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Complications of

Diabetes Mellitus


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Assesment of Glycemic Control

UrinalysisGlycosuriaLimitations of urinalysis : renal threshold (varies between

individual); urinary concentration (fluid intake and urineconcentration may effect); neuropathic bladder (reduce theaccuracy); hypoglycemia(this can not be detect)

Urinary ketonesSemi-quantitatif test for acetoacetat; Ketosis-prone diabetes

Glycated haemoglobin HbA1c is formed by the post-translational, non-enzymatic glycationGlycaemic targets

Frequency of measurement (every 3 or 6 months) Limitations of HbA1c measurements : daily patern of blood

glucose levels? ; blood loss/haemolysis/reduced red cell (lowHbA1c)

Blood glucose

Before breakfast (fasting) 2 hour post prandial


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mmol/l

1. ADA. Diabetes Care2004; 27: S1535; 2. ADA Diabetes Care2002; 25: S3549;

3. Feld S. Endoc rine Pract2002; 8 (Suppl 1): 4082; 4. Asian-Pacific Type 2 Diabetes Policy Group.

Type 2 diabetes: Practical targetsand treatment. 4th Edn; Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.

< 140< 180Postprandial plasma

glucose

< 11090130Fasting/preprandial

plasma glucose

Biochemical index AACE3ADA1,2 IDF4

(Western

Pacific region)

mg/dl mmol/l mg/dl mmol/l

mg/dl

< 6.15.07.2

< 10.0

< 6.5< 7HbA1c(%) < 6.5

< 110< 6.0

< 145< 7.8


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Konsensus PERKENI 2005

Current Indonesian Society of

Endocrinology (Perkeni) treatment targets

HbA1c < 7%

Fasting BG < 100

mg/dl Post prandial BG < 140

mg/dl

Blood pressure < 130/80mmHg

LDL-cholesterol < 100


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Complications of DiabetesMellitus

Chronic Complications ofDiabetes Mellitus

Microvascular

Macrovascular

Acute Complications ofDiabetes Mellitus

Hyperglycemia crisis

Hypoglycemia


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Pathophysiology ofMicrovascular

Complications

A ti ti f P t i Ki


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Activation of Protein Kinase

C


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Diabetic Retinopathy


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Diabetic Retinopathy

Blindness is primarily the result of progressive diabetic retinopathy andclinically significant macular edema.

Diabetic retinopathy is classified into two stages: nonproliferative andproliferative.

Nonproliferative diabetic retinopathy : marked by retinal vascularmicroaneurysms, blot hemorrhages, and cotton wool spots

The appearance of neovascularization in response to retinal hypoxia is

the hallmark ofproliferative diabetic retinopathy.

Duration of DM and degree of glycemic control are the best

predictors of the development of retinopathy; hypertensionis also a risk factor

The most effective therapy for diabetic retinopathy isprevention.


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Hyperglycemia

Renalvasodilatation Increased

intraglomerular

capillary pressure

Protein glycation

Increased glomular

filtration rateHypertension

Increased

protein excretion

Microalbuminuria or

macroalbuminuria

Nephropathy

Glomurular

damage


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Diabetic NephropathyDiabetic nephropathy is the leading cause of ESRD in the US.

Individuals with diabetic nephropathy almost always have diabeticretinopathy.

The stages of diabetic nephropathy are:

Hyperfiltration

Microalbuminuria

Overtproteinuria

Declining GFR

End stage renal failure

Microalbuminuria is defined as 30 to 300 mg/d in a 24-h collection

or 30 to 300 g/mg creatinine in a spot collection (preferredmethod).

The appearance of microalbuminuria (incipient nephropathy) intype 1 DM is an important predictor of progression to overtproteinuria (300 mg/d) or overt nephropathy.

Hypertension more commonly accompanies microalbuminuria orovert nephropathy in type 2 DM


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Diabetic Nephropathy -

Treatment The optimal therapy for diabetic nephropathy is

prevention. Interventions effective in slowing progression from

microalbuminuria to overt nephropathy include: near normalization of glycemia, strict blood pressure control, and

administration of ACE inhibitors or ARBs, and treatment of dyslipidemia.

Blood pressure should be maintained at 130/80 mmHgin diabetic individuals without proteinuria.

A slightly lower blood pressure (125/75) should beconsidered for individuals with microalbuminuria orovert nephropathy

A consensus panel of the ADA suggests modestrestriction of protein intake in diabetic individuals withmicroalbuminuria (0.8 g/kg per day) or overtnephropathy (


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METABOLIC VASCULAR

glucose

sorbitol

H2O

nerve

oedema

myoinositol

NO

production

AGE

formation

vasoconstriction

Arterial

narrowing

Vessel

occlusion

Slow nerve

conduction

Impairingaxonal transport

Altered membrane

potensial


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Diabetic Neuropathy

Diabetic neuropathy occurs in approximately 50% ofindividuals with long-standing type 1 and type 2 DM. The development of neuropathy correlates with the duration

of diabetes and glycemic control; both myelinated andunmyelinated nerve fibers are lost.

