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rate is not causing hypoglycemia. If there is any concern about possible fasting hypoglycemia, a temporary basal rate should be set at 80% of the patient’s usual basal rate. The infusion set should be changed 24h before surgery, and the insertion site should be selected away from the surgical site. The chosen site can be anywhere on the upper outer thighs, upper arms, or abdomen 2 inches away from the umbilicus. Blood glucose should be checked every hour during surgery. Transition to insulin infusion should be considered if blood glucose exceeds and remains above 180mg/dL.

Critical Illness

Patients on insulin pumps need to be transitioned to an intravenous insulin infusion in critical illness [48].

Perioperative Diabetes Management

Patients with diabetes should be given preference for earlymorning surgery. Doing so may decrease the risk of hyperglycemia and hypoglycemia resulting from disruption in typical medication and food schedules. On the day prior to surgery, patients with diabetes should continue their usual hospital-ordered calorie-restricted, carbohydrate-consistent diabetic diet, along with their ordered insulin and/or oral antihyperglycemic medications. Changes that need to be made to the patient’s diabetes medication regimen are listed in Table6.7. The patient’s health care team needs to ensure that the patient is not sent to the preanesthesia unit without receiving their adjusted scheduled dose of long-acting or intermediate-acting insulin. This is especially important in patients with type 1 diabetes who are traditionally at a higher risk of diabetic ketoacidosis if their insulin regimen is disrupted.

Intraoperative

Upon arrival to the preanesthesia unit, diabetes management is largely dependent on the patient’s type of diabetes, blood glucose upon arrival, and the type of surgery. The target blood glucose range in the perioperative period is 80–180mg/

dL [11]. Tighter perioperative glycemic control does not improve outcomes and has been associated with hypoglycemia [51].

Minor Surgeries

The patient’s blood glucose upon arrival to the preanesthesia unit can determine treatment and BG monitoring frequency, as outlined in Table6.3. Patients who have a blood glucose level>180mg/dL and are not responding to subcutaneous insulin within an hour can be started on IV insulin infusion. On the other hand, patients with blood glucose lower than 100mg/dL should be started on IV dextrose infusion, as outlined in Table6.8. All other patients should receive maintenance intravenous uids that do not contain dextrose, such as lactated ringers, normal saline, or ½ normal saline.

Major Surgeries

It is recommended that IV insulin infusion be started for patients undergoing chest, abdominal, vascular bypass, transplant, spinal or brain surgery, total hip or knee replacement surgeries, or surgery anticipated to last longer than 4h. For patients who are started on IV insulin infusion, a dex-

Table 6.7 Preoperative diabetes management night before or the morning of surgery

Diabetes medication management

• Long-acting (glargine or detemir) insulin: Inject 80% of the scheduled dose at bedtime or in the morning before surgery, depending on the patient’s usual administration time

• Intermediate-acting (NPH) insulin: Inject ½ of the usual dose

• Rapid (aspart, lispro, glulisine) or short-acting (regular) insulin: Omit morning dose (including inhaled insulin)

• Premixed insulin (70/30, 75/25, 50/50): Inject ½ of the NPH component of the usual premixed insulin and no rapid or short-acting insulin on the morning of surgery

• Oral and noninsulin injectable diabetes medications: Discontinue on the morning of surgery [9]

Blood glucose monitoring

• Check blood glucose at bedtime and on the morning of surgery and every 4–6h thereafter

• If hypoglycemic at bedtime or overnight, the patient should be treated with glucose gel and not by juice

Table 6.8 Intraoperative diabetes management for nonmajor surgery

BG<80mg/dL

Give at least 100mL D10W IV or

25–50mL (1/2–1amp) of D50

Check BG in 15–30min

BG 80–100mg/dL

↓

Begin D5W at 40mL/h or D10W

↓

at 20mL/h

Check BG in 1h

BG 101–180mg/dL

↓

Continue to monitor Check BG every 2h

BG >180mg/dL

↓

Give corrective rapid-acting insulin

q4h (Table6.3) or start insulin infusion; check BG every hour

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trose containing intravenous uid is necessary. D5W at 40mL/h or D10W at 20 mL/h should be started to provide approximately 50mg of glucose over 24h.

