Disclosure: Complex Case: Complications After Cardiac Surgery - Glucose, Sedation and Thrombocytopenia

Complex Case:
Complications After Cardiac Surgery – Disclosure
Glucose, Sedation and • All planners, presenters, and reviewers of this
Thrombocytopenia session report no financial relationships
relevant to this activity.
Paul M. Szumita, Pharm.D., BCCCP, BCPS, FASHP, FCCM
Clinical Pharmacy Practice Manager
Brigham and Women’s Hospital
Boston, Massachusetts
Learning Objectives Session Outline
• Develop appropriate treatment and monitoring plans • Glucose management in the critical care
for a complex post‐cardiac surgery patient to include
pain, agitation and delirium, glucose management, and setting with focus ADA/AACE/SCCM glucose
heparin‐induced thrombocytopenia. guidelines
• Examine the impact of critical illness on pre‐existing • Pain, agitation and delirium management with
conditions (e.g., endocrine disorders, pain).
a focus on the SCCM 2018 PADIS guidelines
• Summarize quality assurance and process
improvement methods relevant to critical care. • Heparin‐induced thrombocytopenia with a
• Assess the relationship between institutional guideline focus on the 2012 Chest guidelines and 2018
development and evidence‐based critical care American Society of Hematology
literature.
Question 1: JM is a 70‐year‐old woman admitted to Causes of Hospital‐related
cardiac surgery ICU directly from the operating room, Hyperglycemia
still intubated following non‐emergent coronary artery
bypass graft (CABG) surgery. • Known diabetes
On IV propofol 33 mcg/kg/min PMH: CAD, DM Type 2, morbidly obese • Undiagnosed diabetes (unrecognized)
5 days status‐post non‐STEMI Received glucose in the bypass fluid
Intra‐op glucose = 250 mg/dL, therefore IV insulin infusion was initiated. • Hospital‐related hyperglycemia
– Stress hyperglycemia (transient physiologic
What are JM’s risk factors for hyperglycemia in the ICU?
response to the stress of
A. Preexisting diabetes
acute illness or injury)
B. Stress of surgery
C. Preexisting diabetes and stress of surgery – Iatrogenic (corticosteroids, catecholamines,
D. Preexisting diabetes, stress of surgery, and iatrogenic causes (fluids parenteral and enteral nutrition, reduced exercise)
and drugs)
Clement S et al. Diabetes Care. 2004; 27(2):553‐91.
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©2019 American Society of Health-System Pharmacists, Inc. All rights reserved. 1
Hyperglycemia is Prevalent at Hospital Diagnosis and Recognition of Hyperglycemia
Admission and Diabetes in the Hospital
Admission
38% of patients at admission have hyperglycemia Assess all patients for a history of diabetes
Obtain laboratory BG testing on admission
‐Of those patients, nearly one‐third have no history of diabetes
No history of diabetes No history of diabetes but History of

BG <140 mg/dL BG >140 mg/dL diabetes
31% History of diabetes
No history of diabetes Initiate POC BG monitoring Start POC BG monitoring BG monitoring
69% according to clinical status x 24‐48 hours
Check A1c level
A1C level ≥6.5%
Single‐center, retrospective chart review of 1886 patients hospitalized over 15 weeks in a
community teaching hospital. Hyperglycemia defined as BG ≥ 126 mg/dL on admission or while POC BG = point‐of‐care blood glucose testing.
fasting, or random BG ≥ 200 mg/dL on ≥ 2 occasions.
Umpierrez GE et al. J Clin Endocrinol Metab. 2002; 87(3):978‐82. Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38.
A1C Testing Insulin is the Most Appropriate
Consider obtaining an A1C level in patients with: Agent for Critically Ill Patients
• diabetes admitted to the hospital if the result of testing in the previous 2‐3
months is not immediately available
Most potent glucose‐
• hyperglycemia in the hospital (no previous A1C in previous 3 months) lowering agent
Rapidly effective
Examples of when results may be inaccurate
Recent blood transfusion Critically Ill Patients IV Insulin Easily titratable
Hemoglobinopathy (up or down)
Certain anemias
Splenectomy No real
contraindications
End‐stage renal disease (especially if on erythropoietin‐based therapy)
Pregnancy
Moghissi ES et al; American Association of Clinical Endocrinologists; American Diabetes
Schnipper JL et al. Endocr Pract. 2010; 16(2):209‐18. Association. Endocr Pract. 2009; 15(4):353‐69.
American Diabetes Association. Diabetes care in the hospital: standards of medical care in diabetes—2019. Diabetes Care. American Diabetes Association. Standards of medical care in diabetes‐2017. Diabetes Care.
2019; 42(Suppl 1):S173‐S181. 2017;40(Suppl. 1):S120 ‐ S127.
Question 1: JM is a 70‐year‐old woman admitted to cardiac Question 2: According to the 2012 guidelines for
surgery ICU directly from the operating room, still intubated the use of an insulin infusion for the management
following non‐emergent coronary artery bypass graft (CABG)
of hyperglycemia in critically ill patients (American
surgery.
College of Critical Care Medicine‐ ACCM): what is
On IV propofol 33 mcg/kg/min PMH: CAD, DM Type 2, morbidly obese the suggested glucose that should trigger initiation
5 days status‐post non‐STEMI Received glucose in the bypass fluid
Intra‐op glucose = 250 mg/dL, therefore IV insulin infusion was initiated. of insulin therapy?
