead to longerhospital and intensive care unit stays, substantially increased mortality, and contributesignificantly to healthcare costs.2 For centuries, scientists have searched for infectiousrisk factors, as well as for means of infection modification and prevention.

It has been well established that patients with Diabetes Mellitus (DM) are at in-creased risk for both surgical and nosocomial infections.3–5 Infection rates havebeen quoted to be two to five times more prevalent in diabetics than in the nondia-betic population.6 A large, albeit retrospective cohort study, showed that nearly half ofall diabetics have at least one yearly hospitalization or physician claim for an infection.7

The relative risk for diabetic infectious disease-related hospitalization was 2.17. Fur-ther, death attributed to infection was significantly higher in diabetics. A large,

* Disclosures: This review was funded with departmental and institutional support.* Corresponding author. Tel.: !1 434 924 2283; Fax: !1 434 982 0019.E-mail addresses: abm5f@virginia.edu (A.M. Shilling), jr5ef@virginia.edu (J. Raphael).

1521-6896/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical AnaesthesiologyVol. 22, No. 3, pp. 519–535, 2008

doi:10.1016/j.bpa.2008.06.005available online at http://www.sciencedirect.com

12-month prospective study revealed that patients with DM had increased risk forlower respiratory tract, urinary tract, skin, and mucous membrane infections.8 Onestill-unanswered question, however, is whether this increased risk is due to hypergly-cemia itself, or other associated features found in the diabetic disease state such asmicrovascular changes or immunologic dysfunction. A large number of studies havelooked to answer this question. If perioperative hyperglycemia is an independentrisk factor for post-surgical infection, anesthesiologists and surgeons may beempowered to significantly affect infectious outcomes without changing the moredifficult-to-control variables of diabetic status or long-term glycemic control.

Due to the consistency among studies and compelling evidence that diabetes leadsto increased infection risk, major focus has been placed on whether hyperglycemia, asan independent risk factor, is associated with increased infection. Even in nondiabetics,hyperglycemia is associated with an increased risk of morbidity and mortality.9 Theoverwhelming majority of studies examining hyperglycemia and surgical infectionhave focused on the cardiac population, likely because 16–28% of patients undergoingcardiac surgery are diabetic.10–12 Furthermore, deep sternal wound infections, thoughrare, remain a devastating and often lethal complication following cardiothoracic sur-gery, with mortality as high as 14%.13,14 Increased hospitalization, resource utilization,and morbidity are only a few of the consequences of sternal wound infections.

A landmark study, published in 2001, by van der Berghe and coworkers, cast lighton the significance of postoperative hyperglycemia.15 This study included ICU patients,the majority of which had undergone cardiac surgery. They showed that treatinghyperglycemia aggressively with a target blood glucose level between 80–110 g/dL inthe surgical intensive care unit significantly reduced morbidity and mortality, both inthe intensive care unit and during hospital stay. Patients treated aggressively achievednot only lower glucose levels with increased in-hospital survival and decreased infec-tions, but also experienced long-term effects of increased one-year survival. One-yearmortality was decreased from 8.0% to 4.6%. The effect was greatest in patients withmulti-organ failure in the face of sepsis. The results of this trial instigated a flurry ofstudies and aroused interest in the deleterious effects of hyperglycemia, with focuson the cardiac surgical population.

POSTOPERATIVE HYPERGLYCEMIA IN THE CARDIAC SURGERYPATIENT

In a retrospective study, Zerr and colleagues at the PortlandDiabetic Project establishedthat increased mean glucose levels for the first two days following cardiac surgery is anindependent risk factor for deep sternal wound infection in diabetics.16 This groupfound that a continuous intravenous insulin protocol was superior to standard subcuta-neous insulin for glycemic control. Improved glycemic control decreased deep sternalwound infections from 2.4% to 1.5%. The same group conducted a prospective studyof 2,467 diabetic patients undergoing cardiac surgery.17 They looked at both the efficacyof subcutaneous insulin injections versus continuous intravenous insulin infusions inmaintaining glucose less than 200 mg/dL, as well as deep sternal wound infection ratesbetween these two groups. Their results indicated that, indeed, postoperative hypergly-cemia was associated with deep sternal wound infection in diabetics. Furthermore,a continuous insulin infusion, which they also found to be superior to subcutaneous in-sulin in reaching target glucose levels, resulted in a 66% reduction in deep sternal woundinfection. They concluded that hyperglycemia in the postoperative setting may be

520 A. M. Shilling and J. Raphael

a causative factor for deep sternal wound infections. Of note, this group looked solely atthe diabetic population and postoperative glucose control.

