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ICU: Case Presentation
Diabetic Ketoacidosis
Heparin Induced Thrombocytopenia
Hani Ramadan
PharmD Candidate 2007
Oakwood Hospital Dearborn, MI
CC: Weakness and Shortness of Breath.
2/23/07 (ER)
HPI:
CC is a 42 year-old male with a known history of insulin
dependent dabetes for the last eight years and previous
history of diabetic ketacidosis. Patient has been having
symptoms of SOB and lethargy for a week.
PMH:
Insulin dependent diabetes mellitus since 1999, DVT two
years ago in the left common femoral vein, diabetic
ketoacidosis, cellulitis with abscess in 2004 which required
incision and drainage.
Allergies: NKDA
SH: Patient rarely smokes. Social drinker. Does not use drugs.
Medications at Home: Insulin 70/30
Physical assessment:
VS: H=5’10” W=84kg T= 93.3, P= 94, RR=28,BP=102/60
HEENT: conjunctivae and lids have no pallor and no
jaundice. Pupils equal, round and reactive to light and
accomodation. Ears, nose and throat normal. Dry
oropharynx and oral mucosa. Using some accessory
muscles for breathing. Small abscess behind left ear.
Lungs: decreased breath sounds on the right
CV: S1 and S2 plus tachycardic.
Abd: no n/v/d.
Neuro: lethargic. Incomplete assessment.
Labs:
Na 124
K 5.1
Cl 99
WBC 39.3 Scr 2.1 pH 6.8 Glu 372
HGB 16.3 BUN 20 HCO3 3 Anion Gap 13
HCT 48
plt 271 pCO2 20 acetone +2
X-Ray: Right sided pneumothorax with some tension with
midline shift to the left as well as collapse of the RLL.
EKG: NSR with intraventricular block.
Physician’s assessment/plan:
1. Diabetic ketoacidosis: Due to abscess and
noncompliance. Patient started on insulin drip. Patient
received 2 liters fluid bolus and placed on 0.9 normal
saline at 150 ml/h. 2 ampules of bicarbonate per iv push
and 3 ampules of bicarbonate and 1 liter of D5 half
normal saline run at the rate of 150 ml/h.
2. Pneumothorax: Patient had a chest tube placed and pus
in the chest tube has been collected.
3. Abscess of the right thigh: X-ray has been ordered.
Patient has been placed on Vancomycin and Zosyn.
4. Hyponatremia: Will get corrected as the hyperglycemia
resolves.
5. Leukocytosis: secondary to underlying sepsis.
6. Hypothermia: probably from sepsis. Will place warm
blankets
7. Acute renal failure probably prerenal: Replace fluids
and recheck creatinine.
8. Gastrointestinal and DVT px.
DKA Diagnostic Criteria
Mild
Plasma glucose
(mg/dL)
Moderate
>250
Severe
>250
>250
< 7.00
Arterial pH
7.25-7.30
7.00-7.24
Serum
Bicarbonate
(mEq/L)
15-28
10-15
< 10
Serum /Urine
Ketones
Positive
Positive
Positive
Anion Gap
> 10
> 12
> 12
Mentation
Alert
Alert/Drowsy
Stupor/Coma
Common Precipitating Factors
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Infection (pneumonia, UTI, etc.)
Noncompliance with insulin therapy
Medications
Pancreatitis
Stroke
Alcohol/Drug abuse
Clinical Presentation
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Early symptoms: Polyuria, Polydypsia, Polyphagia.
Neurologic symptoms: Effective Posm =2 X PNa +([glucose]/18)
N/V/Abdominal pain*
Hypotension, Dry mucus membranes, Hypothermia.
Kussmaul respirations
Fluid Repletion
 Lowers plasma glucose by 35-70mg/dL per hour.
– Due to hemodilution and urinary losses
 Combined effect with insulin therapy causes plasma
glucose lowering of 100-200mg/dL per hour.
Determine Hemodynamic Status
Hypovolemic
shock
Administer 0.9%
NaCl (1L/h)
Serum Na2+
High
Mild Hypotension
Cardiogenic
shock
Hemodynamic
monitoring
Evaluate Corrected serum Na2+
Serum Na2+
Serum Na2+
Normal
Low
0.45% NaCl
0.9% NaCl
When serum glucose
reaches 250mg/dL
Change to 5% Dextrose with 0.45% NaCl (at 150-20mL/h)
Keep serum glucose between 150-200 mg/dL
Insulin Therapy
• Lowers hepatic glucose production
• May lower plasma glucose by 65-125mg/dL per hour.
