belajar stres hiperglikemia
Post on 02-Nov-2014
128 Views
Preview:
TRANSCRIPT
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.
top related