A multitude of studies prior to, and following the Portland group findings, have con-firmed the deleterious effects of postoperative hyperglycemia and infection in the di-abetic cardiac surgery patient population. A prospective study of 761 cardiac surgerypatients showed not only that diabetics were at an increased risk for wound infections,but also that strict glucose control using an insulin infusion to maintain glucose be-tween 120–160 mg/dL significantly reduced the risk of wound infection in diabetics.6

A chart review of 411 diabetic patients undergoing coronary artery bypass grafting(CABG) demonstrated a significant increase in risk of developing infections includingleg and sternal wound, urinary tract infection (UTI), and pneumonia when serum glu-cose levels (measured up to 36 hours after surgery) were higher than 200 mg/dL.18 Yetanother retrospective study of diabetics undergoing CABG found not only poor gly-cemic control in their population, but also an increase in adverse outcomes includingsepsis and infection in patients with elevated blood glucose within the first 24 hourspostoperatively.19 In addition to insulin treatment, Lazar and colleagues used a glucose,insulin, potassium (GIK) protocol in diabetics undergoing CABG and found improved 2year survival and fewer wound infections (1% versus 10%) in patients randomized toGIK therapy with target glucose of 125–200 mg/dL versus standard therapy.20 Thisgroup hypothesized that GIK, and specifically the insulin component, improved endo-thelial function, decreased vascular inflammation, and reduced thrombogenicity. Thenumber and consistency of these studies indicates that diabetics undergoing cardiacsurgery who experience postoperative hyperglycemia are likely at increased risk forinfectious complications. Of note, the target glucose levels for these studies rangedfrom 120–200 mg/dL, while the van der Berghe target was in the lower range of80–110 mg/dL.

Postoperative hyperglycemia may also increase infection in the nondiabetic cardiacpatient. One prospective study of diabetic and nondiabetic patients undergoing CABGfound that those nondiabetics with postoperative hyperglycemia had an increasedincidence of mediastinitis.21 Thus, tight postoperative glucose control may not onlybenefit the diabetic cardiac patient, but also the nondiabetic patient.

There has been little data refuting the correlation between postoperative hypergly-cemia and infection in cardiac patients, however one large retrospective study in 2003of 1574 patients, (35% with diabetes) undergoing CABG did not find a statistically sig-nificant increase in surgical or nosocomial infection rates in patients with postopera-tive hyperglycemia.22 The authors confirmed that diabetics have higher infection ratesand found that each 50 mg/dL increase in blood glucose was associated with longerpostoperative hospitalization and higher hospitalization cost. One important featureof this study is the large percentage of nondiabetic patients. Whether the non-diabeticpatient benefits equally from tight postoperative glycemic control is less certain.Despite this study, the majority of investigations have shown improved infectious out-comes with aggressive postoperative glucose control in the setting of cardiac surgery,with data being stronger in the diabetic population.

INTRAOPERATIVE HYPERGLYCEMIA IN THE CARDIACSURGERY PATIENT

While the majority of studies demonstrate increased infection in cardiac patients withelevated postoperative glucose levels, the evidence for improved outcomes with

Diabetes, Hyperglycemia, and Infections 521

tighter intra-operative glucose control is less compelling. A retrospective study byGandhi in 2005 found that increased mean introperative glucose in cardiac surgerypatients was not a predictor of infection.23 A more recent prospective, randomizedstudy by the same group examined 400 diabetic and nondiabetic cardiac surgerypatients. They investigated tight intraoperative glucose control (80–100 mg/dL) versustreatment of intraoperative glucose when levels exceeded 200 mg/dl.24 Postopera-tively, all patients received tight glucose control to maintain normoglycemia. Thoughnot adequately powered to detect differences in deep sternal wound infections, ag-gressive intraoperative insulin therapy did not reduce the incidence of sternal woundinfection. Furthermore, they found a statistically significant increased risk of stroke inthe intensive glucose control groups and a non-statistically significant trend towardsincreased death. Notably, the glucose targets for the Gandhi paper most closelyresembles that from van der Berghe15, while the majority of other studies had higherglucose targets.