Postoperative

While the patient is in the postanesthesia unit, the management and frequency of BG monitoring remain similar to that during surgery (Table6.8). If the patient’s BG is greater than 180mg/dL, BG should be checked hourly. A corrective dose of rapid-acting insulin should be administered every 4 h. Upon arrival to the regular oor, it is recommended to start a basal plus nutritional or basal plus corrective rapid-acting insulin regimen [52, 53]. If the patient is not eating, nutritional insulin should be held. It may be started later at reduced doses based on oral nutrition intake [9, 53]. Patients whose status is postcardiac surgery should continue on IV insulin infusion.

Hyperglycemia Management oftheCritically ill Inpatient

It is well established that mortality, morbidity, and length of stay increase when blood glucose levels rise above 180– 200mg/dL in critically ill patients [5, 9]. More recently, it has been established that hypoglycemia in these patients is also associated with increased mortality. It is therefore important to have a form of insulin that both acts and clears rapidly in order to quickly correct and prevent hyperglycemia and hypoglycemia. When regular insulin is injected by intravenous (IV) versus subcutaneous (SC) routes, peak serum levels are reached within 2min by the IV route versus 60min by the SC route, resulting in peak glucose lowering at 15 min by the IV route versus 180 min by the SC route. Rapid glucose lowering by IV insulin is coupled with rapid insulin clearance and allows blood glucose levels to return to baseline 30min postinjection if insulin infusion is stopped [54–56]. The slower performance of SC-administered regular insulin is because regular insulin is crystalized around a zinc molecule in the shape of a hexamer. It takes time for this hexamer to dissociate rst into dimers and then monomers, which rapidly cross the capillary membrane and bind to insulin receptors. Thus, IV insulin infusions are the standard of care in critically ill patients. Exceptions are patients who are predicted to be discharged from the ICU in less than 24h. Those patients may start or continue SC insulin as previously discussed.

Table 6.9 Glucose targets in critically ill patients with and without diabetes

Established diabetes No diabetes

• Status postcardiac surgery or

• Status postischemic cardiac or neurological event

140–180mg/dL 100–150mg/dL

Target Blood Glucose Range

The current blood glucose recommendations for critically ill patients by the American Diabetes Association (ADA) in conjunction with the American Association of Clinical Endocrinologists (AACE) [9] and separately by the Society of Critical Care Medicine [57] are listed in Table 6.9. In order to understand the rationale behind these recommendations, we will briey review the landmark randomized controlled trials leading to them. The Leuven trial in 2001 [58] was a single-center trial that compared a BG target of 80–110mg/dL versus 180–200mg/dL in the surgical ICU.It showed a 42% reduction in mortality and 34% reduction in the length of stay. The Leuven group repeated its study in medical ICUs but was not able to show a similar reduction in mortality. In fact, there was a trend toward increased mortality that was found to be strongly associated with hypoglycemia. [59] The VISEP study [60] compared the two target BG range groups dened by the Leuven trials but in patients with septic shock [58, 59]. The study reported a signicant increase in adverse events (11 vs. 5%) in the 80–110mg/dL group versus the 180–200mg/dL group, and the study was stopped early due to a signicantly increased rate of hypoglycemia (17 vs. 4%) in the tightly controlled group. The NICE-SUGAR study [61], a large multinational study, compared a target range of 81–108mg/dL to 140–180mg/dL in both surgical and medical ICUs. The trial showed a signicant increase in 90-day mortality with the lower target, which was associated with hypoglycemia, although no causal relationship was established [62]. Of note, this was the only study that had a comparison group with blood glucose levels below 180 mg/dL, which is well below the 200 mg/dL threshold that prior studies had shown to increase morbidity and mortality. It is worth noting that the safety of blood glucose levels between 110mg/dL and 140mg/dL is still unanswered. The ADA/AACE recommendations [9] aim to keep the lower end of their target higher enough (140mg/dL) to preemptively prevent less experienced ICU teams from entering their patients into the blood glucose “danger zone” of <110mg/dL, which was associated with higher mortality, as shown in the NICE-SUGAR study [61], and an upper end of the range<180mg/dL to avoid falling into the >200mg/

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dL “danger zone.” It is recommended that blood glucose should be kept in the lower end of this range [9]. However, certain hospitals with lower hypoglycemia rates have chosen tighter target ranges, such as 120–160mg/dL, presuming the unexamined 110–140mg/dL to be safe and trying to keep their upper target range away from 200mg/dL.

