Case study: Diabetic Ketoacidosis

Summary of previous presentation

Classification of DM Clinical presentations Diagnosis Pathophysiology Management (OHA & Insulin)

Outline
Comlications of DM Acute : DKA
Clinical features Precipitating events Pathophysiology Diagnostic criteria Management

Chronic complications
Retinopathy Nephropathy

Complications of DM
Acute
Diabetic ketoacidosis (DKA) Hyperglycemic hyperosmolar state (HHS)

Chronic
Microvascular Macrovascular Others : GIT / genitourinary dysfunction, dermatologic, infections, cataracts and glaucoma.

Acute complications

DKA
Hallmark of type 1 DM, but also occur in type 2 DM. Associated with
Absolute or relative insulin deficiency Volume depletion Acid base abnormalities

Clinical features of DKA

Symptoms usually develop over 24 hours Nausea / vomiting Hyperglycemia (Thirst, polyuria, volume depletion) Dehydration / hypotension / tachycardia Abdominal pain, abdominal tenderness SOB / Kussmaul respiration Fruity odor Lethargy / coma Cerebral edema (mostly in children)

Precipitating events
Inadequate insulin administration Noncompliance New onset diabetes Infection Infarction Drugs Pregnancy

Pathophysiology
Insulin deficiency + Excess glucagon
Normally:

Gluconeogenesis FFA convert to TG / VLDL Glycogenolysis Marked increase in FFA release from adipocytes Increase in FFA, amino acids delivery to liver

Alter hepatic metabolism Favor ketone body formation through activation of enzyme carnitine palmitoyltransferase I

Diagnostic Criteria for DKA

Management of DKA
1. 2. Confirm diagnosis Assess serum electrolytes, acid base status, renal function 3. Fluid replacement 4. Regular insulin (IV/IM) 5. Treat underlying condition 6. Measure capillary glucose (every 1-2h) 7. Measure electrolytes & anion gap (every 4h for 24h) 8. Monitor BP, pulse, respiration, mental status, I/O (every 1-4h) 9. Replace K 10. Continue above measure until patient is stable (glucose goal is 8-14mmol/L) 11. Administer intermediate / long acting insulin as soon as patient is eating.

Fluid replacement
0.9% saline over first 1-3h (5mL/kg/h)
Hemodynamic stability, or until shock corrected

0.45% saline (150-300mL/h)

When plasma glucose reaches 14mmol/L

5% glucose and 0.45%saline (100-200mL/h)

Regular insulin (IV / IM)

Regular insulin IV (0.1 units / kg) IM (0.4 units / kg)

Continuous IV infusion (0.1units / kg / h) (Increase to 2 to 10 fold if no response by 24h)

*** If initial serum K < 3.3mmol/L*** withhold insulin until corrected to > 3.3mmol/L

Potassium replacement
Treatment with insulin & fluids will deplete K+ by: Insulin mediated K transport into cells Resolution of acidosis Urinary loss of K salts of organic acids K+ repletion should commence as soon as Adequate urine output Normal serum K+ are documented. Goal : maintain K+ > 3.5mmol/L. Inclusion into IV fluid (KCL / KPO4 / K acetate) (10 mmol/L/h if K < 5.5mmol/L, 40-80mmol/L/h if K <3.5mmol/L)

Bicarbonate replacement
Usually not necessary, unless: Severe acidosis (pH <7.0 after initial hydration) ADA: pH = 6.9 - 7 50mmol/L sodium bicarbonate in 200mL of 0.45% NS over 1h pH < 6.9 100mmol/L sodium bicarbonate in 400mL of 0.45% NS over 2h

Phosphate
Usually low in DKA Routine phosphate replacement does not improve outcomes in DKA Give phosphate supplement if phosphate < 0.32mmol/L, (normal = 0.8-1.45mmol/L) Give in form of potassium phosphate (potassium replacement) Monitor serum calcium

HHS
Prototypical patient with HHS is elderly with type 2 DM, with several week history Polyuria Weight loss Diminished oral intake Lethargy Mental confusion, coma On examination :

Present

Absent

Dehydration Nausea
Hypotension Vomiting Tachycardia Abdominal pain Altered mental status. Kussmaul respirations.

