Irrational Exuberance: Component Therapy Before Bedside Procedures Jeannie Callum, BA, MD, FRCPC, CTBS Sunnybrook Health Sciences Centre Associate Professor,

Irrational Exuberance:Component Therapy Before Bedside Procedures

Jeannie Callum, BA, MD, FRCPC, CTBS

Sunnybrook Health Sciences Centre

Associate Professor, University of Toronto

Outline

3 recent papers Bedside procedures and the evidence:

Central venous catheters Liver biopsy Thoracentesis & Paracentesis Bronchoscopy &Transbronchial biopsy Renal Biopsy Epidural/Lumbar puncture

Incidence of bleeding after 15,181 percutaneous biopsies and the role of ASAAm J Radiology 2010; 194: 784-789.

Mayo Clinic - January 2002 through February 2008

Solid organ percutaneous biopsies 5,832 Kidney biopsies 3,636 Liver biopsies 1,174 Lung biopsies 384 Pancreas biopsies 4,155 Other biospies


Local practice at the Mayo clinic: Platelets >50 INR<1.6

Primary endpoint was major bleeding within 3 months of the procedure

Major bleeding = RBC transfusion, interventional radiology procedure, operative procedure

Follow-up at 3 months was available for 95% of the patients


Of 15,181 biopsies, 70 bleeding complications (0.5%) within 3 months, including three deaths (3/15,181, 0.02%)

Of the 70 patients with bleeding compared with the remaining patients, the platelet count was lower (194 vs. 257; p <0.001) and the INR was higher (1.2 and 1.0; p < 0.001)

No statistically significant difference in the major bleeding complication rates was seen between patients who took aspirin (within 10 days) compared with those who did not (p = 0.34)

Large-bore tunneled central venous catheter insertion in patients with coagulopathy. Haas B, Chittams JL, and Trerotola SO. J Vasc Interv Radiol 2010; 21: 212-217.

The Society of Interventional Radiology (SIR), recommend that one needs an INR of 1.5 and a platelet count of 50,000/µL for an ultrasound-guided line placement

Single center report from the University of Pennsylvania Medical Center

Reviewed the outcomes of 3,170 tunneled central venous catheter placements in 2,514 unique patients


Their guidelines: Plt count >25 and INR<2 (although some

clinicians tolerated even more abnormal numbers) All performed under ultrasound guidance Patients excluded from the analysis if they had

received FFP or platelets between their last set of laboratory values and the procedure

Objectives: Primary-incidence of bleeding in first 24 hours Secondary-incidence of infection and catheter

failure


567 were placed in patients with platelet counts below 50,000/µL and/or an INR>1.5

They had 27 complications out of 3,170 insertions (1 in 117) 3 of 567 patients with abnormal laboratory

numbers developed complications, of which none were hemorrhagic (1 in 189)

3 bleeding complications (1 in 1057), all with platelet counts above 50,000/µL and INR<1.5


99 patients had platelet counts below 30 and 71 had INRs >1.9 at the time of the procedure, suggesting many of their clinicians feel comfortable doing these procedures with more abnormal laboratory values The lowest platelet count was 3 and the highest

INR was 3.8 Despite these very abnormal laboratory test

results, the complication rate in this group with abnormal laboratory results was identical to that of patients with more normal laboratory numbers


If this institution had followed the Society of Interventional Radiology guidelines: They would have needless transfused 300

patients platelets, 282 patients FFP, and 44 both products

This translates into approximately 344 adult doses of platelets and 1304 units of FFP administered needlessly

Recombinant factor VIIa for the correction of coagulopathy before emergency craniotomy in blunt trauma patientsJ Trauma 2010; 68: 348-52.