Several stage :

Intraneural biochemical abnormalities; sorbitolaccumulation, myoinositol depletion Impairement of electrophysiological measurement;

decreased nerve conduction velocity; asymptomatic Clinical neuropathy; detectable using clinical methods;

maybe symptomatic. Histological changes evident End stage complications. Exp are ulceration and Charcot

neuroarthropathy; major derangements of neuralstructure and function.


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Clinical Features Symmetrical

Sensorimotor NeuropathySymptoms Loss of

sensation ;

Anaesthesia;numbness Loss of pain

perception

Altered

sensation: Paraesthesiae Dysaesthesiae

Pain

Burning

Signs

Sensory loss

Diminished/absent tendon

reflexs Muscle wasting and

weakness

Autonomic dysfunction

Foot uleration


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Burning, feeling like the feet are on fire Freezing, like the feet are on ice,although they feel warm to touch

Stabbing, like sharp knives Lancinating, like electric shocks


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Treatment of Symmetric

Neuropathy

Glucose control

Pain control

Tricyclic antidepressants Amitriptyline,desipramin, nortriptilin,

trazodone

Anticonvulsants

Carbamazepine, gabapentin Topical creams

capsaicin

Foot care


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Macrovascular Complication

Macrovascular complications of diabetes mellitusare condition characterized by atheroscleroticocclusive disease of cerebral, myocard andlower extremities.

Atherothrombosisis the most common cause ofmacrovascular complications

Atherothrombosis is characterized by a sudden(unpredictable) atherosclerotic plaque disruption

(rupture or erosion) leading toplatelet activationand thrombus formation

Atherothrombosis is the underlying condition thatresults in events leading to myocardial infarction,

ischemic stroke, amputation and vascular death


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Macrovascular Disease in

Diabetes Mellitus Cardiovascular and cerebrovascular disease account

for up 70% of death in patients with type 2 DM All patients with type 2 diabetes have greater

predipostition to macrovascular disease, often having aconstellation of risk factors, which have been terminsulin resistance.

It has been hypotethesized that insulin resistance andhyperinsulinemia (environmental and genetic factors),are central to development : Glucose intolerance

Hypertension Dyslipidemia Coagulopathy

These factors promote accelerated atherosclerosis,explaining the increased risk of macrovascular disease.


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Di b t d M l


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Diabetes and Macrovascular

Disease

Libby and Plutsky. Circulation.2002.


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Strategies for Reducing

Macrovascular Complications Prevention proven intervention trials

Hyperglycemia

Dyslipidemia

Hypertension

Antiplatelet therapies

Prevention suggested by epidemiologicanalysis

Disorders of thrombolysis

Endothelial disorders


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The Diabetic Foot


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Diabetic Foot Disease

Approximately 15% of individuals with DM develop a

foot ulcer, and a significant subset will ultimatelyundergo amputation (14 to 24%risk with that ulcer orsubsequent ulceration).

Syndrome of diabetic foot disease Peripheral neuropathy, peripheral vascular disease

and tissue infection Risk factors for foot ulcers or amputation include: male

sex, diabetes 10 years duration, peripheral neuropathy,abnormal structure of foot (bony abnormalities,callus,thickened nails), peripheral arterial disease, smoking,history of previous ulcer or amputation, and poor

glycemic control. The plantar surface of the foot is the most common siteof ulceration.

Ulcers may be primarily neuropathic (no accompanyinginfection) or may have surrounding cellulitis orosteomyelitis.


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Neuropathy

Motor

dysfunction

Neuropathy Neuropathy

Abnormal

Foot posture

Cheiroarthropathy

Reduced pain

Sensation and

proprioception

Increased foot

prssure

Callus

Microvascular

disease

Poor tissue

nutrition and

oxygenation

Ulcer

Macrovascular

diseaseIschemia

Dry, cracked

skin

Arteriovenousshunting

TraumaMechanical,

thermal,

chemical


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Acute Complication of Diabetes

Mellitus

Hyperglycemia crisis

Diabetic ketoacidosis (DKA)

Hyperglycemic Hyperosmolar

State (HHS)

Hypoglycemia

Pathophysiolgy of Hyperglycemia


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Pathophysiolgy of Hyperglycemia

Crisis


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Diabetic Ketoacidosis (DKA)