Another study casting doubt on strict intraoperative glucose control was a prospec-tive, observational study by Ouattara looking at intraoperative glucose control in 200diabetic cardiac surgery patients.25 This group showed that infection was not signifi-cantly more frequent in patients with poor glycemic control, though other outcomesof morbidity including cardiovascular, neurologic, and renal were associated withhyperglycemia. Thus, the data for infection and intra-operative glucose control isless clear and Gandhi’s study24 actually raises concerns for aggressive intra-operativeglucose control. While severe postoperative hyperglycemia may be detrimental, over-zealous intra-operative glucose control may lead to worsened neurologic outcomes.

POSTOPERATIVE HYPERGLYCEMIA IN THE NONCARDIAC PATIENT

While data from the cardiac surgery population is often retrospective, the studies ofhyperglycemia and infection in the noncardiac population are almost nonexistent. Aretrospective study looking at patients undergoing infrainguinal vascular surgery inves-tigated hyperglycemia within 48 hours following surgery.26 Thirty-one percent ofpatients developed a postoperative infection requiring antibiotic treatment within 30days of surgery. Infections included surgical wound infections, graft infections, pneu-monia, and urinary tract infections. The majority of infections were wound-related(23%). Using univariate logistic regression analysis, postoperative hyperglycemia wasassociated with increased postoperative infections (Figure 1). Interestingly, after

*****

*

Figure 1. Percentage of patients undergoing peripheral vascular surgery who experienced at least oneinfection per glucose quartile; * P"0.006; **P"0.28; ***P-0.66. Taken from source26 with permission.

522 A. M. Shilling and J. Raphael

correcting for postoperative glucose levels, they found Type II diabetes to be associ-ated with fewer postoperative infections. One explanation suggested by the authorswas that insulin may have a beneficial, independent effect on infection and the diabeticpatients treated for hyperglycemia experienced the immunologic and anti-inflamma-tory benefits of insulin.

Vriesendorp and colleagues also performed a restrospective study of 151 ASA I andII patients undergoing oesophagectomy.27 They examined the relationship between 48hour post-operative glucose levels and infection. Infections included pneumonia,wound and urinary tract infection, and sepsis. Ninety-seven percent of their patientsdeveloped hyperglycemia (glucose> 6.1 mmol/L) within the first 48 postoperativehours. Thirty-six percent of patients had at least one infectious complication and9.9% had greater than one infection. Using univariate and multivariate regression anal-yses, no association was found between postoperative glucose levels and infection orinsulin administration and infection, despite the common incidence of hyperglycemia inthis patient population. Though retrospective in nature, these patients were enrolledin a prospective, randomized study of different outcomes. Reasons for this conflictingresult compared to the majority of other studies may be due to the patient populationstudied: little cardiovascular disease was present due to ASA 1 or 2 enrollment re-quirements. The authors speculate that in a population with minimal or no cardiacand vascular disease, increased glucose is not associated with infection risk. Thus,the major benefits of treating hyperglycemia may be gained only from patients withcardiovascular compromise or diabetes.

A prospective, randomized study of 78 patients, undergoing intracerebral aneurysmclipping after subarachnoid hemorrhage, examined intensive (blood glucose levels 80–120 mg/dL) versus conventional insulin therapy (blood glucose levels 80–220 mg/dL)begun intra-op and continued up to 14 days postoperatively or until ICU discharge.28

The authors found infection rates of 42% in conventional treatment group versus 27%in the intensive insulin treatment group. Pneumonia was the most commonly-occurringinfection followed by UTI, wound, and sepsis. Interestingly, incidence of vasospasm, neu-rologic outcomes, and mortality were not statistically significant between the two groups.

Another group, led by Pomposelli29, examined postoperative glucose levels and therate of nosocomial infections. One hundred diabetic patients without existing infectionwho were undergoing elective abdominal or cardiac surgery were monitored for peri-operative glucose control and postoperative infection. At least one serum glucoselevel greater than 220 mg/dL on POD 1 was 87.5% sensitive but nonspecific (33.3%)in predicting a nosocomial infection. In patients with hyperglycemia, the infectionrate was 2.7 times higher than those with all serum glucose values less than220 mg/dL. The authors concluded that patients with early postoperative hyperglyce-mia may have an increased incidence of infection; however, these findings must be in-terpreted carefully as association does not necessarily mean causation. Another small,prospective, randomized study of general surgery ICU patients reconfirmed thosefindings as well and found a reduced incidence of nosocomial infection in strict versusstandard glucose control protocols.30

PREOPERATIVE GLUCOSE CONTROL IN THE DIABETICAND NONDIABETIC SURGICAL POPULATION

While the majority of studies have looked at the more-easily controlled and measuredvariables of intraoperative or postoperative glucose, there have been several cardiac