What are JM’s risk factors for hyperglycemia in the ICU? A. ≥200 mg/dL
A. Preexisting diabetes
B. Stress of surgery
B. ≥180 mg/dL
C. Preexisting diabetes and stress of surgery C. ≥ 140 mg/dL
D. Preexisting diabetes, stress of surgery, and iatrogenic causes (fluids and
drugs)
D. ≥ 150 mg/dL
___________________________________________________________________________________________________
Guidelines from Professional Guidelines for the use of an insulin infusion for
Organizations on ICU Blood Glucose (BG) the management of hyperglycemia in critically
Goal ill patients (American College of Critical Care
BG Hypoglycemia Updated since
Medicine‐ ACCM)
BG Treatment BG Target
Year Definition NICE‐
Threshold (mg/dL) (mg/dL)
(mg/dL) SUGAR, 2009 • Suggest that a BG ≥ 150 mg/dL should trigger
2009 180 140‐180 <70 Yes
initiation of insulin therapy
2017 180 140‐180 (most) <70 Yes
2009 180 <180 <40 Yes • Titrated to keep BG < 150 mg/dL for most adult ICU
<150 (Trauma) patients
2012 150 <180 <70 Yes
(Stroke+) • Maintain BG values <180 mg/dL
2017 180 ≤180 Not stated Yes
2008 180 90‐140 Not stated No • Using a protocol that achieves a low rate of
hypoglycemia (BG ≤ 70 mg/dL)
American Diabetes Association. Diabetes Care. 2017;40(Suppl. 1):S120 ‐ S127 Qaseem A et al. Ann Intern Med. 2011; 154:260-7.
Rhodes A, et al. Crit Care Med. 2017; Epub ahead of print Jan 17:1-67. Jacobi J. Crit Care Med. 2012; 40:3251-76.
Kavanagh BP et al. N Engl J Med. 2010; 363:2540-6. Finfer S et al. N Engl J Med. 2009; 360:1283-97. Jacobi J et al. Crit Care Med. 2012; 40:3251‐76.
Guidelines for the use of an insulin infusion for the
Guidelines for the use of an insulin infusion for management of hyperglycemia in critically ill patients
the management of hyperglycemia in critically (ACCM)
ill patients (ACCM) • Trauma ICU patients ‐ suggest that BG ≥ 150 mg/dL should trigger
initiation of insulin therapy
• Suggest BG ≤ 70 mg/dL is associated with an increase – Titrated to keep BG < 150 mg/dL
in mortality – Maintain BG values absolutely < 180 mg/dL
• Even brief severe hypoglycemia (BG ≤ 40 mg/dL) is – Using a protocol that achieves a low rate of hypoglycemia (BG ≤
70 mg/dL)
independently associated with a greater risk of
– Achieve lower rates of infection and shorter ICU stays in trauma
mortality patient
• Risk increases with prolonged or frequent episodes • Ischemic stroke, intraparenchymal hemorrhage, aneurysmal
subarachnoid hemorrhage, or traumatic brain injury patients ‐
• Test and adjust BG every 1‐2 hours ‐ this has not been Suggest that a BG ≥ 150 mg/dL triggers initiation of insulin therapy
studied prospectively – Titrated to achieve BG values absolutely < 180 mg/dL
– Minimal BG excursions <100 mg/dL, to minimize the adverse
effects of hypoglycemia
Jacobi J et al. Crit Care Med. 2012; 40:3251‐76. Jacobi J et al. Crit Care Med. 2012; 40:3251‐76.
Guidelines for the use of an insulin infusion for the Surviving Sepsis Campaign
management of hyperglycemia in critically ill
• A protocolized approach to BG management in ICU patients with severe sepsis
patients (ACCM)
– Commencing insulin dosing when 2 consecutive BG levels are >180 mg/dL
– Should target an upper BG ≤180 mg/dL rather than an upper target BG
• We suggest continuous insulin infusion (1 unit/mL) ≤110 mg/dL (strong recommendation, high quality of evidence)
therapy should be initiated after priming new tubing • BG values should be monitored every 1‐2 hr until glucose values and insulin
with a 20‐mL waste volume infusion rates are stable and then every 4 hr thereafter (Best Practice
Statement)
• Subcutaneous (SC) insulin may be acceptable in the • Glucose levels obtained with point‐of‐care testing of capillary blood should be
ICU if BG goals are maintained interpreted with caution, as such measurements may not accurately estimate
arterial blood or plasma glucose values (Best Practice Statement)
• Use arterial blood rather than capillary blood for point‐of‐care testing using
glucose meters if patients have arterial catheters (weak recommendation, low
quality of evidence)
Jacobi J et al. Crit Care Med. 2012; 40:3251-76. Rhodes A, et al. Crit Care Med. 2017 Mar;45(3):486‐552.
___________________________________________________________________________________________________
Surviving Sepsis: Question 2: According to the 2012 guidelines for the
Guidelines Differences use of an insulin infusion for the management of
hyperglycemia in critically ill patients (American
• Initiate at 180 mg/dL, but no lower threshold College of Critical Care Medicine‐ ACCM): what is the
for glycemic control except hypoglycemia suggested glucose that should trigger initiation of
insulin therapy?
• No evidence for 140‐180 mg/dL range versus
110‐140 mg/dL range, except for hypo A. ≥200 mg/dL
B. ≥180 mg/dL
C. ≥ 140 mg/dL
Although all evidence taken into account, D. ≥ 150 mg/dL
NICE‐SUGAR is the main trial with influence
Rhodes A, et al. Crit Care Med. 2017 Mar;45(3):486‐552.
Association Between Mean Blood Glucose
Question 3: Which statement is true regarding and In‐Hospital Mortality
glucose management in the ICU? 0.8 No diabetes
Mortality rate
All patients
0.6 Diabetes
A. High glucose variability is associated with decreased
mortality. 0.4 Unadjusted association
B. Patients with a preexisting diagnosis of diabetes may benefit 0.2
from lower glucose goals compared to patients without 0
diabetes. 20
Odds ratio (OR)
C. Patients without a preexisting diagnosis of diabetes may 15
Multivariable‐adjusted
benefit from lower glucose goals compared to patients with 10 association
(Reference: Mean BG 100 to
diabetes. 5 <110)
D. IV insulin protocols should not incorporate the “rate of 1
change” in blood glucose and should adjust based on the
absolute value of the current glucose.
Mean Blood Glucose (mg/dL)
Kosiborod M et al. Circulation. 2008;117:1018‐1027.
