The missing platelets… where did they go?

Hilary Rowe, BScPharm

VIHA Pharmacy Resident 2009-10

Intensive Care Unit Rotation

April 13, 2010

Outline

• Objectives

• Patient Case

• Background

• Clinical Question

• Review of Evidence

• Recommendation

• Monitoring

Objectives

• Be able to list the 4 SIRS criteria

• Review pathophysiology for HIT, DIC & thrombocytopenia in sepsis

• Name 2 risk factors for thrombocytopenia in the ICU

• Quantify the risk of thrombocytopenia from Sepsis

Mrs. DG

• ID: 75 yo Female, ht 166cm, wt 65kg• CC: April 6th- arrived at ER with family;

weakness, ↓ oral intake, difficulty speaking

• HPI: 4 days of abdominal pain, bloating & nausea

• ICU Vitals: Temp 359, HR 120, RR 18, MAP <49, BP 95/60 mmHg, APACHE II =28

Mrs. DG

• PMHx: Hypertension, Osteoarthritis

• Meds PTA: Losartan 50mg od

• Allergies: NKA

• SH: From Saskatchewan-on vacation, 2-3 glasses of wine/day, non-smoker

Review of Systems

System Findings Medications

CNS

&

Psych

•Pain•Sedation •Coma score 3 (no eye opening, response to verbal command or motor response)•Delirium

•Hydromorphone infusion 0.1mg/hr•Midazolam Infusion 1mg/hr•Haloperidol

2-10mg IV as directed prn

Review of Systems

System Findings Medications

HEENT •OG tube•ETT

•Chlorhexidine 0.1% bid oral care

Resp •Ventilated- rate 20, peep 8 FiO2=55%, TV 550, Sats 95%•ACVC: Assist/Control with set volume: senses breaths but has minimum set rate, all breaths fully ventilator assisted

•Salbutamol

8-12 puffs q4h & prn

Review of Systems

System Findings Medications

Cardio BP-120/60 on therapy

MAP 67-73

HR-120

Rhythm-NS

•Norepinephrine 0.8mg/kg/min•Vasopressin 0.6units/hr•Dobutamine 2.5mg/kg/min•Hydrocortisone 10mg/hr

System Findings Medications

GI •Ascities-1600 cc fluid tapped•Tender to touch left side

•Docusate 200mg•Ranitidine 50mg IV q12h

Liver •Alb=16↓•ALT=58↑•AST=87↑•Tbili=33↑•GGT 18N•INR 1.1↑, PTT 60↑

•Albumin 25% 100mls tid x 1 day

Review of Systems

Review of Systems

System Findings Medications

GU •SrCr 417 •eGFR 9•Urosepsis•Urine output 15cc/6h

•Pen G 2 Million Units q8h•Cipro 400mg IV q24h

Endo •BG 7th

-0900 6.6

-1630 7.4

-2100 9.3

-0200 10.1

Insulin regular CCIIP

Review of Systems

System Findings Medications

Heme •WBC 3.8↓, RBC 4.05, Hgb 126, Hct 0.36, MCV 90, RCDW 12.8, Plt 85↓, Neuts 2.32, Lymph 0.11↓, •Plts dropped April 7th

•Drotrecogen Alfa 24mcg/kg/hr 96hrs•Heparin D/C’d 7th

•SCD’s started

Fluids & Lytes

•Na 136 •K+ 4.4•Cl110

•CO2 14↓

•PO4 1.51↑

CaCl 1g IV < 1.13

KCl 20mmol in SWFI IV prn

NaHCO3- IV

continuous

System Findings Medications

C&S •Blood- Gram + cocci in chains•Fluid-brown & turbid, 2+ polymorphs, 2+ gram + cocci•Urine-Streptococcus pyogenes

Blood gases

•pH=7.27↓•CO2=27↓

•HCO3-=14↓

•pO2=105↑•Metabolic acidosis with partial compensation

Review of Systems

System Findings Medications

Nutrition •Thiamine 100mg IV od x 3 d•Folate 5mg IV/PO od•MVI I IV then Replavite po od•Vit D 2000 units od

Review of Systems

• Presence of two or more of: • Temperature < 36 °C or > 38 °C • Heart rate > 90 beats per minute • Respiratory rate > 20 breaths per minute or a

PaCO2 less than 32 mm Hg

• White blood cell count < 4  × 109 cells/L or > 12 × 109 cells/L), or greater than 10% bands

DG Temp 359, HR 120, WBC 3.8 × 109 cells/L

SIRS

Medical Problems List

• Septic Shock-Urosepsis origin

• Acute Renal Failure

• Thrombocytopenia ?