DKA was formerly considered a hallmark of type 1DM

The symptoms and physical signs of DKA

Symptoms : Nausea/vomiting, Thirst/polyuria,Abdominal pain, Shortness of breath

Physical findings : Tachycardia, Dry mucousmembranes/reduced skin turgor, Dehydration /hypotension, Tachypnea / Kussmaul

respirations/respiratory distress, Abdominaltenderness (may resemble acute pancreatitis or

surgical abdomen), Lethargy /obtundation /cerebral edema / possibly coma


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Precipitating Factors

Inadequate insulin administration

Infection (pneumonia/UTI )

Gastroenteritis/sepsis

Infarction (cerebral, coronary,

mesenteric, peripheral)

Drugs (cocaine)

Pregnancy


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Precipitating Factors

Infection ( the most common)

Cerebrovascular accident

Alcohol abuse

Pancreatitis

Myocardial infarction

Trauma

Drugs


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Clinical Findings of HHS

HHS should be suspect : elderly patient with orwithout the preexisting diagnosis of diabetes whoexhibits acute or subacute deterioration of CNSfunction and severely dehydrated

Tachycardia Low grade fever

Low or normal blood pressure

Dehydrationdry mucous membrane, absent

axillary sweat, poor skin turgor. Nausea, vomiting, distension, and pain-

gastroparesis is due to hypertonicity

Lethargy, hallucinations, and psychosis


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Priority in the Treatment of

Hyperglycemia Crisis

Replacing volume deficitsnormal saline

according to BP, urine output and CVP value for

old age, total deficits around 6-9 liters.

Correcting hyperosmolarity to 300

milliosmoles/L

Managing any underlying illnesses

Insulin ; RI 0.15u/kg bolus then 0.1/kg/hrinfusion until blood sugar about 250mg/dl or

osmo about 315


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Approach to Therapy

Correcting the hyperosmolar state and

dehydration is the initial aim of therapy.

Insulin therapy should be undertaken

only after the patient is stable

hemodynamically.

Glucose and H2O

H2O lost in urine Loss of ECF, vascular collapse and death


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Hypoglycemia

Clinical Manifestations of


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Clinical Manifestations of

Hypoglycemia Whipples triadsymptoms consistent with hypoglycemia,a low

plasma glucose concentration,and relief of those symptoms when the

plasma glucose concentration is raisedprovides compellingevidence of hypoglycemia.

Symptoms of hypoglycemia can be divided into two categories,neuroglycopenic and neurogenic (autonomic) symptoms.

Neuroglycopenic symptoms are the direct result of CNSneuronal glucose deprivation. They include behavioral changes,

confusion,fatigue or weakness, warmth, visual changes, seizure,loss of consciousness,and,if hypoglycemia is severe andprolonged, death. ( BG < 20 mg/dL )

Neurogenic symptoms are the result of the perception ofphysiologic changes caused by the autonomic nervous systemdischarge triggered by hypoglycemia. ( BG 50 mg/dL )

They include adrenergic symptoms such aspalpitations,tremor, and anxiety and cholinergic symptomssuch as sweating,hunger, and paresthesias.

Cholinergic symptoms,at least sweating, are thought to bemediated by acetylcholine released from sympatheticpostganglionic neurons.

Comprehensive Risk Factors for


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Comprehensive Risk Factors for

Hypoglycemia in DiabetesPremise: Iatrogenic hypoglycemia in type 1 diabetes is the

result of the interplay of therapeutic insulin excess andcompromised glucose counterregulation.1. Absolute or relative therapeutic insulin excess (the

conventional risk factors)a. Insulin doses excessive,ill-timed, wrong typeb. Decreased food intake

c. Increased glucose utilization (e.g.,exercise)d. Decreased glucose production (e.g.,alcohol)e. Increased sensitivity to insulin (e.g.,after exercise,during the

night,glycemic control, weight loss)f. Decreased insulin clearance (e.g.,renal failure)

2. Compromised glucose counterregulationa. Absolute insulin deficiency (C-peptide negativity)

Cell destruction: No in insulin in response to glucoseUnknown: No in glucagon in response to glucose

b. History of severe hypoglycemia or aggressive therapy per se (lowerglucose goals,lower hemoglobin A1c)


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Management of Acute Hypoglycemia

Acute hypoglycemia

Oral glucose

(10-20gr)

30-50 ml Dextrose 40% or

Glucagon 1mg sc/im

Check BG after

15-20 min

Acute hypoglycemia

Repeat oral

glucose10% glucose

IV infusion

Patient

conscious

Patient

unconscious

Recovered Notrecoverd

Patient

unconscious Patientconscious


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Thank you

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