Patients With Diabetes vs. Diabetes vs. No Diabetes
Patients Without Diabetes Patients with Diabetes
0.16
Without Diabetes With Diabetes 0.14 80‐110 mg/dL
Mortality Probability
50 50
0.12
Percentage Mortality
Percentage Mortality
0.10
25 25
0.08
0.06 90‐140 mg/dL
0.04
0 0
0.02
80‐110 110‐140 140‐180 >180 80‐110 110‐140 140‐180 >180
0
Mean BG (mg/dL) Mean BG (mg/dL) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days Post ICU Admission
Krinsley et al. Crit Care. 2013; 17:R37. Lanspa MJ et al. Chest. 2013; 143:1226‐34.
___________________________________________________________________________________________________
Diabetes vs. No Diabetes Glycemic Variability
Patients Without Diabetes p=0.01
0.16 40
0.14 90‐140 mg/dL 35 p=0.0001
Hospital Mortality (%)
p<0.0001 p<0.0001
Mortality Probability
0.12 30
Q1
0.10 25 Q2
0.08 20 Q3
80‐110 mg/dL Q4
0.06 15
0.04 10
0.02 5
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 70‐99 100‐119 120‐139 140‐179 180+
Days Post ICU Admission Mean glucose levels during ICU stay (mg/dL)
Lanspa MJ et al. Chest. 2013; 143:1226‐34. Krinsley JS. Crit Care Med. 2008;36:3008‐13.
Question 3: Which statement is true regarding Successful IV Insulin Protocol
glucose management in the ICU? • IV insulin infusions should be administered using
validated written or computerized protocols that
A. High glucose variability is associated with decreased
allow for predefined adjustments in the insulin
mortality.
infusion rate based on glycemic fluctuations and
B. Patients with a preexisting diagnosis of diabetes may benefit
from lower glucose goals compared to patients without
insulin dose
diabetes. • Achieves and maintains BG successfully within a
C. Patients without a preexisting diagnosis of diabetes may prespecified target range
benefit from lower glucose goals compared to patients with • Includes a clear algorithm for making temporary
diabetes. corrective changes in the IV insulin rate as patient
D. IV insulin protocols should not incorporate the “rate of requirements change
change” in blood glucose and should adjust based on the Clement S et al. Diabetes Care. 2004; 27(2):553‐91.
absolute value of the current glucose. American Diabetes Association. Standards of medical care in diabetes‐2017.
Diabetes Care. 2017;40(Suppl. 1):S120 ‐ S127
Example IV Insulin Protocol
Successful IV Insulin Protocol Blood Glucose
Action
• Incorporates the “rate of change” in BG, not (mg/dL)
•Stop insulin; give 25 mL of 50% dextrose; recheck BG in 30 minutes
just the absolute values < 50
•When BG >75 mg/dL, restart with rate 50% of previous rate
• Incorporates the current IV insulin rate 50 ‐ 75
•Stop insulin; if previous BG >100 mg/dL, then give 25 mL of 50% dextrose;
recheck BG in 30 minutes
• Minimizes hypoglycemia; provides specific •When BG >75 mg/dL, restart with rate 50% of previous rate
•If <10 mg/dL lower than last test, decrease rate by 0.5 units/hr
directions for 76 ‐100 •If >10 mg/dL lower than last test, decrease rate by 50%
its treatment when it occurs •If ≥ last test result, maintain same rate
101 ‐ 150 • Same rate
• Provides specific guidelines for timing and 151 ‐ 200
• If 20 mg/dL lower than previous test, same rate
selection of doses for the transition to • If higher than previous test, increase by 0.5 units/hour
•If ≥30 mg/dL lower than last test, use same rate
subcutaneous insulin > 200 •If <30 mg/dL lower than last test (OR if higher than last test), increase rate
by 1 units/hr
American Diabetes Association. Standards of medical care in diabetes‐2017.
Diabetes Care. 2017;40(Suppl. 1):S120 ‐ S127 Furnary AP et al. Endocr Pract. 2004; 10(suppl 2):21‐33.
___________________________________________________________________________________________________
Multiplication Factor Concept Transition from IV to
Subcutaneous Insulin
CURRENT RATE
• Which patients on IV insulin will need a
X transition to scheduled subcutaneous insulin?
ADJUSTMENT FACTOR – Type 1 diabetes mellitus
(this factor based of rate of change in Bedside Blood Glucose over time) – Type 2 diabetes mellitus on insulin prior to
= admission
– New hyperglycemia requiring
NEW RATE ≥2 units/hour of insulin
Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38.
Transition From IV Insulin to General Principles: Transition from IV
Subcutaneous Insulin to Subcutaneous Insulin
• IV insulin should be transitioned to subcutaneous • Estimate total daily dose (TDD)
basal‐bolus insulin therapy • Calculate the average IV insulin rate (units/hr) over the past 6 hours
– When patient begins to eat and BG levels • Multiply average hourly rate by 24 to get 24 hour requirements
are stable • Multiply by 0.8 ish to get TDD
• Because of short half‐life of IV insulin,
subcutaneous basal insulin should be
administered at least 1‐2 hours prior to
discontinuing the drip ~50% TDD ~50% TDD
– If short‐acting insulin also administered, IV insulin may Basal Nutritional
be able to be stopped sooner, e.g., after 1 hour
Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38.
Rocchio MA, et al. Diabetes Metab Syndr Obes. 2013 Oct 11;6:389‐92.
Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38. Clement S et al. Diabetes Care. 2004; 27(2):553‐91.