1. HIT

2. DIC

3. Sepsis

4. Drug cause- Drotrecogen alfa

• Ascites

• ARDS (Pa02/FiO2=190)

DRP’s

• DG is at risk of neurotoxicity (confusion, delirium, myoclonus) secondary to a toxic metabolite of hydromorphone in renal failure and would benefit from re-assessment of her pain and sedation therapy

• DG is at risk of side effects (confusion) from ranitidine secondary to too high of a dose in acute renal failure

DRP’s

• DG is at risk of a bleed secondary to having thrombocytopenia and being on APC and would benefit from re-assessment of her therapy

Thrombocytopenia

• Defined as < 100 x 109 platelets/L• Most common ICU causes

– Sepsis & DIC

• April 7th – 03:22 85 x 109 platelets/L– 08:30-clumped, 15:30-19C, 22:00 13C

• April 8th

– 6:10 13C, 17:35 8C

Rounds

• Could Xigris, DIC, Sepsis, HIT or a medication error have caused the thrombocytopenia and can we tell which one is the culprit?

Clinical Question

• Heparin can combine with a heparin-binding protein (platelet factor 4) and make an antigenic complex that causes IgG antibodies to be made

• Antibodies bind platelets and cause aggregation= platelet consumption and thrombosis

• >50% ↓in platelets 5-10d after 1st exposure

• 5-10% get a redness around sc site

• 25% get systemic reactions if given IV-fever, chills, ↑ RR, ↑ HR, SOB

HIT

DIC & Sepsis

• Gram + & – organisms cause excessive activation of the clotting cascade – Platelets are consumed– Results in thrombocytopenia

• In severe sepsis microvasculature is damaged by poor perfusion, hypoxia, stasis & acidosis– Platelets adhere to damage– Causes activation of platelets & aggregation– Leads to more platelet consumption

Points 0 1 2 3

Plt x 109/L >100 >50 <50

D-dimer mg/L <1 1-5 >5

Fibrinogen g/L >1 <1

Prothrombin Index% >70 40-70 <40

DIC

•>5 points is required to consider DIC•DG has a score of 7 + some points for INR >1

Lee et al. Singapore Med J 1993

Design Prospective study of illness severity scoring with the APACHE II system, started in 1991

P•Patients admitted to Medical ICU•107 patients mainly Chinese

I •Patients with Sepsis

C •Patients without Sepsis

O•Assess the relationship between clotting abnormalities, APACHE II and sepsis•Determine if organism played a key role

Lee et al. Singapore Med J 1993

DG’s APACHE II= 28, Platelets 85 x 109/L

Lee et al. Singapore Med J 1993

Lee et al. Singapore Med J 1993

DG had Streptococcus pyogenes

Summary• Thrombocytopenia (57%) and DIC (35%)

are common in sepsis• Thrombocytopenia presents early in

sepsis and is a predictor of mortality, independent of APACHE II for Sepsis

• Patients died of multi-organ failure not blood loss from thrombocytopenia

Lee et al. Singapore Med J 1993

Clinical Question

P 75 year old female with Septic Shock

I Xigris 24mcg/kg/hr

C No therapy

O

Risk of thrombocytopenia

Time to onset of thrombocytopenia

Risk of clinically significant bleed

•6.1% ARR (NNT=16, RRR 19.4% P=0.005) in all cause mortality •Due to reduction in refractory septic shock, respiratory failure and improvement in cardiac and respiratory function

Benefit of Xigris

Bernard et al. Critical Care 2003

DesignReview of 7 studies- (2 controlled, 3 open-label & 2 compassionate use studies)

P •Patients with severe sepsis

I •24ug/kg/hr x 96 hr of Drotrecogen Alfa

C•Saline or 0.1% albumin in saline or no comparator

O

•28 day all cause mortality•Serious bleeding during & post infusion or by procedural cause•Serious bleeding by site of hemorrhage•Risk of fatal bleeding event

Inclusion:•Known or suspected infection with SIRS•Presence of acute organ dysfunction

