Hiperglikemia adalah suatu keadaan dimana hasil pemeriksaan kadar gula darah

puasa penderita di atas 110 mg/dL serta kadar gula darah setelah 2 jam pp (post

prandial) di atas 140 mg/dL.1,3 Karbohidrat merupakan sumber glukosa dan

penghasil kalori utama yang digunakan oleh semua sel tubuh manusia dalam proses

metabolisme untuk menghasilkan energi.2-4 Namun apabila kadar gula darah dalam

jumlah yang berlebihan/hiperglikemia merupakan faktor resiko meningkatkan

morbiditas dan mortalitas penderita kritis yang dirawat di ICU.

Hiperglikemia sampai saat ini angka kejadiannya`masih cukup tinggi baik di negara

berkembang maupun negara maju.3,4 Penderita kritis/critically ill patients yang

dirawat di instalasi rawat intensif (ICU) cenderung mengalami hiperglikemia, yang

disebut stress diabetes atau newly diabetes. Hal ini disebabkan oleh karena

terjadinya pelepasan hormon-hormom anti regulasi seperti efinefrin, nor-efinefrin,

katekolamin dan glukagon.

Hiperglikemia dapat meningkatkan senyawa oksigen reaktif (ROS) melalui proses

enzimatik yaitu melalui reaksi oksidasi dan fosforilasi (ox-phos) serta reaksi ADPH � Oxidase. Di samping itu dapat melalui proses non-enzimatik dengan cara

membentuk glucooxidant dan proses glycation.6-8

Telah lama diketahui bahwa ada hubungan yang erat antara hiperglikemia dan

gangguan fungsi imun terutama infeksi.9-11 Kelainan primer hubungan ini adalah

karena adanya disfungsi dari sel fagosit, sehingga tubuh sangat rentan terhadap

invasi kuman.7,12,13,20 Senyawa oksigen reaktif (ROS) yang terjadi pada

hiperglikemia akan mengaktivasi faktor transkripsi Nuclear Factor-kB (NF-kB) yang

memicu produksi mediator dan sitokin infalmasi seperti TNF- dan IL-1 yang

merupakan proximal cytokin. Sitokinsitokin inflamasi tersebut mempunyai efek

otokrin dan parakrin akan dapat memicu produksi sitokin lainnya seperti IL-6,

sehingga terjadi proses kaskade inflamasi secara sistemik.14-16,24 Inflamasi yang

terjadi dapat mengakibatkan penurunan produksi albumin di hati serta peningkatan

permeabilitas endotil sehingga terjadi kebocoran terhadap protein plasma seperti

albumin.17,18,26

Insulin merupakan obat anti diabetes yang dianggap paling rasional saat ini, oleh

karena mempunyai efek anabolik, namun ditengarai masih sering menimbulkan

komplikasi serius seperti hipoglikemia.5,13,19,20 Studi tentang penanganan dan

pengobatan hiperglikemia, khususnya penyakit diabetes, baik secara per oral

maupun intra vena sudah sangat banyak dilakukan. Namun hasilnya secara empiris

dirasakan masih belum maksimal.20-22 Di samping hal tersebut diatas, masih

terjadi perdebatan mengenai kadar gula darah yang harus dicapai dengan terapi

insulin.

Banyak studi melaporkan bahwa dengan mengendalikan gula darah secara ketat

akan dapat memperbaiki luaran klinik penderita hiperglikemia di rumah sakit.21-

23,45 Sampai saat ini penderita kritis yang dirawat di ICU dengan hiperglikemia

masih memakai prosedur standar, dimana disepakati pemberian terapi insulin baru

diberikan apabila kadar glukosa darah 200 225 mg/ dL.16,22,45� Peneliti pada penelitian ini membandingkan efektifitas pemberian terapi insulin

intensif yaitu dengan menurunkan dan mempertahankan kadar gula darah pada

level antara 80 110 mg/dL, dan terapi insulin konvensional yaitu dengan�

mempertahankan gula darah antara 180 200 mg/dL pada penderita kritis�

nonsurgical (medical critical illness) dengan hiperglikemia yang dirawat di ICU.

Inteleukin-6 merupakan sitokin intermediet yang dikatakan mempunyai fungsi ganda

dimana pada keadaan inflamasi produksinya akan meningkat sebagai sitokin pro-

inflamasi dan selanjutnya dapat mengaktivasi sel makrofag dan neutrofil lainnya

untuk menghasilkan sitokin anti-inflamasi.