Diabetes, Hyperglycemia, and Infections 523

and noncardiac studies investigating long-term preoperative glycemic control and post-operative infections. When looking at long-term glucose control, HbA1C is often usedas a surrogate measure. It is accepted that HbA1C reflects average glucose levels overa time period of 90 days. In a small, prospective study in 1992, Bishop and colleaguesexamined 90 patients undergoing penile prosthesis surgery.31 Approximately one thirdof the group was diabetic. They found that all periprosthetic infections occurred in di-abetic patients and the majority of these (80%) were in patients with poorly-controlleddiabetes (HbA1C greater than 11.5%). They concluded that a preoperative elevation inHbA1C is a strong indicator of postoperative infection and recommended denying sur-gery to patients until better glucose control is obtained. Despite the small numbers,this became the standard of care for patients undergoing penile prosthesis surgerybut was later challenged by a larger, prospective study. Wilson and colleagues enrolled389 patients undergoing elective penile prosthesis, the majority of which were not di-abetic (n" 275).32 The investigators used the previously cited 11.5% HbA1C as theircut-off for poor glucose control. Unlike Bishop, they found the incidence of surgicalsite infection to be significantly lower, and found no association between elevatedHbA1C levels and surgical site infections. They concluded that HbA1C levels may notbe a clinical predictor of postoperative infection in penile implant surgery. Despitethe conflicting results of these two studies, it is well defined that a HbA1C of 11.5 cor-relates with a blood glucose level of more than 310 mg/dL. Using this value in theaforementioned studies essentially deems an average glucose below 310 mg/dL inthe diabetic and nondiabetic population acceptable prior to undergoing surgery.Thus, results from these studies may be significantly different when using a moreacceptable HbA1C level.

A prospective study by Latham investigated the role of long-term glucose controlversus postoperative glucose control on infection in the cardiac surgery population.33

They examined diabetic status, postoperative glucose, and HbA1C levels above orbelow 8 mg/dL, and found that the rate of surgical site infection correlated with thedegree of hyperglycemia during the postoperative period. Hyperglycemia, regardlessof diabetic status, was an independent risk factor for surgical site infection. Postoper-ative glucose greater than 200 increased surgical site infection two-fold. They alsofound that a history of diabetes was associated with a 2.7-fold increase in the riskof developing a wound infection. Interestingly, poor chronic glucose control, asevidenced by HbA1C greater than 8, was not associated with an increase in infectionrate. Despite this, the authors found that patients with a HbA1C level less than 8% hadsignificantly less postoperative hyperglycemia than those with higher levels. Anotherstudy of patients undergoing CABG did not find a correlation between HbA1C levelspreoperatively and sternal wound infections.21

Dronge and colleagues retrospectively examined 490 diabetic patients undergoingnoncardiac surgery and their preoperative HbA1C levels.34 Their primary outcomewas any form of infection—surgical or nosocomial. Notably, they used a more univer-sally-accepted definition of acceptable glucose control (HbA1C less than 7%) and foundthat diabetic patients with a HbA1C level less than 7% were significantly less likely toexperience a postoperative infectious complications. This study chose the mostcommonly accepted measure of acceptable long-term glycemic control and is moreapplicable to current practices.

Trick and colleagues14 found that diabetes is an independent risk factor for deepsternal wound infection only when preoperative glucose is greater than 200 mg/dL.Guvener35, in a retrospective cohort study, confirmed that diabetics undergoingCABG have a higher incidence of infectious complications than nondiabetics. They

524 A. M. Shilling and J. Raphael

also found preoperative glucose to be a predictor of post-operative infection afterCABG in diabetics. Reasons why better preoperative glucose control may offerimproved postoperative infectious outcomes is likely multifactorial. First, better pre-operative control of glucose may confer better glucose regimens and postoperativecontrol. Indeed, Latham showed that patients with HbA1C less than 8% had less hyper-glycemia postoperatively.33 Secondly, patients with better long-term glucose controlmay have better general health and an improved metabolic milieu that may be protec-tive from infection.34

Indeed, the evidence seems compelling that not only diabetes, but also postopera-tive hyperglycemia, increases the risk of developing postoperative infection, particu-larly in the cardiac surgical population. The data suggests, but is less convincing, forintra-operative and long-term glucose control. Further, there is evidence that over-zealous intra-operative glucose control may be neurologically detrimental. Becauseanesthesiologists often do not have the opportunity to play a major role in long-term maximization of patients prior to surgery, the evidence supporting improvedoutcomes with postoperative and potentially intra-operative glucose control is en-couraging. These variables are obviously more modifiable and could offer significantbenefits both immediately in the postoperative period, and also in the long-term.What still remains unclear is the glucose threshold in which patient risk increases.It then becomes an important question as to why postoperative glucose controlreduces the incidence of surgical infections, and whether improved long-term controlor intraoperative control has benefits. One further important question is whetherglucose variability is an important factor for infection.