– Slower response due to to resistance
• Diminishes ketone production
• Augments ketone metabolism
• Antilipolytic action
Insulin
IV Route
SC/IM Route
Insulin: Regular
0.15 units/kg as IV
bolus
Insulin: Regular
0.4 units/kg 1/2 IV
bolus, ½ IM or SC
0.1 units.kg-1.h-1 IV
insulin infusion
0.1 units.kg-1.h-1 Regular
insulin SC or IM
If serum glucose does not fall by 50-70 mg/dl in first hour
Double insulin
infusion hourly
until glucose falls
by 50-70 mg/dl
Give hourly IV
insulin bolus (10 units)
until glucose falls
by 50-70 mg/dl
Change to 5% dextrose with 0.45% NaCl at
150-250 ml/h with adequate insulin
(0.05-0.1 units.kg-1.h-1 IV infusion or
5-10 units SC every 2h) to keep the
serum glucose between 150 to 200 mg/dl
until metabolic control is achieved.
When serum glucose reaches 250 mg/dl
Plasma Sodium
 Increased plasma osmolality => Na+
 (1meq/L:62mg/dl) [pGlu < 400 mg/dl]
 (1meq/L:25mg/dl) [pGlu > 400 m/dl]
 Glycosuria-induced osmotic diuresis => Na+, K+
 Attenuated in CKD or maintenance dialysis
Plasma Potassium
 Paradoxical hyperkalemia at presentation.
 Acidemia
 Insulin deficiency
 Glucosuria induced osmotic diuresis
Potassium
If serum K+ is <3.3 mEq/L: Hold insulin
and give 40 mEq K+ per h (2/3 KCL and
1/3 KPO4) until K  3.3 mEq/L
If serum K+  5.0 mEq/L
do not give K+ but check
K+ every 2 hrs
If serum K+  3.3 but < 5.0 mEq/L:
Give 20-30 mEq K+ in each liter of IV
fluid (2/3 as KCL and 1/3 as
as KPO4) to keep serum K+ at 4-5 mEq/L
Plasma Bicarbonate and Anion Gap
 Severity of MA depends on:
 Rate of ketoacid production.
 Duration of increased ketoacid production.
 Rate of acid excretion in the urine.
Assess Need For Bicarbonate
pH <6.9
pH 6.9-7.0
NaHCO3
(100 mmol)
Dilute in
400 ml H20
Infuse at
200 ml/h.
NaHCO3
(50 mmol)
Dilute in
200 ml H20
Infuse at
200 ml/h.
Repeat HCO3 administration
Every 2 h until pH > 7.0.
Monitor serum K+.
pH >7.0
No HCO3
Plasma Phosphate
 Masked hyperphosphatemia.
 Insulin deficiency
 Acidosis
Monitoring Strategies
• Plasma glucose
– Every 1 to 2 hours
• Electrolytes, Phosphate, Arterial pH
– Every 2 to 6 hours
Drug Related Problem
2/28
Adverse Drug Reaction
(HIT) Suspected
Patient is on lovenox from 2/24-2/27. Patient is on Heparin 2/28.
Platelets: (2/25: 191) (2/28: 82)
Patient is also on Protonix, Vancomycin and Zosyn.
Patient has diabetes, history of DVT and cellulitis.
Recommendation: D/C Heparin. Start Argatroban.
Outcome
Heparin d/c. SCD’s, PF4 ordered.
Warkentin TE, Greinacher A et al. Heparin-induced thrombocytopenia: recognition, treatment and prevention:
The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest 2004 Sep;126(3 Suppl):311s-337s.
Day#5 (03/02/07)
O: Patient has empyema and had a thoracotomy. Patient was found to have
extensive occlusive and nonocclusive disease of his lower extermities with
DVT. Patient today underwent successful placement of IVC filter.
Vitals: Afebrile, BP:90/40, HR:86, RR:16-18.
Labs:
Na 141
K 3.7
Mg 2.2
P 3.7
Ca 1.10
pH: 7.41
pCO2: 32
HCO3-:20
Hgb 8.9
Hct 25
Scr: 5.56
BUN: 61
Glu: 189
Plt: 169
INR: 1.1
Antiplatelet F4: +ve
Chest: no wheezing or rales.
Heart: no murmurs, S2 or S3.
Abdomen: Soft and nontender. No masses or organomegaly.
Extremities: 1-2+ peripheral edema. Swelling suggestive of DVT.
Patient is on CPAP trials of pressure 4-12, CPAP of 5 appears to be doing well.
A: Bilateral lower extremity DVT. Heparin Induced Thrombocytopenia.
P: Initiate Argatroban therapy.