Dengan mengacu pada mekanisme tersebut di atas dapat disimpulkan bahwa

dengan menurunkan kadar gula darah sampai pada level normoglikemia berarti

akan menurunkan derajat osmolalitas darah dan proses osmotik diuresis, inhibisi

aktivitas calpain, menurunkan produksi sitokin serta memperbaiki permeabilitas

pembuluh darah sebagai hasil akhir meningkatnya kadar albumin darah.

BG is tightly regulated by the following two types of mechanisms1: (1) the hormonal

system, which consists of a balance between the hypoglycemic insulin

hyperglycemic counterregulatory hormones (i.e., glucagon, epinephrine, and

cortisol); and (2) the neural mechanism, which consists of the activation ofmessages

issued from glucose sensors of various organs.

These hormonal and neural signals modulate carbohydrate metabolism by

controlling glucose fluxes, including endogenous production and the entrance of

glucose into the cells. The translocation of glucose transporters (GLUTs) is

the prominent mechanism for the modulation of glucose transport across cell

membranes.9 Among those transporters, GLUT 1 is the predominant transporter for

non–insulinmediated glucose uptake (fig. 1). GLUT 2 regulates the flow f glucose

across liver cell membranes. GLUT 4 is the main insulin-responsive GLUT and

therefore modulates the insulin- mediated glucose uptake in adipose tissue and

cardiac and skeletal muscles. Some lipids, including ceramides, can interfere with

the reading of the GLUT transporter-4 gene and the translocation of the protein to

the membrane. This mechanism of insulin resistance can represent a target forfuture

treatment.

Karena glukosa merupakan substrat preferensial selama kritis kondisinya sakit,

hiperglikemia stres dianggap untuk waktu yang lama waktu sebagai respon

menguntungkan, memungkinkan suatu ketentuan yang memadai energi untuk

jaringan. Namun, dalam kondisi stres, yang secara keseluruhan kelebihan glukosa

besar terjadi di non-insulin-dimediasi jaringan pengambilan glukosa. Ini hasil

akumulasi dari penghambatan peraturan-down dari GLUT 1 transporter oleh

mediator proinflamasi, hormon counterregulatory, dan hipoksia. Efek merusak

beberapa telah terkait dengan konsentrasi glukosa yang tinggi dalam

cells.1Kerusakan protein mitokondria terjadi, dan pembentukan spesies oksigen

reaktif meningkat sebagai konsekuensi dari pergeseran dari glikolisis menuju jalur

metabolisme aksesori (Yaitu, pentosa fosfat, hexosamines, dan poliol).

Efek lain dari konsentrasi glukosa berlebih termasuk eksaserbasi jalur inflamasi,

penurunan pelengkap kegiatan, modifikasi dalam sistem kekebalan tubuh bawaan,

penurunan fungsi mitokondria endotel dan hati, penghapusan preconditioning

iskemik, dan protein glycosylation.

Meskipun ada beberapa kesamaan, mekanisme pathogenetic diabetes tipe 2 dan

hiperglikemia stres berbeda. Pada diabetes, penyebab hiperglikemia merupakan

kombinasi resistensi insulin dan sekresi oleh pankreas yang rusak -Sel?.

Selama hiperglikemia stres, kompleks interaksi antara hormon counterregulatory

(misalnya, katekolamin, hormon pertumbuhan, dan kortisol) dan sitokin

menyebabkan berlebihan produksi glukosa hepatik dan resistensi insulin perifer

(Gbr. 1). Ini interaksi yang sangat kompleks sebagian besar variabel lebih time.1, 12

Peningkatan output hepatik hasil glukosa dari glukoneogenesis dan, pada tingkat

lebih rendah, dari glikogenolisis. Glukoneogenesis dipicu untuk sebagian besar oleh

glukagon dibandingkan dengan epinephrine dan kortisol. Glikogenolisis dipicu

terutama oleh katekolamin dan diabadikan di bawah pengaruh epinephrine dan

kortisol.