SURGICAL STRESS RESPONSE

Even in the 1800’s, the serious challenges posed by diabetes were acknowledged.Treves wrote, ‘‘Diabetes offers a serious bar to any kind of operation, and injuries in-volving open wounds, haemorrhage, or damage to the blood vessels are exceedinggrave in subjects of this disease. A wound in the diabetic patient will probably notheal while the tissues appear to offer the most favourable soil for the developmentof putrefaction and pyogenic bacteria. The wound gapes, suppurates, and sloughs. Gan-grene readily follows an injury in diabetics, and such patients show terrible pronenessto the low form of erysipelas, and cellulites’’.36 One hundred fifty years ago, Reybosoobserved glucosuria, a condition induced by ether anesthesia, in which glucose is dis-charged in the urine, and in 1877 Claude Bernard described hyperglycemia duringhemorrhagic shock.37 Today, it is well known that any type of acute stress or injuryresults in insulin resistance, glucose intolerance, and hyperglycemia; a constellationtermed ‘‘diabetes of injury’’.38,39

Regardless of diabetic status, surgery qualifies as a significant stress on the body andthe degree of hyperglycemia perioperatively depends on the type, severity, and extentof surgery (Figure 2). Superficial surgeries such as on the eye and ear may cause a smallincrease in glucose, while intraabdominal and cardiac surgeries tend to cause a more pro-nounced response.40 While blood glucose levels typically increase to 126–180 mg/dL inelective intraperitoneal procedures41, nondiabetics undergoing coronary artery bypasssurgery trend toward glucose levels reaching or exceeding 270 mg/dL42,43 Surgical stressactivates neuro-endocrine pathways, stimulating both the adrenergic system andhypothalamic-pituitary-adrenal axis. The hypothalamus, in response to stressful events,releases Corticotropin Releasing Hormone (CRH) which causes a resultant release of

Diabetes, Hyperglycemia, and Infections 525

Adrenocorticotropic Hormone (ACTH) from the pituitary, resulting in release of gluco-corticoids by the adrenal cortex. Concomitantly, the adrenergic response to stress in-cludes release of catecholamines such as epinephrine and norepinephrine. Theresultant endocrine milieu of the stress response is characterized by increased counter-regulatory hormones and catecholamines, cortisol, and glucagon. A rise in the level ofGrowth Hormone (GH) and cytokines such as IL-1, TNF, IL-6 is also observed.

It is now clearly understood that hyperglycemia frequently results from the stressresponse. Furthermore, in the diabetic patient, impaired glucose control leads to anexaggerated hyperglycemic response. There are several mechanisms causing the signif-icant rise in glucose. First, increases in hepatic gluconeogenesis and glycogenolysisoccur due to counter-regulatory hormones. The release of epinephrine and norepi-nephrine stimulate hepatic glycogenolysis and gluconeogensis. This is the major causefor increased glucose levels, though decreased glucose uptake and clearance due toinsulin resistance is another reason for increasing glucose levels during stress. Mostinsulin resistance occurs in skeletal muscle, but adipose, liver, and cardiac tissuesmay also contribute to this. In addition, there is a large release of proinflammatory cy-tokines and acute phase reactive proteins such as TNF-alpha, IL-1, IL-6, and C-ReactiveProtein (CRP) that also lead to peripheral insulin resistance. Furthermore, failure ofglucose to exhibit its normal negative feedback on gluconeogenesis also occurs duringstress. With high levels of catecholamines, the feedback leading to insulin secretionand glucagon inhibition is diminished. Yet another mechanism in which stress can causeglucose surges is that, hyperglycemia, itself, is pro-inflammatory and perpetuates theglycemic response. At the cellular level, hyperglycemia increases pro-inflammatorytranscription factors which, in turn, induce transcription of proinflammatory cytokinesTNF-alpha, IL-1, IL-2, IL-6, IL-8 and IL-18. This further leads to worsened hyperglyce-mia.44,45 Importantly, surgical stress-induced hyperglycemia leads to inflammation and

Figure 2. Relationship between the increment of post-operative endogenous glucose production and theduration of the exposure of the peritoneum during abdominal hysterectomy. Taken from source40 withpermission.