Case Study Example‐Moving to Effective Inpatient Subcutaneous Insulin
Stepdown Unit Regimens Have Three Components
• Patient is stable; will be moved out of the ICU • Basal insulin
and will begin scheduled meals – Controls fasting and pre‐meal glucose
• The average dose of IV insulin was • Nutritional insulin
3 units/hour over the past 6 hours
• TDD (subcutaneous) is ~72 units – Controls glucose from nutritional sources, such as
discrete meals, tube feeding, or parenteral nutrition
– 80% of 40 ~ 58 units
(PN)
Basal insulin = 50% of TDD = ~29 units • Supplemental/Correction insulin
Nutritional = 50% of TDD = ~10 units per meal (x 3 – Used to cover unexpected hyperglycemia that was not
meals) controlled by scheduled basal and nutritional insulin
___________________________________________________________________________________________________
Starting Basal‐Nutritional from
Sliding‐scale Insulin (SSI)
Scratch
• Calculate starting total daily dose (TDD) • Definition
– 0.3 ‐ 0.4 units/kg/day (hypoglycemia risk factors) – Use of a mealtime insulin, typically regular insulin,
– 0.5 ‐ 0.7 units/kg/day (conservative standard) as the sole insulin for managing diabetes
• Adjust TDD up or down based on • Potential problems
– Past response to insulin – Poor control of hyperglycemia (does not address
– Presence of hyperglycemia‐inducing agents, stress basal insulin needs)
– This is very conservative and safe (adjust up as – Insulin “stacking”
needed) – Hypoglycemia
• Basal insulin = 40‐50% of TDD • Not preferred method of subcutaneous insulin
– Long‐acting insulin daily or BID or intermediate‐acting
insulin BID delivery
American Diabetes Association. Standards of medical care in diabetes‐2015. Diabetes Care. 2015; 38(suppl 1):S1‐90.
Browning LA, Dumo P. Am J Health Syst Pharm. 2004; 61(15):1611‐4.
Clement S et al. Diabetes Care. 2004; 27(2):553‐91. Hirsch IB. JAMA. 2009; 301(2):213‐4.
Question 4: You are a clinical pharmacist on ICU rounds, and your patient JM
Hypoglycemia and Mortality:
was converted from IV to subcutaneous insulin yesterday. She receives a
long‐acting insulin 15 units subcutaneous at bedtime, rapid‐acting insulin
Australian Database Analysis
subcutaneous 5 units before meals, and low‐dose supplemental Hypoglycemia Incidence Hospital Adjusted OR
subcutaneous insulin before meals. Her most recent fasting pre‐meal blood Mortality (%) (95% CI)*
glucose values are: breakfast 95 mg/dL, lunch 101 mg/dL, and dinner 78
mg/dL. Which of the following do you recommend based on these None 92.9% 15.7% 1.0
measurements?
< 73 mg/dL 6.2% 29.5% 1.5 (1.3-1.6)
A. Increase the low‐dose supplemental insulin to a medium dose < 40 mg/dL 0.9% 57.4% 2.6 (2.1-3.2)

*Covariate adjustment for age, sex, surgical status, primary diagnosis, comorbid illness, APACHE II, mechanical ventilation, acute kidney
B. Recommend discontinuing insulin regimen and restart home injury, and hospital site
metformin Similar trends were seen when patients were stratified by MICU, SICU, CT ICU, and Sepsis
C. Reassess the insulin regimen because of the two fasting blood
glucose levels < 100 mg/dL Database analysis of 24 Australian ICUs, 66,184 adult ICU admissions for >24 hours from
January 1, 2000, to December 31, 2005.
D. Modify the insulin regimen because of the two fasting blood
glucose <100 mg/dL
Bagshaw SM et al. Crit Care Med. 2009 Feb; 37(2):463‐70.
Levels of Hypoglycemia in
Current Recommendations for
Hospitalized Patients
Critically Ill Patients
• Level 1 hypoglycemia
– Glucose concentration less than 70 mg/dL but greater Hyperglycemia
than or equal to 54 mg/dL • BG level 140‐180 mg/dL
• Level 2 hypoglycemia • Intravenous insulin preferred
– Glucose concentration less than 54 mg/dL
—Threshold at which neuroglycopenic symptoms begin to occur
and requires immediate action to resolve the hypoglycemic Hypoglycemia
event
• Reassess the regimen if Blood Glucose level is <100 mg/dL
• Level 3 hypoglycemia • Modify the regimen if Blood Glucose level is <70 mg/dL
– A severe event characterized by altered mental and/or
physical functioning that requires assistance from
another person for recovery
Moghissi ES et al. American Association of Clinical Endocrinologists; American Diabetes Association. Endocr
American Diabetes Association. Diabetes care in the hospital: standards of medical care in diabetes—2019. Pract. 2009; 15(4):353‐69.
Diabetes Care. 2019 Jan; 42(Supplement 1): S173‐S181. Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38.
___________________________________________________________________________________________________
Essential Part of Any Insulin Use:
Scenarios Prompting Increased Monitoring
A Hypoglycemia Protocol and Possible Decreases in Insulin Dose
• Clear Definition of Hypoglycemia
– Glucose level (ADA) < 70 mg/dL
• Nursing Order to Treat Without Delay • Patient is switched to NPO status
– Stop insulin infusion (if patient is on one) • Reduction in food intake
– Oral glucose (if patient is able to take oral)
– IV dextrose or glucagon (if patient is unable to take oral) • Discontinuation of enteral feeding or PN
– Repeat blood glucose monitoring 15 min after treatment for
hypoglycemia and repeat treatment if BG not up to target • Discontinuation or reduction in IV dextrose
– Directions for when and how to restart insulin
• Documentation!
• Timing of premeal insulin if meal disrupted due to
• Look for the cause of hypoglycemia and determine if other medical procedures or patient transport
treatment changes are needed
• Reduction in corticosteroid administration
ACE/ADA Task Force on Inpatient Diabetes. Endocr Pract. 2006; 12:458‐68.
American Diabetes Association. Standards of medical care in diabetes‐2015. Diabetes Care. 2015; 38(suppl 1):S1‐90.
Management of Hyperglycemia in Hospitalized Patients in Non‐Critical Care Setting: An Endocrine Society Clinical Practice NPO = nothing by mouth
Guideline. J Clin Endocrinol Metab, 2012; 97:16‐38.