Laboratory values in DKA and HHS

DKA Glucose (mmol/L) Na (mmol/L) K (mmol/L) Phosphate Creatinine 13.9 - 33.3 125-135 Normal or high Low Slightly high HHS 33.3 66.6 135-145 High Normal High

Osmolality (mOsm/mL)
Plasma ketones HCO3 (mmol/L) Arterial pH Arterial pCO2 (mmHg) Anion gap Magnesim, chloride

300-320
++++ < 15 6.8-7.3 20-30 High Normal

330-380
+/Normal to slightly low > 7.3 Normal Normal to slightly high Normal

Chronic complications (Microvascular)

Possible molecular mechanisms

Hyperglycemia
(Increased intracellular glucose)

Increase Advanced glycation end products Sorbitol, Diacylglycerol, Fructose 6 phosphate

Complication of diabetes

Altered Cell function, Gene expression, Renal, Vascular connective tissue

Retinopathy
Proliferative diabetic retinopathy Newly formed vessels appear near the optic nerve and macula and rupture easily Lead to hemorrhage, fibrosis, retinal detachment Non-proliferative diabetic retinopathy Increased retinal vascular permeability, Alterations in retinal blood flow, Abnormal retinal microvasculature, Lead to retinal ischemia.

Treatment
Prevention : Regular eye examinations Intensive glycemic and BP control Fasting: 4.4-6.1mmol/L Non fasting: 4.4-8mmol/L BP:130/80 Aspirin (650mg/day) does not appear to influence the natural history of retinopathy Treatment : Laser photocoagulation

Nephropathy
Related to chronic hyperglycemia. Involve effects of Growth factor Angiotensin II Hemodynamic alterations in renal microcirculation glomerular hyperfiltration Structural changes of glomerulus (Ex: basement membrane thickening, glomerular hyperthrophy) Leads to ESRF

Natural history of diabetic nephropathy

Management of diabetic nephropathy

Good glycaemic Control FBS < 6 mmol/l HbA1c < 6.5% Tight control of BP DM: 130/80 Proteinuria >1g/d: 125/75 Reduce proteinuria with ACEI / ARB Smoking cessation Lipid control Salt and protein restriction 0.6-0.8g / kg / day protein in patient with overt nephropathy and/or renal impairment < 5g NaCL / day

Case Presentation

Patients Identity
Name Age Gender Race Height Weight BMI : : : : : : : MH 66 Male Malay 158cm 52kg 20.8

Presenting complaint
Fever X 3/7 Vomited a few times Noted by family the glucometer result was too high

History of presenting complaint

Not taking OHA X 3/7 Lethargic and bed bound X 3/7 Scrotal area was swollen, red, macerated for a few days Blurred vision for quite some times.

Past Medical History & Drug History

Type 2 DM (10 years) T. Gliclazide (Diamicron MR) 120mg OM T. Metformin 1g tds HbA1C : Nov 2007 : 11.5
Hypertension (8 years) T. Perindopril 4mg od T. Amlodipine 5mg od

Social / Family History

Staying with family Brother has Type 2 DM

Review of System
BP RR PR T SPO2 Dstix : 104/56 : 88 : 24 : 37.8oC : 91% : 24.6mmol/L
(SC actrapid 16 units stat)

Lung : Clear Abdomen : Soft & non tender CVS : DRNM

Impression / Diagnosis
Diabetic ketoacidosis (DKA)

Lab Investigations

Arterial Blood Gas

Day
pH

1
7.3

3
7.3

4-8

pCO2
pO2 HCO3

28
61 14.5

31.5
97 17.2

UFEME
Day Bacteria Glucose Ketones pH Protein RBC Count Leucocytes 1 Negative 2 Negative 3 Negative 4-8