28 ‘coagulopathic’ patients in Austin, Texas Aka borderline laboratory abnormalities

(defined as an INR>1.3) 75% had subdural hematomas Compared 14 patients that got r7a with the 14

that did not (Not randomized!) – 1.2 mg! rFVIIa group was older (59 vs 41, p 0.04) rFVIIa group was more likely to be on warfarin (57

vs. 14%, p 0.05) no statistical difference in admission INR (rFVIIa 2.6

vs. no-rFVIIa 1.9, p 0.10)


There were no thromboembolic complications in either group

There were 7deaths (50%) in the rFVIIa group and 4 deaths (29%) in the no-rFVIIa group (p =0.22)


Prothrombin complex concentrate vs rVIIa for reversal of coumarin

anticoagulation

Dickneite G. Thrombosis Res 2006; Jul 12: Epub ahead of print

Dickneite G. Thrombosis Res 2006; Jul 12: Epub ahead of print

Prothrombin complex concentrate vs rVIIa for reversal of coumarin

anticoagulation

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjectsBlood Epub April12, 2010

N BT pre BT post warf

BT post treatment

Placebo 24 18.7 29.5 26.3

40 ug/kg 12 20.7 32.3 28.9

80 ug/kg 24 18.6 31.9 27.7

N PT pre PT post warf

PT post treatment

Placebo 24 13.0 27.3 26.7

40 ug/kg 12 12.9 26.8 14.7

80 ug/kg 24 13.3 30.4 15.0

Bleeding Time (same results for blood loss)

PT

What is the evidence from systematic reviews?

INR and aPTT do NOT predict which patient will bleedSegal et al. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion. 2005;45:1413-25

Eckman MH, Erban JK, Singh SK, Kao GS. Screening for the risk for bleeding or thrombosis. Ann Intern Med 2003; 138: W15-W24.

17 studies Role of PT and aPTT in predicting post-

operative hemorrhage

“For nonsurgical and surgical patients without synthetic liver dysfunction or a history of oral anticoagulant use, routine testing has no benefit in assessment of bleeding risk.”

Bleed No Bleed

Rate

PT elevated 2 241 1 in 121

PT not elevated

23 1561 1 in 68

All Patients 25 1802 1 in 72

FFP given before a procedure will not correct an INR <2

The relationship between the INR and coagulation factors

50 %

30 %

100 %

INR 1 1.7 2.0 2.2 3.01.3

zone of normalhemostasis

zone of anticoagulation

15 ml/kg FFP

60 ml/kg FFP = 4 L FFP

Effect of FFP on patients with INRs between <1.8

Abdel-Wahab OI, et al. Transfusion 2006; 46: 1279-85

57 trials evaluated Liver disease, cardiac surgery, warfarin-related

hemorrhage, massive transfusion, prevention of IVH in infants, burns, etc.

…for most clinical situations, the RCT evidence base for the clinical use of FFP is limited…the strongest RCT evidence seems to indicate that the prophylactic use of FFP is not significantly or consistently effective across a range of different clinical settings.

Stanworth et al. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol. 2004;126:139-52.

Globally there is no evidence…

What about for specific procedures?

What is the evidence for specific procedures? Bedside procedures and the evidence:

Central venous catheters Liver biopsy Thoracentesis & paracentesis Bronchoscopy & transbronchial biopsy Renal Biopsy Epidural/Lumbar puncture

Central venous catheters

57 year old woman with AML needs a Hickman line insertion to commence chemotherapy today

Her INR is 1.9 and PTT 41 this morning – she has suspected mild DIC and vitamin K deficiency (not eating and on broad spectrum antibiotics)

Given iv vitamin K 10 mg iv this AM Platelet count is 38 No active bleeding and no bleeding history What would you request?

What do we know?

Bleeding complications relate to inadvertant puncture of the carotid or subclavian artery Denys BG, et al. Circulation. 1993;87:1557-62. Vanherweghem JL, et al. Am J Nephrol. 1986;6:339-45.

Systematic review of complications of CVC insertion (jugular or subclavian) reported 48 episodes of pneumothorax and/or hemothorax after 3420 procedures (1.4%), although only one-third of the episodes were hemothorax (=0.5% risk of a hemothorax). Ruesch S, et al. Crit Care Med. 2002;30:454-60.

What do we know?

A meta-analysis of 8 RCTs found that the use of Doppler ultrasound to guide line placement reduced the incidence of placement complications (OR 0.22, 0.10-0.45) Randolph AG, et al. Crit Care Med. 1996;24:2053-8.