526 A. M. Shilling and J. Raphael

further hyperglycemia. Additionally, studies have shown that glucose fluctuations maylead to a greater oxidative stress and increased cytokine production.45,46

EFFECTS OF HYPERGLYCEMIA ON IMMUNE-SYSTEM

Since it is well-documented that surgical stress can lead to profound hyperglycemia,even in the nondiabetic patient, the next logical question is: why does hyperglycemialead to susceptibility to infection? Hyperglycemia and diabetes cause a number of del-eterious effects on immune defense mechanisms–both cellular and humeral (Figure 3).Included are changes in leukocyte function, altered microvascular response, andchanges in the complement cascade, cytokine network, and chemokine formation.Some of the earliest research on the harmful effects of hyperglycemia was focusedon leukocyte function. In vitro, hyperglycemic conditions may affect leukocyte functionin several ways, such as a decrease in chemotaxis, phagocytosis, adherence, andbacteriocidal activity. The actual degree of leukocyte function and responsiveness indiabetic subjects has been shown to be inversely related to the extent of hyperglyce-mia.47 It was shown almost 40 years ago that chemotaxis may be inhibited by hyper-glycemia and the effects may actually be reversed with insulin.48–50

Like chemotaxis, phagocytosis has been shown in multiple studies to be impaired bydiabetes and hyperglycemia.50,51 Even glucose levels of 200 mg/dL may impair phago-cytic function in vitro or in the clinical setting. Encouragingly, decreased phagocytosismay improve, but not completely normalize, after 36 hours of normoglycemia.52 In an-imal models, hyperglycemia caused impairment of phagocytosis in both monocytes andgranulocytes and the immune dysfunction was partially reversed by insulin.53 An animalstudy of post-burn rabbits and maintenance of normoglycemia with exogenous insulin,showed improved monocyte phagocytosis by more than a mean of 150% when animalswere treated with insulin. These animals demonstrated improved oxidative-mediatedkilling and suppressed growth hormone secretion.54 Within the last decade, it hasbeen shown that neutrophil dysfunction in the setting of hyperglycemia can be im-proved in vivo as well. A study by Rassias and colleagues55 looked at intraoperativeand postoperative hyperglycemia in diabetic patients undergoing cardiac surgery.They found that nonspecific phagocytic activity of neutrophils diminished one hour af-ter separation from cardio-pulmonary bypass with hyperglycemia, but improved withaggressive glucose control. Though this study was not designed to compare infectionrates, three patients in the standard insulin treatment group had infectious complica-tions (septic mediastinitis, nosocomial pneumonia, and urinary tract infection), whilenone of the aggressively-treated patients developed any infections.

In addition to it’s effects on chemotaxis and phagocytosis, there is evidence that hy-perglycemia may affect polymorphoneutrophils (PMN) adherence and apoptosis. Ina small study involving diabetic patients, it was shown that PMN adherence to a syn-thetic nylon column was decreased in the presence of hyperglycemia, but this effectwas reversed after restoring normoglycemia.56,57 Several studies have shown that hy-perglycemia may increase WBC apoptosis but this has also been questioned by otherinvestigators.58 Six studies have evaluated glycemic threshold for dysfunction of neu-trophils and the median glycemic threshold was found to be 200 mg/dL with a rangebetween 130–275 mg/dL.18

Another means in which hyperglycemia may affect leukocyte function is throughantigen presentation by monocytes. Antigen presentation and clearance, an importantcomponenent of infection prevention, may be diminished by hyperglycemia. Turina et al

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showed that monocyte expression of human leukocyte antigen (HLA)-DR was signif-icantly depressed in a hyperglycemic medium (400 mg/dl glucose) after only 24 hourscompared to monocytes in a normoglycemic medium (100 mg/dl). Interestingly, theaddition of insulin was associated with a greater depression in monocyte expressionof surface antigen. Decreased levels of monocyte HLA-DR have been shown to

Figure 3. The effects of hyperglycemia on the immune system. Taken with permission from Mauermann WJ,Nermergut EC. Anesthesiologist’s role in the prevention of surgical site infection. Anesthesiology 2006;105(2):413-421.