Current Recommendations for
Question 4: You are a clinical pharmacist on ICU rounds, and your patient JM
was converted from IV to subcutaneous insulin yesterday. She receives a long‐ ICU Patients
acting insulin 15 units subcutaneous at bedtime, rapid‐acting insulin
subcutaneous 5 units before meals, and low‐dose supplemental subcutaneous
• Critically ill patients in intensive care unit settings
insulin before meals. Her most recent fasting pre‐meal blood glucose values – BG level absolutely below 180 mg/dL and perhaps less
are: breakfast 95 mg/dL, lunch 101 mg/dL, and dinner 78 mg/dL. Which of than 150 mg/dL
the following do you recommend based on these measurements?
– BG greater than 150 should be a trigger to consider
treatment
A. Increase the low‐dose supplemental insulin to a medium dose
– Intravenous insulin preferred
B. Recommend discontinuing insulin regimen and restart home
metformin • Hypoglycemia
C. Reassess the insulin regimen because of the two fasting blood – Reassess the regimen if BG level is < 100 mg/dL
glucose levels < 100 mg/dL
D. Modify the insulin regimen because of the two fasting blood glucose – Modify the regimen if BG level is < 70 mg/dL
<100 mg/dL AACE and ADA Consensus Statement on Inpatient Statement on Inpatient Glycemic Control. Endocr Pract. 2009; 15:353‐69.
Jacobi J. Crit Care Med. 2012 Dec; 40(12):3251‐76.
Question 5: If the average time to target seems longer Quality Assessment/Improvement
than the published literature at your institution, what
first step should be taken to address this issue? • Plan‐do‐study‐act (PDSA)
• Objectives are to improve quality and to assess
whether an intervention leads to the improvement
A. Perform a quality assessment analysis to identify needs
– What are we trying to accomplish?
B. Convene a team to develop a guideline/protocol
—Baseline assessment is key
C. Assess potential barriers to change in clinical practices
– How will we know that a change is an improvement?
D. Assess sustainability of change in clinical practices
– What changes can we make that will result in
improvement?
Speroff T, O’Connor GT. Qual Manag Health Care. 2004; 13:17‐32.
___________________________________________________________________________________________________
Plan‐Do‐Study‐Act Role of the Pharmacist in Quality
• Step 1: Plan Improvement
– State objective of test
– Make predictions about what will happen and why Physical/local Active member of Political lobbying Protocol selection/
• Step 2: Do champions clinical team within institution development
– Carry out test on a small scale
– Document
Implementation
• Step 3: Study Bedside advocate of protocols
Education Formulary decisions
– Compare the data to your predictions
• Step 4: Act
– Determine what modifications should be made Safety initiatives
Quality assessment/
improvement leader
– Prepare a plan for the next test
Agency for Healthcare Research and Quality. Plan‐Do‐Study‐Act (PDSA) cycle.
https://innovations.ahrq.gov/qualitytools/plan‐do‐study‐act‐pdsa‐cycle (accessed 2019 Jan 3). Szumita PM. Pharmacy Times. 2007; (April):110‐22.
Case JM
Question 5: If the average time to target seems longer
than the published literature at your institution, what • 70‐year‐old female admitted to cardiac surgery
first step should be taken to address this issue? ICU directly from the operating room still
intubated following a non‐emergent coronary
A. Perform a quality assessment analysis to identify needs
artery bypass graft (CABG) surgery
– 5 days status‐post non‐STEMI
B. Convene a team to develop a guideline/protocol
• PMH: CAD, DM Type II, morbidly obese
C. Assess potential barriers to change in clinical practices
D. Assess sustainability of change in clinical practices
• Propofol 33 mcg/kg/min
• Critical‐Care Pain Observational Tool (CPOT) = 5
• RASS = +2
• CAM‐ICU = negative
SCCM/ACCM Guideline: Pain, Agitation,
SCCM/ACCM Guideline: Pain, Agitation,
Delirium, Immobility and Sleep Disturbances
(PADIS) in Adults ICU Patients Delirium, Immobility and Sleep Disturbances
High level focus of 2018 PADIS Guideline
(PADIS) in Adults ICU Patients
• Pain/agitation recommendations
• Multimodal (pharm and non‐pharm) pain management High level focus of 2018 PADIS Guideline
• Protocol driven/pain‐first approach • Immobility
• Procedural pain guidance
• Light sedation for most • Mobilization encouraged
• Dexmedetomidine and propofol preferred over benzodiazepine • Safety parameters for starting and stopping mobilization
• Delirium • Sleep Disturbances
• Non‐pharmacologic prophylaxis • Common issue
• No routine antipsychotics for the treatment of delirium
• Dexmedetomidine for agitated delirium if precluding extubation from • More data needed
mechanically vented patient
• ABCDEF bundle
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the
management of pain, agitation/sedation, delirium, immobility, and sleep management of pain, agitation/sedation, delirium, immobility, and sleep
disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
___________________________________________________________________________________________________
Question 6: Your institution recently implemented a pain‐
analgesia‐delirium‐immobility‐sleep disruption (PADIS)
PADIS via ABCDEF
guideline based on the most recent Society of Critical Care
Medicine (SCCM) guidelines. What would be the most
• Goal to increase the following:
– Liberation form ventilator
appropriate quality assessment analysis?
– Early ICU and hospital discharge
A. Before and after analysis of compliance with guidelines for assessment – Return to normal brain function
of PADIS, medication utilization rates, and duration of mechanical – Independent functional status
ventilation
– Survival
B. A propensity matched before and after analysis of compliance with
guidelines for assessment of PADIS, medication utilization rates, and
• Awakening and Breathing trial coordination
duration of mechanical ventilation • Choice of sedative and analgesics
C. Before and after analysis of compliance with guidelines for assessment • Daily delirium monitoring
of PADIS, medication utilization rates, and ICU mortality
• Early mobility exercise
D. A propensity matched before and after analysis of guidelines for
compliance with guidelines for assessment of PADIS, medication
• Family involvement
utilization rates, and ICU mortality
Morandi A, et al. Current Opinion in Critical Care 2011, 17:43–49
Prospective Pre‐Post ABCDE Bundle Question 6: Your institution recently implemented a pain‐
Implementation analgesia‐delirium guideline based on the most recent
Society of Critical Care Medicine (SCCM) guidelines. What
35. post pre Important patient metrics/outcomes
29 would be the most appropriate quality assessment
30. p = 0.04 Protocol Routine P value
analysis?