Greater experience by the physician performing the CVC insertion reduces the risk of procedural complications Sznajder JI, et al. Arch Intern Med. 1986;146:259-61.

Sunnybrook

All our lines are placed with ultrasound guidance by experienced interventional radiologists 0.5% x 0.22 = 0.11% (1 in 909 major

bleed rate)

CVC insertionFoster PF, Moore LR, Sankary HN, et al. Central venous catheterization in patients with coagulopathy. Arch Surg. 1992;127:273-5.

202 CVC insertions performed on liver transplant patients with severe hemostatic abnormalities

No attempts were made to correct laboratory abnormalities before the procedure

Mean coagulation factor levels were 29% of normal (range=10-39%), mean PTT was 92 sec (range=78-100 seconds), mean platelet concentration was 47 (range=8-79)

Despite these values and the lack of any pre-procedure therapy, no serious bleeding complications occurred

CVC insertionDoerfler ME, Kaufman B, Goldenberg AS. Central venous catheter placement in patients with disorders of hemostasis. Chest. 1996;110:185-8.

76 patients who received 104 central catheters 22 catheters were placed with platelet counts

of 50-100, 30 catheters with counts of 20-50, and 11 with counts below 20

13 percent of patients had a combination of thrombocytopenia and prolongation of the PT/PTT

None were given transfusions of platelets or FFP before the procedure

None had serious complications, intrathoracic bleeding, or an unexpected drop in hematocrit

More evidence 115 patients undergoing CVC insertion with

thrombocytopenia (mean 24,000/µL) found no difference in the platelet counts of patients with and without bleeding complications. Barrera R, et al. Cancer. 1996; 78:2025-30.

388 consecutive catheterizations in patients with heme malignancies with thrombocytopenia present in 28% of patients (32 patients 50-99, 41 patients 30-49, and 36 patients <30) and abnormal coags were present in 19% Bleeding occurred after line insertion in only 5 cases (1 in 78 patients)

and all 5 patients had platelet counts below 30,000/µL. No difference in bleeding rates between patients with normal and abN

coags Nosari AM, et al. Leuk Lymph. 2008;49:2148-55.

More evidencePetersen GA. Does systemic anticoagulation increase the risk of internal jugular vein cannulation? (letter) Anesthesiology. 1991;75:1124.

516 consecutive patients with internal jugular lines before cardiac surgery

252 (49%) were anticoagulated with heparin An observer who was unaware of the

anticoagulation status of each patient recorded the presence of an insertion site hematoma

Of the 22 hematomas that occurred 13 were in anticoagulated patients 9 were in non-anticoagulated persons This difference was not significant

More evidenceFisher NC, et al. Intensive Care Med. 1999;25:481-5.

658 CVC line insertions Median INR was 2.4 (1–16) (580 cases >1.5) Median platelet count was 81 (9 – 1,088) (531 <150) In 453 cases both abnormalities were present Patients were not given any pre-procedure

transfusion of FFP or platelets 1patient, with near normal tests, developed a

hemothorax after inadvertent puncture of the subclavian artery

There were no other major hemorrhagic complications

More evidenceHass B, et al. J Vasc Interv Radiol 2010; 21: 212-217.

Of 3188 tunneled CVCs placed: 428 had platelet counts <50 (down to 3) 361 had INR>1.5 (up to 3.8)

They excluded any patient that had been transfused product between the last reading and the procedure

3 had bleeding complications None had platelet counts <50 or INR>1.5

Bottom line

No evidence for any pre-procedure component therapy

Based on the evidence, the most conservation stance you could take would be to require a platelet count in excess of 25-30

There is no INR above which patients appear to be at higher risk

Liver biopsy

45 year old with cryptogenic cirrhosis needs a diagnostic percutaneous liver biopsy (with ultrasound guidance)

His INR is 2.2, PTT 48, and platelet count 48

He has no bleeding history What would you order before the

procedure?

Liver Biopsy

The perfect patient population to test NOT giving prophylactic transfusions: Patients often have abnormal laboratory

tests of coagulation They are often thrombocytopenic They have multiple other derangements of

hemostasis You can’t compress the liver if it bleeds

Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J of Heaptology 1986; 2: 165-73.