Heparin Induced
Thrombocytopenia
Type 1: (HAT)
Type 2:
 Typical onset
 Rapid onset
 Delayed onset
Presentation of HIT
 A fall in platelet count of  50% from
baseline.
 Platelet count fall may be less in some patients.
 Coagulopathy.
Incidence of HIT
 Higher in patients with previous heparin exposure than no
previous exposure.
 Surgical > medical.
 Highest amongst patients undergoing orthopedic surgery tx
with UFH (3-5%).
 Adults undergoing cardiac surgery tx with UFH (1-2%).
 Intermediate risk in general medical patients (0.8-3.0%)
 Rare amongst obstetrics, pediatric patients, patients
undergoing chronic hemodialysis.
Atypical manifestations
 Thrombosis few days before thrombocytopenia
 Skin lesions/necrosis at heparin injection sites
 Anaphylaxis
 Venous gangrene of limbs
Management of HIT
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Diagnosis of exclusion
Discontinue all sources of heparin.
Confirm diagnosis with laboratory testing.
Consider alternative anticoagulant.
Monitor for thrombosis.
Monitor platelet count recovery.
Laboratory Diagnosis
 Eliza PF4-heparin antibody test. (Immunoassay)
 Positive predictive value range: 10-93%
 Negative predictive value is high: >95%
 Functional assays
 Positive predictive value: 89-100%
 Negative predictive value: 81%
Arepally et al. Heparin-induced Thrombocytopenia. NEJM august 2006; 809-817
Pharmacotherapy
Argatroban
(Chest 1C)
DTI
Lepirudin
(Refludan)
(Chest 1C+)
Bivalirudin
(Angiomax)
(Chest 2C)
Fondaparinux
(Arixtra)
DTI
Hepatic t1/2: 3951min
Renal
t1/2: 0.81.7 hours
DTI
Factor Xa
inhibitor
FDA approved for
HIT
FDA approved for
HIT
20%
Renal
t1/2: 25-
Renal
t1/2: 17-21 Not yet approved
hours
for isolated HIT
36 min
Not yet approved
for isolated HIT
Drug Lab Interactions

INR change is thought to depend on the argatroban dose
and the thromboplastin agent used for measurement.
 In order to calculate actual INR from measured INR
1) Reduce the dose of Argatroban to a dose of
2mcg/kg/min.
2) Repeat INR level 4-6 hours after reduction.
3) Based on the thromboplastin ISI utilized the following
equations are used to calculate actual INR value:
0.19 + 0.57 (INRwa) = INRw (Innovin, Dade)
0.18 + 0.45 (INRwa) = INRw (Thromboplastin Cplus)
Treatment
 For patients who have HIT and thrombosis:
 Therapy with alternative anticoagulant. (DTI)
 Transition to warfarin therapy once platelets recover to
above 100 000 mm3 (preferably >150 000 mm3)
 Oral Anticoagulants are initiated with DTI for at least 5
days until the INR is therapeutic for at least 48hrs.
 Continue warfarin therapy for 6 months.
 Monitor aPTT*, INR, PT, platelet count.
A Comparison of Lepirudin and Argatroban
Outcomes. Smythe MA, et al. Clin Appl
Thrombosis/Hemostasis. 2005
Oct;11(4):371-374.
Objective: To compare the efficacy and safety outcomes of
lepirudin and argatroban.
Study Design
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–
–
Retrospective cohort study.
Baseline demographic/clinical recording.
Randomization to Argatroban or Lepirudin.
Argatroban n = 29
Lepirudin n = 61
Outcome Measures
 Primary Efficacy Outcome:
 Effective anticoagulation: aptt > 1.5, fewer dose increase.
 Primary Safety outcome:
 In hospital major bleeding.
 Secondary Efficacy Outcome:
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Time to first therapeutic aPTT.
Percent of aPTTS that were therapeutic.
Number of hold orders for a supratherapeutic aPTT.
% of patients requiring a dose adjustment.
Number of dose titration requirements.
Results
 Time to first therapeutic aPTT was the only
efficacy outcome that differed between the
groups. (P<0.05)
Limitations
 Patient heterogeneity.
 Sample size.
 Time of follow up.
Conclusions
 Lepirudin and Argatroban demonstrated
comparable safety and efficacy.
 To identify if clinically meaningful differences
exist, a large prospective study is needed to
compare outcomes of lepirudin and argatroban.
Argatroban Anticoagulation in Patients with
Heparin-induced Thrombocytopenia.
Lewis BE, et al. Arch Intern. Med.
2003;163:1849-1856.
Study Design
 Multicenter, nonrandomized, prospective study
using a historical control cohort.
 Study group (n = 418): HIT (189), HITTS(229)
study arms.
 Control (n = 185)
 Baseline demographic/clinical features comparable.