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correlate with infections in critically ill patients.59–61 Most studies have concluded thatthe bactericidal activity of neutrophils is decreased in both diabetics and in hypergly-cemic environments. This may vary, however, with the organisms being investi-gated.62,63 One study conducted to specifically elucidate immune-suppression asa result of the diabetic state versus hyperglycemia examined 37 nondiabetic patientsgiven a 75 gram glucose solution. This resulted in significant hyperglycemia as ex-pected.64 Within two hours, there was a significant lymphopenia and lymphocyte sub-set redistribution. The authors speculate that leukocyte sequestration to the vascularendothelium by cellular adhesion molecules (CAM) is partly responsible for the lym-phopenia. Indeed, it has been shown that hyperglycemia increases expression of bothintracellular adhesion molecules and E-selectins.65

Data has suggested that PMN respiratory oxidative burst is inhibited by high glu-cose concentrations in vitro. This, in part, explains the decreased intracellular pathogenlysis that occurs during hyperglycemia. Phagocytosis is also impaired by decreasedoxidative burst generation in monocytes.53,66

Both the diabetic state and hyperglycemia are proinflammatory. Type I and IIdiabetics have increased levels of TNF-alpha, IL-6, and IL-8.67,68 As mentioned pre-viously, increased levels of IL-6 IL-18, and TNF-alpha have also been found in hyper-glycemic environments.45 While inflammatory responses are important ineradication of infectious agents, the resulting edema can lead to hypoxia as wellas microvascular and macrovascular dysfunction. Also, a relatively small dose of75 grams of glucose in healthy subjects causes inflammatory changes and oxidativestress.69 Thus, additional detrimental effects of hyperglycemia include increasedreactive oxidative species (ROS), increased oxidative stress, and overproductionof free radicals.44

Hyperglycemia can lead to nonenzymatic glycosylation of proteins as well as the ad-dition of sugar molecules to lysine residues on extracellular proteins. These glycosyl-ation processes result in protein inactivation and dysfunction of immunoglobins. It hasbeen shown that glycosylation of the C3 element of the complement system preventsit from invading bacterial surfaces.70 Glycosolation of collagen as well as increased col-lagenase activity results from hyperglycemia in animals, thus decreasing wound colla-gen levels, impairing wound healing, and potentially increasing susceptibility toinfection. In the surgical setting, a decrease in tensile strength of intestinal anastomosiswas shown in hyperglycemic animals, but was reversed to normal strength in diabeticanimals when glucose was normalized.71

Hyperglycemia may exert some of its detrimental effects on the endothelium aswell. Endothelium-dependent vasodilation is attenuated by hyperglycemia in bothin vitro and in vivo studies.72,73 It has also been shown that in diabetes, nitric oxide(NO) production is decreased and the vascular response to NO may be blunted.The resultant failure of vasodilation may hinder phagocytes from reaching their infec-tious target. A study by Williams et al. looked at the effects of hyperglycemia onendothelium-dependent vasodilation in humans.74 Using the brachial artery, they foundthat acute hyperglycemia impairs endothelium-dependent vasodilation in healthy hu-mans. Proposed mechanisms for the endothelial dysfunction include hyperglycemia-mediated formation of oxygen-derived free radicals which inactivate nitric oxide, for-mation of glycosylation end products, activation of protein kinase C which may lead toincreased generation of vasoconstrictor prostanoids75, and phosphorylation of endo-thelial cell muscarinic receptors.76 An enzyme inhibiting nitric oxide synthetase, Asym-metric Dimethylarginine (ADMS), has been shown to be increased in a subsetof patients with hyperglycemia77 and may be an independent predictor of mortality.

Diabetes, Hyperglycemia, and Infections 529

Further, hyperglycemia can cause small vessel vasculopathy, thus leading to tissue hyp-oxia, ischemia, and impaired antibiotic prophylaxis.78

The hyperglycemic environment may enhance the virulence of various microor-ganisms. Candida albicans shows competitive binding and inhibition of complement-mediated phagocytosis in a hyperglycemic environment.70 Glucosuria enhancesEscherichia coli growth and may be a reason for the increased incidence of urinarytract infections in diabetics.79 Enzymes important in DNA repair, inflammation, andprogrammed cell death may also be affected by hyperglycemia.80

As we are learning more about the mechanisms by which hyperglycemia affectsimmunity, it becomes clear that glucose levels need to be monitored and controlled,particularly in the perioperative setting when patients are prone to infectious complica-tions. There is mounting evidence that postoperative hyperglycemia, in both the diabeticpatient population as well as the nondiabetic population, may increase infectious compli-cations. The strongest data is in the cardiac surgical population, particularly in thepostoperative setting, though there is suggestion that generalized perioperative hyper-glycemia may be deleterious. Large, prospective, randomized trials investigating perio-perative glucose control in the operating setting do not exist and there is an immenseneed for future studies, particularly in the noncardiac surgery patient population.