A very large series of 68,276 percutaneous biopsies published in 1986 found that major bleeding occurred in only 42 patients. 1 in 1626 patients

Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981;26:388-93.

200 consecutive patients undergoing liver biopsy with laproscopic ‘observation’ for bleeding

No degree of abnormal lab tests warranted pre-procedure therapy at this institution

There was no correlation of liver bleeding time and laboratory test results

Even patients with INR>3 and platelets<50 did not bleed more than patients with ‘better’ test results

Random distribution

McGill DB, et al. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology. 1990;99:1396-400.

9000 liver biopsies performed over a 21 year period

Patients had pre-procedure INR’s up to 1.8 and platelet counts as low as 55

Post-biopsy hemorrhage occurred in 32 patients

The lab values did not differ between the 32 with substantial bleeding and the rest of the patients

Makris M, et al. A prospective investigation of the relationship between hemorrhagic complications of percutaneous needle biopsy of the liver and coagulation screening tests. Br J Haematol. (abstract) 1992;81:51.

104 patients undergoing liver biopsy who were screened for bleeding complications with post-procedure CT scans

Half of the patients had abnormal coagulation tests pre-procedure including numerous patients with PT values corresponding to INRs > 2.0, PTTs >50, and platelet counts as low as 50

Two patients bled post-procedure and both of these had normal pre-procedure coagulation values

Bottom line

Bleeding is very rare There is no data to support the notion

that patients with abnormal lab values will bleed more than patients with normal lab values at the time of percutaneous liver biopsy

Thoracentesis & Paracentesis 67 year old EtOHic male is admitted

through the ER with query spontaneous bacterial peritonitis resulting in sepsis

INR 5 Platelet count 23 He needs a diagnostic peritoneal tap What would you give him prior to the

procedure?

Pache I, and Bilodeau M. Severe hemorrhage following abdominal paracentesis for ascites in patients with liver disease. Ailment Pharmacol Ther. 2005;21:525-9.

Severe hemorrhage following abdominal paracentesis is exceptionally rare

A recent large series of 4729 patients observing severe hemorrhage in only 0.19% of patients 1 in 525 patients

McVay PA, Toy PT. Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities. Transfusion. 1991;31:164-71.

A review of outcomes in 608 consecutive procedures (391 paracenteses, 207 thoracenteses, and 10 both)

None of the patients was given prophylactic components

Bleeding complications occurred in 0.2% No difference between normal PT/PTT compared

with those with a prolonged PT/PTT No differences between platelet counts above

100 compared with those with counts of 50-100 or 25-50

Grabau CM, et al. Performance standards for therapeutic abdominal paracentesis. Hepatology. 2004;40:484-8.

1,100 paracenteses at a center where no degree of thrombocytopenia or pre-procedure coagulation test result was deemed unsafe for the procedure

All procedures were performed without ultrasound guidance and without the transfusion of platelets or plasma

The lowest platelet count was 19 (IQR 42-56) and the highest INR was 8.7 (IQR 1.4-2.2)

There was no significant bleeding in any patient

Guidelines

In the 2009 American Association for the Study of Liver Diseases Practice Guidelines on the management of adult patients with ascites due to cirrhosis, the guideline committee recommended that “Because bleeding is sufficiently uncommon, the routine prophylactic use of fresh frozen plasma or platelets before paracentesis is not recommended.” Runyon BA. AASLD Practice Guidelines Committee. Management of adult

patients with ascites due to cirrhosis: an update. Hepatology. 2009;49:2087-107.

Transbronchial biopsy

68 year old man on ASA for a bare metal stent placed 1 year ago is booked for bronchoscopy and transbronchial biopsy

He has a history of 2 TIAs His platelet count is normal Would you stop his ASA?

Bronchoscopy and Biopsy

Complications at the time of bronchoscopy are rare, in one large report a major complication was seen in only 0.08% of 24,521 procedures

Complications are higher with transbronchial biopsy, estimated in one large series at approximately 2% for all patients Credle W, Smiddy J, and Gruber B. Deaths and complications of

fiberoptic bronchoscopy. Am Rev Respir Dis 1974; 109: 67-72. Cordasco EM Jr, Mehta AC, and Ahmad M. Bronchoscopically

induced bleeding. A summary of nine years’ Cleveland Clinic experience and review of the literature. Chest. 1991;100:1141-7.