For patients whose status is postcardiac surgery, the Society of Critical Care Medicine recommends a target range of 100– 150mg/dL [57] (see Table6.9). However, tight control (100– 140 mg/dL) on IV insulin infusion in postcardiac surgery patients has been shown to lower adverse outcomes for patients without diabetes. Patients with diabetes have no increased complications in the 140–180mg/dL target group when compared to the 100–140mg/dL target group [63, 64]. Other patients without diabetes who may benet from tighter glycemic control are those who are admitted for an acute ischemic cardiac [65] or neurological event, provided these targets can be achieved without signicant hypoglycemia. [57]

Effective insulin infusion protocols must use dynamic as opposed to static algorithms that use the last blood glucose, the rate of change in blood glucose, as well as the current insulin infusion rate when recommending the new insulin infusion rate [11]. This will help prevent hyperglycemia if the rate of correction is too slow and hypoglycemia if the rate of correction is too fast. Many different paper-based and computer-based dynamic algorithms are available, and no single protocol or algorithm has been established as the most effective for achieving and maintaining glucose targets or achieving the lowest hypoglycemia rates [66, 67]. It is important that the hospital’s chosen protocol is validated and that the hospital has demonstrated safety and efcacy [67]. The key elements of an intravenous insulin infusion protocol are listed in Box 6.3 [66–68]. In general, a potential hypoglycemic or hyperglycemic scenario should be anticipated and proactively addressed with clear guidelines in the protocol. For example, in the event of abrupt TPN/PPN, steroid, or vasopressor discontinuation, the infusion rate should be reduced by 50%, with the resumption of blood glucose checks once every hour until blood glucose levels are stable. It needs to be noted that patients with diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome will need modied insulin infusion protocols that prevent a rapid correction of hyperglycemia.

N. Khazai and O. Hamdy

Box 6.3: Key Elements of an Intravenous Insulin Infusion Protocol

1. Clear instructions on the criteria for the initiation of IV insulin infusion.

2. Clearly the stated target blood glucose.

3. Clear instructions on how to calculate the initial IV insulin infusion rate.

4. Instructions on the frequency of blood glucose monitoring.

5. Clear instructions on the management of hypoglycemia.

6. Guidance for handling situations where TPN, PPN, steroids, or vasopressors are added or removed.

7. Guidance for transitioning from IV insulin to SC insulin.

8. Instructions on how to change insulin infusion rate.

Transitioning o Insulin Drip

Once critically ill patients become clinically stable and ready for transfer out of the ICU and are tolerating at least 50% of their diet or are on a stable regimen of TPN or PPN, they are ready to come off the insulin infusion. Not all patients who were on an insulin infusion in the critical care unit will need to transition to SC insulin. Patients who need to be transitioned are those with type 1 diabetes, with type 2 diabetes, or without diabetes requiring more than 1–2units/h of insulin. [69] The Joslin Diabetes Center guidelines for transitioning patients from intravenous (IV) to subcutaneous (SC) insulin are listed in Box 6.4 [69, 70].

Box 6.4: Guidance for Transitioning from IV to SC Insulin

1. Determine the average hourly rate of insulin over the past 8h.

2. Multiply this number by 24 to determine total IV insulin requirements in the past 24h (TDD-IV).

3. Use 60–80% [71, 72] of the total TDD-IV to derive your TDD of SC insulin (TDD-SC).

4. If the patient was on NPO, the TDD-SC number is equivalent to the patient’s basal insulin.

5. If the patient was eating over the past 24h, then ½ of the TDD-SC is bolus and the other half basal.

6. Overlap IV insulin infusion for a minimum of 4h if subcutaneous insulin glargine is given without subcutaneous fast-acting insulin.