25. 24 p = 0.04 Delirium 73 (48.7) 91 (62.3) 0.02
Median Time (days)
21 A. Before and after analysis of compliance with guidelines for
anytime; n(%)
20. 17 assessment of PADIS, medication utilization rates, and duration of
ICU days 33.3(18.8‐ 50(30‐ 0.003
15. delirious; 50) 64.3) mechanical ventilation
median(IQR)
10. B. A propensity matched before and after analysis of compliance with
Out of bed in 99 (66.0) 70(48) 0.002
ICU; n(%) guidelines for assessment of PADIS, medication utilization rates, and
5. duration of mechanical ventilation
Unplanned 7 (7.5) 7(7.5) 0.98
0. extubation;
n(%)
C. Before and after analysis of compliance with guidelines for
vent-free 28-day assessment of PADIS, medication utilization rates, and ICU mortality
Re‐intubation; 11 (11.7) 16 (17.2) 0.28
mortality n(%) D. A propensity matched before and after analysis of guidelines for
Single center, prospective, pre‐post ABCDE bundle implementation study at Nebraska Medical Center. 296 ICU
compliance with guidelines for assessment of PADIS, medication
patients (medical/surgical) , pre (n = 146) Feb‐Oct 2011 and post (n = 150) Oct 2011 to April 2012 . utilization rates, and ICU mortality
Balas MC, et al. Crit Care Med. 2014 May;42(5):1024‐36.
Question 7: Which of the following would be the best option
2018 SCCM PADIS Guideline Pain
for JM based on her assessments {Critical Care Pain Recommendations
Observational Tool (CPOT) = 5, RASS = +2, CAM‐ICU = • Management of pain for adult ICU patients
negative} and the current infusion rate for IV propofol of 33 should be guided by routine pain assessment and
mcg/kg/min? pain should be treated before a sedative agent is
considered
A. Change propofol to dexmedetomidine for goal RASS 0
– Good practice statement
B. Give quetiapine 50 mg PNGT Q12H ‐ goal RASS 0 to ‐1 and
• Suggest using an assessment‐driven, protocol‐
CAM‐ICU negative
based (analgesia/analgosedation), stepwise
C. Fentanyl bolus 12.5 ‐ 37.5 mcg Q20min PRN CPOT > 2 approach for pain and sedation management in
D. Increase propofol infusion goal RASS 0 to ‐1 critically ill adults
– conditional recommendation, moderate quality of
evidence
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation,
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
___________________________________________________________________________________________________
Nursing‐Implemented Sedation Protocol:
Impact of Pain Assessment on Outcomes in the ICU Barnes Jewish Hospital Pilot Study, U.S.
25. Significant patient
• A higher degree of pain assessment with a validated tool via Protocol n = 162 characteristics/metrics/outcomes
Routine n = 159 20. Protocol Routine P value
protocol or education is associated with:
18.8
Median Time (days)

– Improved pain scores p < 0.001 CIVS† 66 (40) 66 (42) 0.9
14.
– Reductions in length of ventilation and ICU/hospital stay p = 0.13
Duration CIVS, 3.5 ± 4 5.6 ± 6.4 0.003
12.5 hr*
– Reduced mortality p = 0.003
Bolus† 118 (72) 127 (80) 0.14
– ↑↓ prescrip on and consump on of opioids 7.5
6.3 4.8 5.7 Reintubated† 14 (8.6) 21 (13) 0.2
– Reduced consumption of sedatives
– Reduced need for bolus analgesics in non‐communicative 2.3 Trached† 10 (6.2) 21 (13.2) 0.04
*Data presented as median †Data presented as n (%)
– Increased use of nonopioid analgesics 0. CIVS; Continuous intravenous infusion sedation
Duration of MV ICU LOS Hospital LOS
– No effect on opioid related adverse drug events (ORADE)
Single center, prospective, trial of 332 consecutive ICU patients requiring mechanical ventilation randomized to
protocolized sedation (n = 162) or routine care (n = 159) at Barnes Jewish Hospital from 8/97 to 7/98. Protocol
used goal oriented sedation to target Ramsey with bolus requirements before initiation of continuous infusion
Payen JF et al. Anesthesiology. 2009;111:1308‐1316 Gélinas C, et al. Int J Nurs Stud. 2011 Dec;48(12):1495‐504. and up titration of opioids and benzodiazepines.
Payen JF, et al. Anesthesiology. 2007;106:687‐695. Erdek M, et al.. Int J Qual Health Care. 2004 Feb;16(1):59‐64.
Chanques G, et al. Crit Care Med. 2006;34(6):1691–9. van Gulik L, et al. Eur J Anaesthesiol. 2010 Oct;27(10):900‐5. Brook AD et al. Crit Care Med. 1999; 27(12):2609‐15.
No Sedation vs. Propofol/Midazolam
Systematic Implementation of Pain and Sedation
Infusion with Daily Sedation Interruption (DSI)
tools: Montpellier University Hospital, France Significant patient characteristics/metrics/outcomes
Significant patient
characteristics/metrics/outcomes 60. No Sedation = 55 58. No Sedation Sedation + P value
80 Post implemenation n = 130
Pre Post P value DSI n = 58 DSI
63 p = 0.003
Incidence of pain or
p < 0.01 Propofol/hr, 0 (0‐0.5) 0.77 <0.001

45.
