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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.2123,45 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 proinflamasi 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 noninsulinmediated 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, 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?. penghapusan preconditioning

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-), 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 betacells 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.1517 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, NFB, and hexosamine pathway.19 These downstream permeability, effects lead to blood-flow abnormalities, and increased vascular gene

angiogenesis,

capillary

occlusion,

pro-inflammatory

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, preand 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 proinflammatory 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 proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), interleukin (IL)6, and IL-1,26,3133 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.4143 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, hyperglycemiainduced 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.