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Hypoglycemia

The early recognition and treatment of hypoglycemia, utilizing a hospital-wide nurse-led protocol, signicantly reduces adverse outcomes [73, 74]. Treatment depends on the severity of the hypoglycemic episode and whether or not the patient is conscious. The hypoglycemia management guidelines by Joslin Diabetes Center are listed in Table6.10 [75]. The recurrence of hypoglycemia is common. In one study, 84% of patients with severe hypoglycemia had one prior episode of hypoglycemia. [11] Failing to adjust insulin regimen after a hypoglycemic event is common [11] and is a strong predictor of the recurrence of hypoglycemia and declining renal function [9]. Therefore, it is important for treating providers to review the patient’s insulin regimen and adjust basal or corrective bedtime insulin doses in the event of fasting hypoglycemia or bolus and/or corrective insulin doses in the event of postprandial hypoglycemia. [5] The Joslin Diabetes Center guidelines on insulin adjustments for hypoglycemia are detailed in Box 6.5 [75]. In about 20% of cases, rebound hyperglycemia is experienced after a hypoglycemic event. Close communication between physicians and nursing staff prior to making any changes to the patient’s insulin regimen is quite important. Overcorrection with carbohy-

drates is frequently the main cause of rebound hyperglycemia. For example, giving no more than 20g of carbohydrate for the correction of blood glucose between 50 and 70mg/dL and calculating the D50 dose based on blood glucose readings at the time of the hypoglycemic episode instead of injecting a full ampule are good practices. Examples and serving sizes of simple carbohydrates used to treat hypoglycemia are listed in Box 6.5. It needs to be noted that patients with gastroparesis should receive treatment with glucose gel due to their delayed gastrointestinal absorption. Blood glucose should be checked 15min later, and if blood glucose remains <70mg/dL, another 15g of simple carbohydrates should be given. As discussed in the previous section, for critically ill patients, the consensus threshold for hypoglycemia is considered 100mg/dL.

Box 6.5: Examples of 15g of Carbohydrate

• 4 glucose tablets

• 1 tube glucose gel

• 4oz. (1/2 cup of juice or regular soda)

• 4 teaspoons of sugar.

Table 6.10 Hypoglycemia management (noncritically ill patients)

Treatment

Conscious on oral feeding BG: 50–69mg/dL 15–20g of simple carbs

BG<50mg/dL 20–30g of simple carbs

Conscious but NPO On IV insulin • Stop insulin infusion

• Inject bolus dose D50W IV.Dose in mL=(100– BG)×0.4

• Start D10W IV at 25cc/h

• Once BG is back to >100mg/dL, stop D10W and resume insulin infusion at 50% of the previous rate

On SC insulin • Inject bolus dose D50W.Dose in mL=(100—BG)×0.4

• Start D10W IV at 25cc/h

• Once BG is back to >100mg/dL, stop D10W and resume the insulin regimen after appropriate adjustments are made

Unconscious No IV access • Give 1mg glucagon IM or 0.5mg for patients <50kg body weight

• Once IV access is established, proceed with the steps outlined for the conscious patient

Insulin adjustment

Fasting hypoglycemia • Reduce long-acting basal insulin by 20% if BG is 50–70mg/dL

• Reduce long-acting basal insulin by 30% if BG is <50mg/dL

• If the patient received corrective insulin prior to the event, consider increasing the sensitivity factor (SF) of corrective insulin

Postprandial Hypoglycemia • Reduce bolus (nutritional) insulin by 20–50% for the duration that the patient’s oral food intake is

below baseline

• If the patient received corrective insulin prior to the event, consider increasing the sensitivity factor (SF) of corrective insulin

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Summary

During hospital admission, proactive glycemic control for critically ill and noncritically ill patients with diabetes is important to prevent hospital complications and mortality, whether patients are managed in surgical or medical units. Hyperglycemia needs to be avoided with the institution of long-acting basal plus nutritional and corrective rapid-acting bolus insulin and not only by corrective regular insulin doses before the sliding scale. The timely detection of hypoglycemia and nurse-led management protocols have become a standard of care. Timely changes in treatment are greatly facilitated by glucose meters that are wirelessly connected to the hospital’s electronic health record system, as well as by using computerized physician insulin order entry systems. This combination allows physicians to rapidly access patient’s blood glucose readings from anywhere in the hospital and immediately intervene. Good communication between the hospital teams and the availability of certied diabetes educators are shown to improve diabetes control during hospital admission and ensure patient safety after discharge. As tight glycemic control may be associated with an increased hypoglycemia risk, further studies are still needed to determine the ideal blood glucose targets for both critically ill and noncritically ill patients. With increasing attention to medication errors and iatrogenic complications in the hospital setting, safely achieving euglycemia will be of paramount importance.