Kozak EA, Brath LK. Do “screening” coagulation tests predict bleeding in patients undergoing fiberoptic bronchoscopy with biopsy? Chest. 1994;106:703-5

274 patients undergoing 305 fiberoptic bronchoscopy and biopsy procedures at a tertiary care institution

Prolonged hemostatic studies prior to the procedure were noted in 10% (n=28) of patients

35 patients bled, but 32 of these had normal pre-procedure hemostatic values

3 patients had severe bleeding and each of them had normal pre-procedure test results

Diette GB, Wiener CM, White P Jr. The higher risk of bleeding in lung transplant recipients from bronchoscopy is independent of traditional bleeding risks: results of a prospective cohort study. Chest. 1999;115:397-402

720 bronchoscopies performed over a one-year period at Johns Hopkins and used multivariate analysis to determine factors that correlated with bleeding complications

They found that bleeding did not correlate with coagulation parameters or platelet count

Brickey DA, Lawlor DP. Transbronchial biopsy in the presence of profound elevation of the international normalized ratio. Chest 1999;115:1667-71

Transbronchial biopsies on 18 pigs who were treated with escalating doses of warfarin

Goal = to determine the INR level at which excess bleeding would occur following the procedure

Excess bleeding - > 100 mL in > 50% of animals They had planned to apply different post-procedure

therapies to staunch the bleeding But…the warfarin treated animals never developed

bleeding despite having INR levels >10 11 of 18 pigs had INR>7 at the time of the biopsy

Herth FJ, Becker HD, Ernst A. Aspirin does not increase bleeding complications after transbronchial biopsy. Chest. 2002;122:1461-4

Effect of aspirin on the extent of bleeding at the time of bronchoscopy and transbronchial lung biopsy

1217 patients - 285 were taking aspirin at the time of the procedure

57 patients (4.7 %) had bleeding complications

Incidence of minor (1.8 vs 2.9%), moderate (1.1 vs 1.4%), and severe (0.8 vs 0.9%) bleeding was not statistically different among those taking aspirin and those who did not

Plavix is not Aspirin Ernst A, Eberhardt R, Wahidi M, et al. Effect of routine clopidogrel use on bleeding complications after transbronchial biopsy in humans. Chest. 2006;129:734-7

Prospective observational study Patients undergoing transbronchial

biopsy were not required to cease aspirin or clopidogrel before the procedure

The post-procedure severe bleeding rate was 28% for clopidogrel alone, 50% for combined use, and 2 of 574 (0.3%) of the control group (of whom 111 were on aspirin alone)

Bottom line

There is no strong evidence to support component therapy to protect patients from bleeding complications Although, I feel sympathy for a respirologists

nervousness for doing this procedure given the consequences

Don’t worry about ASA use For transbronchial biopsy, platelet count >25-

30 and INR <2 is reasonable compromise Stop oral P2Y12-R antagonists

Renal biopsy

A 64 year old woman with acute onset of combined hepatic and renal dysfunction is booked for a renal biopsy

INR is 1.9 Platelet count is 142 Creatinine in 345 Hemoglobin is 103 Would you give her FFP?

Manno C, et al. Predictors of bleeding complications in percutaneous ultrasound-guided renal biopsy. Kidney Int. 2004;66:1570-7

471 consecutive percutaneous renal biopsies Hematoma seen in 33.3% of patients (clinically

silent in 90%) 4 major hematomas observed (0.8%) When patients with and without bleeding

complications were compared - no difference in the baseline platelet count or PT

The PTT was higher in the patients with these clinically silent hematomas, 102.7% compared to 100.1% (p=0.01), making this finding of questionable importance

Waldo B, et al. The value of post-biopsy ultrasound in predicting complications after percutaneous renal biopsy of native kidneys. Nephrol Dial Transplant. 2009;24:2433-9.