Selection
 Inclusion:
 Men and non-pregnant women  18 years clinically diagnosed
with HIT.
 Exclusion:
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Unexplained activated aPTT > 2 times the control value at baseline.
Bleeding diathesis unrelated to HIT.
Lumbar puncture in the past 7 days.
Hx of previous aneurysm/ hemorrhagic stroke.
Recent thrombotic stroke unrelated to HIT
A known bleeding site
Current pregnancy or breastfeeding.
Terminal illness with a life expectancy of < 2 weeks.
Documented coagulation disorder
Outcome Measures
 Primary efficacy end point:
 Composite of all-cause mortality, all-cause
amputation, new thrombosis in 37 days.
 Secondary efficacy endpoints:
 Death due to thrombosis.
 Increased platelet count.
 Bleeding.
Results
 In the HIT arm the primary end point was
significantly reduced in the treatment arm compared
with controls. P=0.04
 In the HITTS study arm, the composite end point
occurred in 95 patients (45%) and 26 (56%) controls.
P=0.07
 Argatroban compared with control resulted in
significant reductions in new thrombosis.
 Patients with HIT (5.8% vs.23%, p<0.001)
 Patients with HITTS (12.1% vs. 34.8%; p<0.001)
Limitations
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Historical control.
Risk factors not completely assessed.
Incidence of confirmed HIT unknown.
Median aptt value unknown.
Disease severity unknown.
Liver function unknown.
Confounding variables not addressed.
Conclusion
 Argatroban therapy compared to historical
control improves outcomes particularly new
thrombosis and death due to thrombosis in
patients with HIT.
CC: Weakness and Shortness of Breath.
2/23/07 (ER)
HPI:
CC is a 42 year-old male with a known history of insulin
dependent dabetes for the last eight years and previous
history of diabetic ketacidosis. Patient has been having
symptoms of SOB and lethargy for a week.
PMH:
Insulin dependent diabetes mellitus since 1999, DVT two
years ago in the left common femoral vein, diabetic
ketoacidosis, cellulitis with abscess in 2004 which required
incision and drainage.
Allergies: NKDA
SH: Patient rarely smokes. Social drinker. Does not use drugs.
Medications at Home: Insulin 70/30
Physical assessment:
VS: H=5’10” W=84kg T= 93.3, P= 94, RR=28,BP=102/60
HEENT: conjunctivae and lids have no pallor and no
jaundice. Pupils equal, round and reactive to light and
accomodation. Ears, nose and throat normal. Dry
oropharynx and oral mucosa. Using some accessory
muscles for breathing. Small abscess behind left ear.
Lungs: decreased breath sounds on the right
CV: S1 and S2 plus tachycardic.
Abd: no n/v/d.
Neuro: lethargic. Incomplete assessment.
Labs:
Na 124
K 5.1
Cl 99
WBC 39.3 Scr 2.1 pH 6.8 Glu 372
HGB 16.3 BUN 20 HCO3 3 Anion Gap 13
HCT 48
plt 271 pCO2 20 acetone +2
X-Ray: Right sided pneumothorax with some tension with
midline shift to the left as well as collapse of the RLL.
EKG: NSR with intraventricular block.
Summary
References
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Lewis BE, et al. Argatroban Anticoagulation in Patients with Heparin-induced Thrombocytopenia. Arch
Intern. Med. 2003;163:1849-1856.
Smythe MA, et al. A comparison of Lepirudin and Argatroban Outcomes. Clin Appl
Thrombosis/Hemostasis 2005 Oct;11(4):371-374.
Warkentin TE, et al. Management of heparin-induced thrombocytopenia: a cirtical comparison of
lepirudin and argatroban. Thrombosis Research. 2003;110: 72-82.
Warkentin TE, Greinacher A et al. Heparin-induced thrombocytopenia: recognition, treatment and
prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004
Sep;126(3 Suppl):311s-337s.
Dang CH et al. Evaluation and Treatment with Diret-Thrombin Inhibitors in patients with HeparinInduced Thrombocytopenia. Pharmacotherapy 2006;26(4):461-468.
Argatroban package insert. GlaxoSmithKline.
Gowthami M. et al. Heparin-Induced Thrombocytopenia. NEJM 2006;355:809-17.
Phathogenesis of Diabetic Ketoacidosis, Treatment of Diabetic Ketoacidosis; Uptodate 2006.
ADA position statement. Hyperglycemic Crises in Patients with Diabetes Mellitus. Diabetes Care;jan
2003;26(1):S109.
Herbst et al. Insulin Strategies for Primary Care Providers. Clinical Diabetes 2002;20:11-16.