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53. Umpierrez GE, Smiley D, Hermayer K, et al. Randomized study comparing a basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial. Diabetes Care. 2013;36(8):2169–74.

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Part II

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Pathophysiology

Physiology andPathophysiology

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ofWound Healing inDiabetes

IrenaPastar, NathanC.Baluko, AndrewP.Sawaya, NicoleM.Vecin andMarjanaTomic-Canic

Abstract

Wound healing is a dynamic process comprising of overlapping phases of hemostasis, inammation, proliferation, and remodeling that involve multiple cell types. This highly organized and coordinated series of processes result in the restoration of tissue and barrier integrity. Deregulation in any of these processes leads to a delayed or a nonhealing phenotype as seen in diabetic foot ulcers (DFUs). The functions and cell-to-cell communication between different cell types contributing to wound healing (keratinocytes, broblasts, endothelial cells, neutrophils, and macrophages) and their deregulation in chronic nonhealing ulcers are discussed here in detail. The balance of signaling factors, including growth factors cytokines and chemokines, and gene expression regulators, along with their spatiotemporal control, is indispensable for successful wound healing, while their dysregulation contributes to pathophysiology of DFUs. Additional factors that contribute to the delayed healing seen in diabetes include deregulated immune response, macro- and microvascular complications, neuropathy, and microbial dysbiosis. Discussion of therapeutics including cell therapy, stem cells, and stem cell-derived extracellular vesicles provide approaches for potentially effective treatments of patients with DFUs is also included.

Physiology ofWound Healing

Wound healing is an evolutionarily conserved process that aims to restore the damaged epithelial barrier between the body and the outside world. This complex process involves

I. Pastar · N. C. Balukoff · A. P. Sawaya · N. M. Vecin · M. Tomic-Canic (*) Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA e-mail: mtcanic@med.miami.edu

many cellular responses including inammation, proliferation, migration, angiogenesis and tissue remodeling. Immediately after the injury, blood components are released into the wound site, activating the clotting cascade. The resulting clot induces hemostasis, releases chemotactic cytokines, and provides a matrix for the inux of inammatory cells. Inammation is characterized by leukocyte migration and arrival to the site of injury. Neutrophils arrive rst to remove contaminating bacteria and release pro- inammatory cytokines [1]. They are followed by monocytes, which differentiate into macrophages at the site of tissue injury. Macrophages play an important role in augmenting the inammatory response and removing nonviable tissue. At the same time, many different cell types respond to initial inammatory signals and migrate to the wound site, including keratinocytes, endothelial cells, and both circulating and local progenitor cells. Once they arrive and proliferate, the processes of reepithelialization, neovascularization, and granulation tissue formation commence. Granulation tissue formation begins during the inammatory phase, forming a “beefy red” and highly vascular region of the healing tissue, predominantly relying on neovascularization [1, 2]. As the wound closes, the immature brin matrix and granulation tissue are replaced by collagen and scar.

Wound healing as a process does not end at wound closure, although this is the visible sign of complete healing. After closure, the remodeling phase begins, which is characterized by continuing collagen deposition and cross-linking. During remodeling, balance is established between collagen synthesis and degradation, which gives the scar its tensile strength [1, 3]. Wound healing in adults results in scar formation, brosis, and contracture. However, fetal skin, up to midway through the third trimester, heals without scar formation, using a unique regenerative pathway [4].

Cellular responses to injury involve direct cell-cell and cell-matrix interactions, as well as indirect crosstalk between different cell populations via soluble mediators. Thus, wound healing is orchestrated through the integration of multiple signals (growth factors, cytokines, and chemokines) released

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by participating cells including keratinocytes, broblasts, endothelial cells, neutrophils, macrophages, and platelets. The appropriate balance of these signaling factors as well as their spatiotemporal control is essential for successful wound healing [5–9]. The functions of various contributing cells, i.e., keratinocytes, broblasts, endothelial cells, neutrophils, and macrophages, are discussed in more detail below.