Tumor necrosis factor? mungkin mempromosikan neoglucogenesis dengan

merangsang glukagon produksi. Peningkatan resistensi perifer ditandai oleh

ketidakmampuan otot rangka dan adipocytes untuk menyerap glukosa, terkait

dengan perubahan sinyal insulin dan down-regulasi GLUT transporter-4. Central

insulin resistensi digunakan untuk menentukan penurunan kemampuan insulin untuk

menekan produksi glukosa hepatik dan tampaknya kurang terpengaruh daripada

resistensi insulin perifer selama stres (gbr. 1).

Selama periode perioperatif, peningkatan glukosa reabsorpsi atau clearance

glukosa menurun ginjal telah dilaporkan dan mungkin berkontribusi terhadap

hyperglycemia.13 Namun, stres bedah itu sendiri adalah pemicu yang paling

penting, melalui induksi resistensi insulin dipicu oleh sitokin dan counterregulatory

hormones.12 Tingkat resistensi insulin telah berhubungan dengan besaran dan

durasi bedah stres.

The increase in blood glucose during acute illness is aconsequence of complex

mechanisms that are a part of stress and inflammatory responses. Cortisol is the

main mediator of stress response, but other stress hormones such as

catecholamines, glucagon and growth hormone also have hyperglycaemic effects

[10,11]. Mediators of systemic inflammatory response, such as interleukin-1 (IL-1)

and tumor necrosis factor alpha (TNF-α), cause hyperglycaemia and peripheral

insulin resistance by inducing the release of stress hormones. They also alter insulin

receptor signalling [12-16] and create insulin resistance. Due to these actions,

glucose uptake in fat and muscle cells is reduced and hepatic gluconeogenesis is

not suppressed despite hyperglycaemia. Consequent to inhibition of pancreatic beta-

cells by cytokines and catecholamines, insulin concentrations may be normal or

even decreased [17-19]. Medical interventions, such as enteral and parenteral

nutrition, administration of vasopressors and glucocorticoids, add even further to

disturbed glucose homeostasis.

Despite the fact that endocrine and metabolic changes probably occur in all acutely

ill patients, evident hyperglycaemia is not present in all of them. Its occurrence is

certainly associated with the severity of illness, and has been associated with

unfavourable outcomes in several acute conditions [2,3,20,21].

Nevertheless, all patients with severe infections, severe myocardial infarction or

other critical illnesses do not develop hyperglycaemia and some will have

hyperglycaemia even in milder disease. A patient's predisposition (pancreatic

reserve and baseline insulin resistance) obviously plays an important part in the

development of hyperglycaemia. We hypothesised that hospital acquired

hyperglycaemia reveals this predisposition, that is, those patients are at risk for

developing type 2 diabetes in the period subsequent to acute illness.

Dalam patofisiologi sepsis, proinflamasi sitokin termasuk TNFa, IL-1, dan IL-6

diketahui memainkan peran penting, dan sitokin dioverproduksi masuk ke dalam

aliran darah menyebabkan hypercytokinemia, yang menyebabkan kegagalan organ

melalui jaringan mediator humoral aktivasi dan kerusakan endotel vaskular [10,11].

Stres berat dapat menyebabkan hiperglikemia pada pasien tanpa diagnosisdiabetes

sebelumnya. Ini tingkat stres (seperti pada penyakit serius) mungkin memiliki

mekanisme pathophysiologic berbeda dari tipe 1 atau diabetes tipe 2. Respon stres

adalah interaksi yang kompleks kontra-regulasi hormon, sitokin, dan perubahan

sensitivitas insulin (Gambar 1). Glukagon, epinefrin, kortisol, hormon pertumbuhan,

dan norepinephrine meningkat glukoneogenesis dan glikogenolisis, sehingga

meningkatkan glukosa production.

Tumor necrosis factor-alpha mungkin juga berkontribusi oleh glukoneogenesis

meningkat dan plasma glucagon.5 produksi insulin juga meningkat, namun

sepsisdan penyakit kritis merusak jalur sinyal insulin, menyebabkan glukosa

transporter menurun GLUT-4 pengambilan glukosa, yang pada gilirannya

menyebabkan insulin resistance.6

Noninsulin-mediated uptake occurs by cytokine upregulation of Glut-1,7,8 which

causes increased oxidative metabolism and decreased nonoxidative metabolism.