4+ 2+
5

2+ 2+
5

1+ 1+
6

1+ 1+
Negative 1.015 Negative Negative Yellow

2+
Negative

2+
Negative

3+
1.005 Negative Negative Yellow

3+
1.005 Negative Negative Yellow

Other cells a) SG b) UBG c) Bil d) Colour

Full Blood Count

Day TWBC Hb RBC HCT 1 11.6 12.3 4.21 38.0% 2 3 7.8 11.4 3.70 33.5% 181.0 4-8

Platelet 187.0

Renal Profile
Day Urea Na K Cl Ca Mg PO4SrCr ClCr Uric acid 128 37.0 0.31 121 39.1 400 110 43.0 111 42.6 1 7.8 138.3 4.6 103.8 2 4.6 142.9 4.31 108.2 1.82 3 4.5 140.2 3.59 111.1 4-6 7 3.0 140.5 3.55 107.1 8

Liver Profile
Day Albumin T.Bilirubin T.Protein 1 2 23 9 72 3-8

ALP
ALT AST

140
57 79

Lipid Profile
Date Lipid profile 8.1.2008 Results (mmol/L)

T.Chol (<5.7mmol/L) 6.1

TG (< 1.7mmol/L)
HDL (> 1.7mmol/L) LDL (<3.9mmol/L)

2.0
0.5 3.7

Vital Signs
Day BP T 1
104/ 58

2
123/ 71

3
129/ 60

4
150/ 79

5
139/ 80

6
121/ 76

7
142/ 72

8
139/ 73

37.8

37

37

37

37

37

37

37

RR
PR

22
80

20
104

20
80

20
100

20
91

20
91

20
91

20
100

Input / Output chart

Day 1 2 3 4 5 6 7 Input 1000 3340 955 1265 1090 695 700

Output

600

1150

1200

900

1650

1700

1500

Balance

+400

+2190

-245

+1365 -560

-1005 -800

Culture and sensitivity

Date Date sampling Sample Micro-organism Sensitivity Resistant 11.1.08 7.1.08 Genital swab staphylococcus spp. Erythromycin, gentamicin, Penicillin oxacillin

Ward Medications

Ward medications
Drug Day start Day stop

IV Ceftriaxone 2g od
IV Amoxycillin / clavulanate potassium Tablet aspirin 150mg od Tablet amlodipine 5mg od SC actrapid 16 units stat SC insulatard 14 units ON SC actrapid 10 units tds SC actrapid 8 units tds SC actrapid 14 units tds SC insulatard 16 units ON Cream aqueous prn

1
2 1 7 1 3 3 4 7 7 7

8
8 8 8 1 7 4 7 8 8 8

Clinical Progress & Pharmaceutical Care plans

Clinical progress: Day 1

Low BP (104/56) High T (37.8) High glucose (24.6mmol/L) Urine ketone: 2+ Patient dehydrated. Scrotal: Red, marcerated Groin: erythematous + blister Fundoscope:
Dense cataract Diabetic retinopathy Plan (4pm): Withhold anti HPT IV ceftriaxone 2g stat & od IV drip 4 pints/24h IV insulin 5 units/h (Change to IVD D5% once GM<12, NS if GM>12) 2 hourly GM monitor Genital swab (C&S) NS dressing Continue medication: T. aspirin 150mg od Plan (10pm): Add 1g KCL alternate pint

Impression: a) Uncontrolled DM Missed medication b) Scrotal cellulitis

PCI (Day 1)
PCI Pharmacist Recommendation
Monitor a) Vital signs b) Glucose level c) Serum electrolyte d) ABG e) Renal function f) I/O chart Add PO4 to IV infusion Change to IVD D5% when glucose level reach

Outcome

Management of DKA
Patient had: a) Low BP (104/56) b) High glucose (24.6 mmol/L) c) ABG : Metabolic acidosis Low pH: 7.3 Low pCO2: 28 Low HCO3: 14.5 d) Low phosphate (0.31mmol/L) Fluid replacement &insulin infusion 5 units/h had been given (Patient = 52kg)