In the preoperative setting, it is vital to question patients and screen appropriatepatients for diabetes. In cardiac surgery patients, strict postoperative glycemic controlis of paramount importance. Still to be determined is the glucose concentration inwhich infection risks increase. The original target of less than 220 mg/dL has beenshown to be inadequate and more recent data suggests lower values may be beneficial.Unfortunately, studies show improved benefit when glucose targets are in the broadrange of 80–200 mg/dL. The optimal target glucose level is still undetermined. One fur-ther question is whether glucose fluctuations play an important role in the detrimentaleffects of hyperglycemia. It is prudent to maintain normoglycemia and limit glucosefluctuations as much as possible.

Many studies have demonstrated that correction of stress-induced hyperglycemiawith insulin decreases infection and other morbidities. Insulin has a multitude of ben-eficial effects including enhanced neutrophil phagocytosis and chemotaxis. Insulin hasanti-inflammatory properties such as reducing inflammatory cytokines and suppressingproinflammatory transcription factors. Insulin also reduces superoxide ion generation,thus reducing ROS-induced tissue injury. The anti-inflammatory and antioxidant effectof insulin can be seen within two hours of administration and 2 units an hour of insulinis similar to the effects of 100 mg of intravenous hydrocortisone.81 Insulin may alsodecrease CRP concentration which is an important component in the acute phase re-sponse. Insulin has also been shown to have a beneficial effect on lipid metabolismwhich may alter infection by scavenging endotoxin in the circulation.82 Finally, insulinmay lower triglyceride and free fatty acid concentrations.83

An insulin infusion protocol has proven superior to intermittent subcutaneous bo-luses in improving glucose control, though concerns for hypoglycemia have beenraised. In the Portland study, 0.04% of diabetic patients had symptomatic hypoglycemia,though several studies have been stopped due to safety concerns for hypoglycemia.44

One study of nondiabetic cardiopulmonary bypass surgery patients found that 40% ofpatients treated with insulin developed hypoglycemia requiring treatment.43 When us-ing an insulin infusion, glucose levels should be aggressively checked. We recommendchecking glucose hourly, especially when changes in management are being instigated.

As we learn more about hyperglycemia, it is important that anesthesiologistsbe aware of the potential deleterious effects of hyperglycemia and means in which

530 A. M. Shilling and J. Raphael

we may modify patient risks. Even in the nondiabetic patient population, surgicalstress often leads to hyperglycemia and should be monitored and treated. This isparticularly true in the cardiac surgery patient population. The optimal glucoselevel is still undetermined at this time, though the original thought of keeping glu-cose less than 200 mg/dL may be indadequate. More recent data suggests lowertargets of 80–120 mg/dL, but is the most conclusive in the post-operative cardiacsurgery patient. Aggressive insulin therapy is certainly the mainstay for glycemiccontrol, though various anesthetic techniques such as neuraxial and regional an-esthesia may improve glycemic control by modification of the stress response.40

Pharmacologic modulation of the stress response is also promising and warrantsfurther investigation.

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Practice points

All patients undergoing surgery should be questioned preoperatively about diabe-tes and screened for diabetes if deemed necessary.Diabetic patients should be counseled preoperatively regarding the need to main-tain good glucose control, as well as their increased risk for infectiondevelopment.Even in nondiabetic patients, surgical stress often leads to insulin resistance andhyperglycemia and should be monitored and treated. This is particularly true inthe cardiac surgery patient population.Tight postoperative glycemic control should be practiced, especially in patientsthat have undergone cardiac surgery. The physician should aim for normoglyce-mia and try to avoid fluctuations.

Future research

The role of perioperative glycemic control in infection prevention is still notclearly elucidated, particularly in the noncardiac surgery patient.The significance of long-term glucose control and surgical infection risk needs fur-ther evaluation.Further research needs to be conducted on the optimal target glucose levelsintra-operatively and postoperatively..Means of modifying the surgical stress response such as neuraxial anesthesia andpharmacologic agents need to be further investigated.

Diabetes, Hyperglycemia, and Infections 531

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