Stress causes an even greater derangement in glucose metabolism in patients with

diabetes, because they cannot increase insulin secretion as a compensatory

response. The exaggerated glucose response observed following stress dose

counter-regulatory hormone infusion in otherwise healthy subjects with diabetes

compared with subjects without diabetes helps explain why glucose control

frequently deteriorates in ill diabetes patients.

Hiperglikemia dan Hipoglikemia: Penyebab Umum Dokter harus akrab dengan

penyebab eksogen hiperglikemia dan hipoglikemia untuk meminimalkan peristiwa

atau recurrence.10, 11 Penyakit / infeksi, overfeeding (nutrisi dukungan, dekstrosa

yang mengandung kristaloid, dekstrosa penyerapan selama dialisis peritoneal, dan

obat-obatan dirumuskan dalam mengemulsi lemak, seperti propofol), obat

(misalnya, kortikosteroid, infus simpatomimetik, atau imunosupresan), insulin tidak

cukup, dan / atau volume deplesi dapat menyebabkan hiperglikemia. sejak

dijelaskan

Adverse Effects of Acute Hyperglycemia : During short-term hospitalization,

hyperglycemia can adversely affect fluid balance (through glycosuria and

dehydration), immune function,13,14 inflammation, and outcome. In vitro studies

report that hyperglycemia is associated with abnormalities in white cell function,

including granulocyte adhesion, chemotaxis, phagocytosis, respiratory burst,

superoxide formation, and intracellular killing.

Hyperglycemia can also impair complement activity. Glucose, through complement

glycation, has the potential to compete with microorganisms for the attachment of

complement, thereby inhibiting opsonization.15–17 These abnormalities improve

with glucose control. Acute hyperglycemia is also known to cause endothelial cell

dysfunction. It is thought that the stressful environment decreases the ability of the

noninsulin-mediated Glut-1 transporter to down regulate, which is the normal

physiologic protective mechanism to hyperglycemia. This causes an uncontrolled

influx of high levels of glucose into the cell, leading to a vicious cycle of up-regulation

of more Glut-1 transporters

Hyperglycemia within the cell increases production of reactive oxygen species,

which then creates a cascade of cellular effects, increasing polyol pathway influx,

advanced glycation end products, NFĸB, and hexosamine pathway.19 These

downstream effects lead to blood-flow abnormalities, increased vascular

permeability, angiogenesis, capillary occlusion, and pro-inflammatory gene

expression. Most of this work has been done to describe the mechanisms behind

chronic complications of diabetes, but in critical illness, there is evidence that

wholebody glucose uptake is increased, specifically by tissues that are not insulin

dependent.21 Increased catabolism, lipotoxicity, sympathetic nervous system

activation, and extracellular matrix deposition also contribute to tissue effects of

hyperglycemia.

In May 2009, AACE/ADA revised their inpatient glycemic targets to 140-180 mg/dL

in the ICU and non-ICU preprandial glucose levels below 140 mg/dL and all random

glucose levels below 180 mg/dL (Table 1).

Continuous infusion of regular insulin is suggested for critically ill ICU patients, pre-

and postoperative patients, peripartum women with hyperglycemia, severe

hyperglycemia with metabolic decompensation (diabetic ketoacidosis and

hyperosmolar non-ketotic states), and any patient in whom tight glycemic control is

clinically indicated. Paper-based and computer-based insulin infusion algorithms are

available to help clinicians achieve optimal glycemic control.44,48,49

Conversion from IV to SC insulin commonly occurs when the critical illness resolves

when the patient is extubated, off vasopressors, and ready to begin eating, or is at a

stable tubefeed rate. When the patient is being converted from an IV insulin drip, the

drip rate is used as a guide to determine total daily insulin requirements.

Stress hyperglycemia results from the excessive release of counterregulatory

hormones and cytokines, such as glucagon, epinephrine, cortisol, growth hormone

and insulin-like growth factor, and from the overproduction of inflammatory

mediators, such as tumour necrosis factoralpha (TNF-a), interleukin-1 and

interleukin-Inflammatory mediators initiate the metabolic response to injury and can

precipitate MODS. During acute illness there is an increase in the systemic

inflammatory response that is characterized by increased production of pro-

inflammatory cytokines, such as interleukin-1, interleukin-6,TNF-a and macrophage

inhibitory factor,19 and a decrease in the anti-inflammatory cytokines, interleukin-2,