Time

Glucose (mmol/L)

330pm 24.6 6pm 8pm 10pm 20.7 13.4 11.3

14

mmol/L

PCI (Day 1)
PCI Pharmacist Recommendation T. paracetamol 1g stat and prn Monitor Temperature, WBC count. Review antibiotics used in cellulitis Sanford 2007 (pg18, 86, 92): Early mild disease T. Trimetoprim sulfamethoxazole double strength (160TMP/800SMX) 2 tab bd with T. Rifampin 300mg bd. Severe disease IV Imipenem (1g IV od) / IV meropenem (0.5g IV qid) / IV ertapenem (0.5-1g tds) Plus IV / PO linezolid 600mg bd / IV vancomycin (based on weight) Outcome Antibiotics remained unchanged.

Management of cellulitis
Patient a) Scrotal: Red, marcerated b) Groin: erythematous + blister c) High WBC: (11.6X10/L) d) Fever (37.8oC) IV ceftriaxone 2g od had been given.

PCI (Day 1)
PCI Pharmacist Recommendation Outcome

Retinopathy screening & treatment

Patient: Dense cataract Diabetic retinopathy

ADA 2007: Patient was referred to Optimal glycemic control ophthalmologist. Optimal BP control Refer to ophthalmologist. Perform examination annually by ophthalmologist. (Examinations will be required more frequently if retinopathy is progressing)

Clinical progress: Day 2

BP: 123/71 Dry tongue, patient dehydrated Scrotal & groin: red, inflammed
Time 12am 2am 4am 6am 8am 10am 1220pm 4pm 6pm 820pm 10pm Glucose (mmol/L) 6.3 7.2 9.2 12.6 14.4 12.3 8.4 6.7 5.8 6.2 3.3

Plan: Increase to 5 pints NS/24h IV insulin 2 units/h IV Augmentin 1.2g stat and tds 2 hourly GM monitor I/O charting

Withold insulin infusion

PCI (Day 2)
PCI Pharmacist Recommendation Monitor glucose level. Withhold insulin infusion Oral glucose (10-20g) Treatment effect should be apparent in 15 min. Outcome Insulin infusion was withhold.

Prevention of hypoglycemia
Patients glucose level dropped to 3.3mmol/L.

PCI (Day 2)
PCI Pharmacist Recommendation ADA 2007: For those over 40 years old, Statin therapy to achieve an LDL reduction of 30-40% regardless of baseline LDL levels. Outcome No lipid lowering agent was given.

Lipid management
Patients lipid profile shown:
Patient was 66 years old.

Can be Initiated with: a) Lovastatin (20mg ON) b) Simvastatin (10-20mg ON) c) Atorvastatin (10-20mg od)

Clinical progress: Day 3

Imp: Fluid overload Not sleep well yesterday Groin: still erythematous with blister
Time 12am 1am 4am 6am 8am 10am 12pm 2pm 640pm 10pm Glucose (mmol/L) 4.4 5.1 4.8 4.3 3.9 4.7 4.3 7.2 8.3 7.1

Plan (1am): IVD 2 pints D5% Start IV insulin 0.5units / h GM 2 hourly Plan (8am) Reduce drip to 1 pint D5% Overlap with sc insulin SC actrapid (10 units tds) SC insulatard (14 units ON) Withhold insulin infusion Continue daily dressing

PCI (Day 3)
PCI Pharmacist Recommendation Outcome Patient was started with a) SC actrapid (10 units tds) b) SC insulatard (14 units ON) Total: 44 units/day (0.85 units/kg/day)

Review of Oral hypoglycemic agent

Pharmacotherapy handbook: Insulin therapy Patient HbA1C was 15.1 (0.7 2.5 (11.5 - Nov 2007) units/kg/day) Can be started Patient was on maximum dose on basal bolus of OHA insulin regimen a) T. Gliclazide MR 120mg OM Perform HbA1C b) T. Metformin 1g tds test in 3 months time. Patients CLcr trend: D1: 37.0mL/min D2: 39.1mL/min