Median Time (days)
60 Mechanical 120 65 0.01 mg/kg* (0.1‐1.6)

agitation (%)
Ventilation, p = 0.03
hrs*
34 Midaz/hr, 0 (0‐0) 0.003 <0.001
42 p < 0.01 p = 0.02 mg/kg* (0‐0.02)
40 Duration CIVS, 84 48 0.03 30.
29 hrs* 22.8 MSO4/hr, 0.005 0.0045 0.39
18 mg/kg* (0.001‐0.01) (0.002‐0.006)
Duration CIVI 96 60 0.02
20 Opioid, hrs* 15. 13 Si er use† 11 (20) 3 (5) 0.02
12
Nosocomial 17 (17) 11 (8) <0.05 6.9 Ventilator ‐ 6 (11) 7 (12) 0.85
infec on† Associated
0 *Data presented as median hr; †Data presented as n (%)
0. Pneumonia †
Pain Agitation CIVS; Continuous intravenous infusion sedation
Vent Free ICU LOSHospital LOS *Data presented as median (IQR)
†Data presented as n (%)
Single center, prospective, two‐phase, controlled study of 230 ICU patients requiring > 24hr stay before (n = 100) and Single center, prospective, open label trial of 140 ICU patients requiring mechanical ventilation randomized to a protocol
after (n = 130) implementation of a pain and sedation at Montpellier University Hospital in France. Education and of the institutions standard of “no sedation” (n = 70) or propofol/midazolam infusion with daily sedation interruption (n =
encouragement of use of pain scale and sedation assessment tools. 70) at Odense University Hospital, Denmark. 27 patients were excluded from the statistical analysis because mechanical
ventilation was stopped within 48 hrs.
Chanques G et al. Crit Care Med. 2006; 34(6):1691‐9. Strøm T et al. Lancet. 2010 Feb 6; 375(9713):475‐80.
Impact of Pain‐Sedation‐Delirium Protocol 2018 SCCM PADIS Guideline Pain
on Subsyndromal Delirium Recommendations
60. Significant patient
Protocol n = 561 55. characteristics/metrics/outcomes • Self assessment (ungraded recommendation)
Protocol PRE P value
45. p < 0.001 – Self‐report of pain is the standard for pain assessment in patients who
Mean Time (days)
Delirium† (34.2) (34.7) 0.9 can communicate reliably

27.
Subsyndromal (24.6) (33) 0.009 – 0‐10 NRS administered either verbally or visually is a valid and feasible
30. Delirium†
pain scale
Lorazepam 2.75 ± 5.79 ± 0.02
15.
p = 0.01 p = 0.009 equivalents,
mg*
7.94 31.78 • Behavioral assessment tools (ungraded recommendation)
5.9 7.5 5.36.3 MSO4 <0.001 – Among critically ill adults unable to self‐report pain and in whom
22.3 ± 103.5 ±
equivalents, 40.1 239.2 behaviors are observable:
0. mg*
— Behavioral Pain Scale in intubated (BPS) and non‐intubated (BPS‐NI) patients
Duration of MV
ICU LOSHospital LOS *Data presented as mean †Data presented as n (%)
Subsyndromal delirium; max ICDSC 1‐2 in ICU — Critical‐Care Pain Observation Tool (CPOT)
Single center, observational trial of 1,133 adult ICU patients requiring > 24hr of ICU care before (PRE) (n = 572) and
after (n = 561) implementation of a protocol for pain, sedation, and delirium management at Hospital Maisonneuve‐
Rosemont from 8/03 to 11/05. Protocol used goal oriented sedation to target RASS and numeric rating scale (NRS).
Skrobik Y et al. Anesth Analg. 2010 Aug; 111(2):451‐63. delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Pain Pain Assessment Scales: Unable to
Recommendations Communicate
• Behavioral pain assessment tools
• Physiologic measures (ungraded recommendation) – Facial expression, movement, ventilator interaction
– Vital signs (i.e., heart rate, blood pressure, respiratory rate, oxygen
saturation, end‐tidal CO2) are not valid indicators for pain in critically
• Consensus guidelines recommended scales
ill adults and should only be used as cues to initiate further – Clinical Pain Observation Tool (CPOT) (Range 0‐8)
assessment using appropriate and validated methods such as the — Score > 2 suggest significant pain
patient’s self‐report of pain (whenever possible) or a behavioral scale – Behavioral Pain Scale (BPS) (Range 3‐12)
(i.e., BPS, BPS‐NI, CPOT). — Score > 5 suggest significant pain
• Proxy report(ungraded recommendation) • Limitations:
– When appropriate, and when the patient is unable to self‐report, – Validation still needed:
family can be involved in their loved one’s pain assessment process — Diverse languages/cultures
— Traumatic brain injury
– Cannot use in patients with paralysis Gélinas C et al. Am J Crit Care. 2006; 15:420‐27.
Arbour C et al. Pain Manag Nurs. 2014 Jun; 15(2):506‐18.
Herr K et al. Pain Manag Nurs. 2011 Dec; 12(4):230‐50.
Arbour C et al. Crit Care Nurse. 2011 Dec; 31(6):66‐8.
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, delirium,
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
2018 SCCM PADIS Guideline Pain 2018 SCCM PADIS Guideline Pain
Recommendations Recommendations
• Pain at rest is influenced by both psychological (e.g., • Suggest using low‐dose ketamine (1 ‐2 mcg/kg/min) as an
anxiety, depression) and demographic (e.g., young age, adjunct to opioid therapy when seeking to reduce opioid
one or more comorbidities, past history of surgery) consumption in post‐surgical adults admitted to the ICU
– conditional recommendation, very low quality of evidence
factors.