Exclusion:•At high risk of serious bleed•Severe thrombocytopenia (plts < 30 x 109/L)•Taking antiplatelet medications•Receiving systemic heparin anticoagulation

Bernard et al. Critical Care 2003

Mortality rate• Controlled trials 25.2% (236/940; 95% CI 22.4-28)• Open-label studies 25.2% (398/1578; 95% CI

23.1-27.4)• Compassionate use 26.1% (70/268; 95% CI 21-

31.8)• Clinical trials 25.3% (704/2786; 95% CI 23.7-26.9)• Placebo 31% (273/881; 95% CI 28-34.2)

Bernard et al. Critical Care 2003

Bernard et al. Critical Care 2003

•58/79 SBE during infusion were considered related to the drug (2.1%; 58/2786)•8/69 SBE post infusion were considered related to the drug (0.3% of all treated patients)

Bernard et al. Critical Care 2003

•22/53 (42%) patients who experienced a SBE during the infusion period had thrombocytopenia

• High proportion of SBE was due to invasive procedures

• 58/148 SBE’s were due to procedures in the drotrecogen alfa group

• PROWESS trial– 53.5% (16/30) in drotrecogen alfa group

vs. 23.5% (4/17) in placebo group had a SBE due to a procedure

Bernard et al. Critical Care 2003

Bernard et al. Critical Care 2003

•Non ICH SBE with fatal outcome-3 events in drug group during infusion-1 involved thrombocytopenia (19x109/L) and PTT >150 sec

Bernard et al. Critical Care 2003

Summary: • Heparin exposure

– 75% of patients in PROWESS trial were exposed to heparin, 11/18 with SBE had used heparin

– 14/49 in open-label trials and 3/10 in compassionate use trials who had SBE were exposed to heparin

• SBE were highest on day 1 – 56% were procedure related– 12 non-procedure related events occurred– 9 had platelets < 30 x109/L– 3 had an INR > 2

Bernard et al. Critical Care 2003

• Most serious ADR is bleeding

• NNH=66 in PROWESS (3.5% SBE with therapy vs. 2% with placebo)

• Bernard et al. found SBE rate to be 5.3% overall in the 7 trials assessed

Bernard et al. Critical Care 2003

Conclusion• Bleeding occurs most often on day 1 of

infusion• Occurs most often with procedures• ICH during infusion is associated with

severe thrombocytopenia or meningitis• Therapy should be stopped if platelets <

< 30 x109/L

Bernard et al. Critical Care 2003

• Xigris was started April 6th at 23:15 and platelets declined April 7th by 08:30– SBE occurred most often on 1st day of infusion-

associated with thrombocytopenia– Timing seems appropriate

• Patient is also at risk of sepsis induced thrombocytopenia & DIC

• Naranjo ADR scale= 3, possible

What do you think?

Who was the culprit

Goals of Therapy

Patients Goals• Full code

Team Goals• Cure urosepsis• Improve renal function• Wean patient from ventilator• Prevent Bleeding• Prevent Clotting• Decrease morbidity & mortality• Minimize adverse drug events

Therapeutic Options

•Continue Drotrecogen Alfa

Discontinue Drotrecogen Alfa

•Continue Heparin

Discontinue Heparin

Start Sequential compression devices

•Give Platelets

Monitoring

Adverse Events

Monitor Who When How Long

INR & PTT Dr. & Rx Each morning

Daily while in ICU

Platelets Dr. Daily Daily while in ICU

Bleeding-ETT, urine, bowel, vomit, nose…

Dr. & Nurse

QID Daily while in ICU

Monitoring

Efficacy

Monitor Who When How Long

Ventilation Dr., RT, Rx Daily While in ICU

Use of vasopressors

Dr., RN, Rx Daily While in ICU

Need for hydrocortisone

Dr., Rx Daily While on vasopressors

Questions?

References

• Bernard GR, Macias WL, Joyce DE et al. Safety assessment of drotrecogen alfa (activated) in the treatment of adult patients with severe sepsis. Critical Care 2003;7:155-63.

• Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. NEJM 2001; 344 (10): 699-709.

• Lee KH, Hui KP, Tan WC. Thrombocytopenia in sepsis: a predictor of mortality in the intensive care unit. Singapore Med J 1993;34:245-46.

• Marino PL. The ICU Book 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2007. page 684-7.

• Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2): 239-45.