Cellular Components ofWound Healing

Keratinocytes

Keratinocytes play several critical roles in the wound healing process and are among the most important cells that respond to injury and accelerate healing. Under normal conditions, their main role is to form the barrier of the skin. Once the skin is wounded, keratinocytes play many important roles, including the release of cytokines and growth factors, which recruit other cell types, stimulate matrix formation, and promote angiogenesis [10, 11]. Simultaneously, keratinocytes also migrate and proliferate within the wound bed to accelerate closure and restore the skin barrier [9].

In healthy skin, keratinocytes proliferate in the basal cell layer and differentiate in the suprabasal layers. Basal keratinocytes are mitotically active and help form the basement membrane by promoting crosstalk with dermal broblasts, melanocytes, and Langerhans cells. Once keratinocytes migrate above the basal cell layer, they change phenotypically and begin to differentiate. During this process, keratinocytes stop dividing, change their keratin production from K5/K14 to K1/K10, and begin producing a number of other insoluble proteins [12]. Terminal differentiation results in the loss of nuclei and protein cross-linking, giving rise to a cornied layer that forms the epidermal barrier [9, 13, 14]. The perpetual process of keratinocyte differentiation and upward migration maintains a strong barrier to the outside world.

Because keratinocytes are responsible for barrier maintenance, they are equipped for rapid response to injury. When the epidermal barrier is disrupted, keratinocytes release prestored interleukin-1 (IL-1), which is the rst signal that alerts nearby cells to barrier damage [10, 15]. In addition to the common initiator, IL-1, certain cytokines, and growth factors such as tumor necrosis factor alpha (TNF-α) and epidermal growth factor (EGF) are released by keratinocytes that together with IL-1 act in both an auto- and paracrine manner [9, 16–19]. This process, termed the “keratinocyte activation cycle,” is characterized by changes in cellular behavior (migration, proliferation), induced secretion of multitude of other growth factors and cytokines, and expression of K6, K16, and K17 keratin proteins, which are often considered as the rst markers of epidermal healing [20, 21].

To close a breach in the epidermal barrier, keratinocytes at the wound edge rst loosen their adhesion to each other and the basal lamina. Additionally, keratinocytes display remarkable exibility, which allows migration over the extracellular matrix (ECM) deposited by activated dermal broblasts. This process is facilitated by rearrangement of integrin receptors and reassembly of the associated actin cytoskeleton and keratin lament network [14]. Growth factors and cytokines such as EGF, keratinocyte growth factor (KGF), transforming growth factor alpha (TGF-α), broblast growth factor (FGF), interleukin-1 (IL-1), and interleukin-6 (IL-6) have been shown to be crucial regulators of keratinocyte proliferation, migration, and reepithelialization as well as communication with other cell types [7, 10, 15].

First, the migrating epithelial tongue advances to cover the wound with a thin layer. Then, keratinocytes proliferate to ensure an adequate supply of cells to encase the wound. Once the wound is healed, dened as being fully epithelialized with no drainage and covered by a keratinocyte monolayer, the proliferation signals cease, and the stratication process begins again. Thus, keratinocytes become “deactivated” and revert to their previous normal differentiation pattern.

Fibroblasts

Complex interactions and crosstalk between broblasts, keratinocytes, and other cell types participating in wound healing are crucial for successful wound closure. Under normal conditions, broblasts synthesize collagen and ECM, maintaining the structural integrity of the skin. Fibroblasts play a vital role in wound healing as they migrate, proliferate, and supply ECM for tissue repair. Another of the many important roles of broblasts is to provide contractile properties to the wound as myobroblasts. Much like keratinocytes, broblasts’ various roles are tightly regulated by cytokine and growth factor signaling during the process of wound healing.

Fibroblasts as a whole exhibit signicant functional diversity and reside in most tissues of the body. There are multiple lineages of broblasts with varying functions based on their site of origin and embryonic expression of certain genes [22]. Dermal broblasts of the skin arise from at least two distinct lineages that are regulated by epidermal β-catenin activation [23]. The rst reside in the upper dermis where they play a role in hair growth and are required for follicle formation. These broblasts are stimulated by epidermal Shh (sonic hedgehog) signaling [23, 24]. The second lineage resides in the lower dermis, and their main function is producing the structural ECM including collagen bers. It is responsible for the bulk of dermal repair and are regulated by

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