interleukin-4 and interleukin-10.20,21 Acute hyperglycemia further upregulates the

production of several of these inflammatory cytokines.High levels of extracellular

glucose inhibit G6PD (glucose 6-phosphate dehydrogenase) and impair oxygen

radical production in activated neutrophils.23 In vivo, hyperglycemia could therefore

impair microbial killing by neutrophils in a dose-dependent fashion. Neutrophil

dysfunctionand impaired intracellular bactericidal activity. have been demonstrated

when glucose concentrations are high. In an animal trauma model,26 maintenance

of normoglycemia enhanced innate immunity by preserving phagocytosis and the

monocyte oxidative burst function. These findings suggest that acute glucose control

may lower the risk of infection that is so prevalent in our sickest patients.

Mechanisms of stress hyperglycemia in hospitalized patients Hyperglycemia is a

frequent manifestation of critical and surgical illness, resulting from the

acutemetabolic and hormonal changes associated with the response to injury and

stress.26,27

Acute illness, surgery, and trauma raise levels of counterregulatory hormones such

as glucagon, epinephrine, cortisol, and growth hormone. The counterregulatory

response results in a number of alterations in carbohydrate metabolism, including

insulin resistance, increased hepatic glucose production, impaired peripheral

glucose utilization, and relative insulin deficiency.

Epinephrine stimulates glucagon secretion and inhibits insulin release by pancreatic

b-cells.28 High cortisol levels increase hepatic glucose production, and stimulate

protein catabolism and increased circulating amino acids concentration, providing

precursors for gluconeogenesis.29,30 In addition, acute stress increases pro-

inflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), interleukin (IL)-

6, and IL-1,26,31–33 which increase insulin resistance by interfering with insulin

signaling. TNF-a activates c-Jun NH2-terminal kinase (JNK), a signaling protein

molecule that phosphorylates insulin receptor substrate-1 (IRS-1) and prevents

insulin-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) involved in

tissue glucose uptake. Downstream effect process decreases insulin stimulation of

glucose uptake and causes hyperglycemia.34,35 Thus stress adversely affects

multiple biological processes resulting in diminished insulin action and if the

pancreas is unable to compensate by increasing insulin production, the end result is

the appearance of hyperglycemia. Furthermore, in the presence of hyperglycemia,

the pancreatic b-cells develop desensitization that results in further blunting of

insulin secretion and increasing serum glucose levels.

Counterregulatory hormones in the setting of stress lead to enhanced lipolysis and

increasing fatty acids (FFAs) concentration.37,38 In patients with ischemic

cardiovascular events, high FFA levels can aggravate ischemia/reperfusion damage

by limiting the ability of cardiac muscle to uptake glucose for anaerobic

metabolism.39,40 FFAs, normally the substrate of choice for healthy myocardium,

are toxic to an ischemicmyocardium39,40 leading to cardiac arrhythmias,

sympathetic overactivity, increased blood pressure, oxidative stress and endothelial

dysfunction.41–43 Increased FFA levels also produce dosedependent insulin

resistance in peripheral tissues44 andincrease hepatic glucose output in both

diabetic and non-diabetic individuals.27,45 Hyperglycemia state caused by these

mechanisms often times is worsened by exogenous use of glucose in form of

nutritional supports or intravenous dextrose in critical care settings.13

The development of hyperglycemia leads to generation of reaction oxygen species

(ROS), Lipid peroxidation, elevated cardiovascular inflammatory markers. (Fig. 1)

Acute hyperglycemia may induce cardiac myocyte death through apoptosis or by

exaggerating ischemia-reperfusion cellular injury.It also has deleterious effect on

endothelial function by suppressing formation of nitric oxide (NO) and impairing

endothelium-dependent flow mediated dilation.48 In addition, hyperglycemia-

induced abnormalities in hemostasis including increased platelet activation,

adhesion and aggregation,reduced plasma fibrinolytic activity and increased

plasminogen activator inhibitor-1 (PAI-1) activity.50

In vitro and in vivo studies have also shown that hyperglycemia also impairs immune

system function by reducing phagocytic activity of macrophages, impairing

chemotaxis of polymorphonuclear neutrophils (PMNs), increasing expression of

adhesion molecules and free radical production in immune cells which will ultimately

increase the risk of infection and multiple in hospital complications.