162 patients undergoing percutaneous renal biopsy

No difference in the PT, aPTT, serum creatinine or hemoglobin at the time of biopsy between patients with (n=26) and without a complication (n=136)

Bottom line

No published evidence to support correction of the INR/PTT or platelet count before this procedure

Lumbar puncture

19 year old female with ALL planned for a diagnostic and therapeutic LP (IT MTX)

Her platelet count is 38 Her INR is 1.3, PTT 34 Would you transfuse anything prior to

the procedure?

Complications are really rare Risk of spinal hematoma following epidural

anesthesia - 1 in 280,000 procedures Stafford-Smith M. Can J of Anaesthesiology.

1996; 43:R129-141. The risk of spinal hematoma following

lumbar puncture is thought to be lower than that for epidural anesthesia, although reliable estimates are unavailable van Veen JJ, et al. Brit J of Haem 2010;148:15-

25

Van Venn JJ, Vora AJ, and Welsh JC. Lumbar puncture in thrombocytopenic patients. Brit J of Haematology 2004; 127: 233-4

Lumbar punctures in 226 children with leukemia

Baseline platelet counts were: < 10 in 19 patients 10-20 in 49 20-50 in 89 patients

No bleeding complications in any patient

Ruell J et al. Platelet count has no influence on traumatic and bloody lumbar puncture in children undergoing intrathecal chemotherapy. Br J Haematol. 2007;136:347-8

Ruell et al reported no bleeding complications after 738 lumbar punctures in 54 children with leukemia with platelet counts between 30 and >90

In addition, there was no correlation between the platelet count and the incidence of ‘bloody taps’

Howard SC, et al. Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. JAMA. 2000;284:2222-4. Howard SC, et al. Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia. JAMA. 2002;288:2001-7.

5,000 lumbar punctures in 958 consecutive children with leukemia 170 done in patients with counts between 10-20 742 done in patients with counts between 20–50 858 done in patients with counts between 50–

100 Platelet transfusions were not given prior to the

LP No patient developed spinal hematoma or a

clinical bleeding complication

Bottom line

There is no evidence that patients with platelet counts between 10-100 have a higher risk of complications than patients with higher platelet counts

What about regional anesthesia? No complications in 170 patients undergoing

regional anesthesia with counts between 50-100 Frenk V, Camann W and Shankar KB. Regional anesthesia in parturients with low

platelet counts. Can JAnaesth. 2005;52,114.

No complications in 65 patients of 10,369 births undergoing regional anesthesia with counts <150 (only 9 patients had counts<100) Bernstein K, Baer A, Pollack M, et al. Retrospective audit of outcome of regional

anesthesia for delivery in women with thrombocytopenia. J Perin Med. 2008;36,120–3.

No complications in 25 patients of 10,203 births undergoing regional anesthesia with platelet counts <100 Deruddre S, Peyrouset O and Benhamou D. [Anesthetic management of 52 deliveries

in parturients with idiopathic thrombocytopenic purpura]. J Gynecol Obstet Biol Reprod (Paris). 2007;36,384–8.

van Veen JJ, et al. The risk of spinal haematoma following neuraxial anesthesia or lumbar puncture in thrombocytopenic individuals. Brit J of Haematol. 2010;148:15-25

In a superb review of the risks of spinal hematoma following regional anesthesia, the authors conclude that there is sufficient literature to conclude that a platelet count >80 is sufficient for an epidural or spinal anesthesia

They also state that it is likely that it is safe to perform this procedure at lower platelet counts but at this time there is insufficient literature to recommend a lower level

Summary Bleeding complications at the time of a

procedure are exceptionally rare Mildly abnormal test results do not imply

clinically abnormal clotting (coagulopathy) Platelet reserve is likely MORE important

than deficits in coagulation factors It is time to switch to a ‘therapeutic’ mode

(not ‘prophylactic’) – only treat bleeding when it happens If you are very conservative and nervous

clinician PLT 25 and INR 2

Documents

Irrational Exuberance: Component Therapy Before Bedside Procedures Jeannie Callum, BA, MD, FRCPC, CTBS Sunnybrook Health Sciences Centre Associate Professor,