Clinical progress: Day 4

C&S: Staphylococcus spp Taking orally (not much) Plan: Continue IV antibiotics Daily dressing with NS GM 4 hourly Off IV D5% Reduce dose: SC actrapid 8 units tds

Time

Glucose (mmol/L) 6.5 6.6 5.6 5.3 6.7

1225am 6.6 2am 4am 6am 4pm 8pm

1030pm 6.4

PCI (Day 4)
PCI Pharmacist Recommendation Monitor ABG daily until metabolic acidosis resolved. Outcome

ABG monitoring Patients ABG was monitored on day 1 and 3. ABG trend Day pH pCO2 1 7.3 28 3 7.3 31.5

pO2

61

97
17.2

HCO3 14.5

Clinical progress: Day 5

Sleep well Afebrile Plan (8am): Continue medications

Time
430am 8am 11am 530pm

Glucose (mmol/L)
9.8 10.3 20.1 16.7

PCI (Day 5)
PCI Pharmacist Recommendation Outcome

Glucose level was high.

Assess patient on present of

Time 430am 8am 11am 530pm

Glucose (mmol/L) 8.0 10.3 20.1 16.7

hypoglycemic symptoms Increase dose of: Insulatard from 14 to 16 units. Actrapid from 8 to 14 units. Novo Nordisk Diabetes Care Services leaflet: Blood Glucose Level Above Target Value Add

Up to 1 mmol/L
1 to 2 mmol/L > 2 mmol/L

2iu
4iu 6iu

Clinical progress: Day 6

GM 8am: 13.7 GM trend (Day 5) 9.8/20.1/16.7/9.3 Afebrile
Time 12am 4am 8am 1220pm 6pm 1030pm 1140pm Glucose (mmol/L) 9.3 6.4 13.7 9.9 10.4 5.1 5.1

Plan: Increase dose SC actrapid 14 unit tds GM monitor 4 hourly

Clinical progress: Day 7

Afebrile Respond to Antibiotics for scrotal cellulitis
Time 2am 6am 8am 1240am 6pm 1030pm Glucose (mmol/L) 5.2 6.4 8.0 6.0 6.1 4.9

Plan: GM monitoring qid Increase dose SC insulatard 16 units ON GM monitor 4 hourly Restart T. Amlodipine 5mg od Aqueous cream prn at scrotal area.

Clinical progress: Day 8

Patient slept well. Afebrile
Time 8am Glucose (mmol/L) 5.6

Plan: Off IV antibiotics Start oral Augmentin 625mg bd Discharge today

1230pm

4.6

Discharge Medications
T. Aspirin 150mg od SC Insulatard 16 units ON SC Actrapid 14 units tds T. Amlodipine 5mg od T. Amoxycillin / clavulanic acid 625mg bd X 3/7

PCI (Day 8)
PCI Pharmacist Recommendation Patient have DM and renal insufficiency, give anti-hypertensive a) T. perindopril 4mg od ADA 2007 recommend: ACEI for DM patients > 55 years old at high risk of CVD. ACEI may be superior to dihydropyridine CCB in reducing cardiovascular events. Outcome

Management of hypertension T. amlodipine restarted on D7

Patient discharge with T. amlodipine 5mg od

Patient BP trend in ward

Patients CLcr in ward ACEI and ARB delay progression to

macroalbuminuria.

References
Malaysian Practice guideline (2004):
Management of Type 2 Diabetes Mellitus Diabetic nephropathy

American Diabetes Association (2007): Standards of Medical Care in Diabetes.Diabetes Care 2007;30:S4-41 BSPED Recommended DKA Guidelines. JNC 7 hypertension guideline Sanford guide to antimicrobial therapy Diabetic ketoacidosis, David E. Trachtenbarg, MD. American family physician. DiPiro,J.TTalbert,R.L. Yee,G.C.et al (2005).Pharmacotherapy, A pathophysiology Approach. 6th Edition,Appleton & Lange Harrisons principle of internal medicine

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