• Suggest not routinely using IV lidocaine as an adjunct to
– ungraded opioid therapy for pain management in critically ill adults
• Suggest using acetaminophen as an adjunct to an – conditional recommendation, low quality of evidence
opioid to decrease pain intensity and opioid • Suggest not routinely using a COX‐1 selective NSAID as an
consumption for pain management in critically ill adjunct to opioid therapy for pain management in critically
adults ill adults
– conditional recommendation, low quality of evidence
– conditional recommendation, very low quality of evidence
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, delirium, Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, delirium,
immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
• Recommend using a neuropathic pain medication (e.g., • Suggest offering massage for pain
gabapentin, carbamazepine, and pregabalin) with
opioids for neuropathic pain management in critically management in critically ill adults
ill adults – conditional recommendation, low quality of
– strong recommendation, moderate quality of evidence evidence
• Suggest using a neuropathic pain medication (e.g., • Suggest offering music therapy to relieve both
gabapentin, carbamazepine, and pregabalin) with
opioids for pain management in ICU adults after non‐procedural and procedural pain in
cardiovascular surgery critically ill adults
– conditional recommendation, low quality of evidence – conditional recommendation, low quality of
evidence
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation,
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
___________________________________________________________________________________________________
• Pain during a procedure is influenced by pre‐procedural • When suggest using an opioid, at the lowest effective dose,
pain intensity, the type of procedure, underlying surgical or for procedural pain management in critically ill adults
trauma diagnoses, and demographic factors (younger age, – conditional recommendation, moderate level of evidence
female sex, and non‐white ethnicity). • Suggest using an NSAID administered intravenously, orally
– ungraded or rectally as an alternative to opioids for pain management
during discrete and infrequent procedures in critically ill
• Pain during a procedure is influenced by pre‐procedural adults
pain intensity, the type of procedure, underlying surgical or – conditional Recommendation, low quality of evidence
trauma diagnoses, and demographic factors (younger age, • Suggest not using an NSAID topical gel for procedural pain
female sex, and non‐white ethnicity). management in critically ill adults
– ungraded – conditional recommendation, low quality of evidence
• Suggest offering cold therapy for procedural pain • Suggest not using either local analgesia or nitrous
management in critically ill adults oxide for pain management during chest tube
– conditional recommendation, low quality of evidence removal in critically ill adults
• Suggest offering relaxation techniques for – conditional recommendation, low quality of evidence
procedural pain management in critically ill adults • Recommend not using inhaled volatile
– conditional recommendation, very low quality of anesthetics for procedural pain management in
evidence critically ill adults
– strong recommendation, very low quality of evidence
Question 8: JM currently is receiving IV norepinephrine 20 mcg/min,
Question 7: Which of the following would be the best vasopressin 0.04 units/min, epinephrine 5 mg/min, and propofol 75
option for JM based on her assessments (Critical Care mcg/kg/min, with fentanyl IV bolus doses prn CPOT >2.
Which of the following would be the best recommendation based on current
Pain Observational Tool (CPOT) = 5, RASS = +2, CAM‐ medication therapy, hemodynamics and vital signs?
ICU = negative) and the current infusion rate for IV MAP = 66 mmHg
HR = 91 bpm
propofol of 33 mcg/kg/min? CPOT 0, RASS ‐3, CAM‐ICU positive
A. Change propofol to dexmedetomidine for goal RASS 0
A. Replace propofol with a dexmedetomidine infusion titrated to achieve a
B. Give quetiapine 50 mg PNGT Q12H ‐ goal RASS 0 to ‐1 and goal RASS of 0 to ‐1 and negative CAM‐ICU
CAM‐ICU negative B. Replace propofol with a midazolam infusion titrated to achieve a goal RASS
C. Fentanyl bolus 12.5 ‐ 37.5 mcg Q20min PRN CPOT > 2 of 0 to ‐1 and negative CAM‐ICU
D. Increase propofol infusion goal RASS 0 to ‐1 C. Titrate down the propofol infusion to achieve a goal RASS of 0 to‐1 and
negative CAM‐ICU
D. Add quetiapine 50 mg NG every 12 hr to achieve a goal of negative CAM‐
ICU
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Agitation Light vs. Deep Sedation on Clinical Outcomes
and Mental Health after Critical Illness
Recommendations 25.
Light n = 65
• Suggest using light sedation (versus deep Deep n = 64 20 Significant patient
characteristics/metrics/outcomes
Median Time (days)
18.8
sedation) in critically ill, mechanically ventilated 16
Light Deep P value
adults 12.5
p =0.47
PTSD score 52 57 0.39
– conditional recommendation, low quality of evidence p = 0.02 p = 0.03
ICU
discharge*
• In critically ill intubated adults, daily sedative 6.3
3
5.5
4
5.5 PTSD score
4wks post
46 56 0.07
interruption (DSI) protocols and nursing‐ ICU*
0.
protocolized‐ (NP) targeted sedation can achieve
Duration of ICU LOS Hospital
and maintain a light level of sedation. MV LOS
*Data presented as mean
PTSD = Posttraumatic stress disorder
– ungraded Single center, prospective, open label trial of 137 ICU patients requiring mechanical ventilation
randomized to light (Ramsey 1‐2) or deep (Ramsey 3‐4) sedation at Geneva Hospital Switzerland.
Extensive exclusion criteria, removing high risk patients and those with baseline cognitive dysfunction.
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. Treggiari MM et al. Crit Care Med. 2009 Sep; 37(9):2527‐34.
2018 Light vs. Deep Sedation: Daily Interruption of Sedative Infusions in
Systematic Review and Meta‐Analysis Mechanical Ventilation Patients
Study/Subgroup Odds Ratio (95% CI) Mean Difference (95% CI) 18. Daily Interruption n = 68 16.9
van den Boogaard 2012 Control n = 60 p = 0.19
Shehabi 2012
Shehabi 2013 Australia pilot 13.3
Shehabi 2013 Malaysia 13.5
p = 0.02
Median Time (days)
Shehabi 2013 p = 0.004
Tanaka 2014 9.9
Samarin 2014 9.
Balzer 2015 Duration 7.3
Stephens 2017 Mortality 6.4
of MV
p < 0.001 4.9
p < 0.001
Total 4.5
0.01 0.1 1 10 100 ‐ Favors Light 0 Favors Deep

25
Favors Light Favors Deep 25
Sedation Sedation Sedation Sedation
0.
Mechanical Ventilation ICU LOS Hospital LOS
Stephens RJ, et al. Crit Care Med. 2018 Mar;46(3):471‐479. Kress et al. N Engl J Med. 2000 May 18; 342(20):1471‐7
Daily Interruption of Sedative Infusions Paired Sedation and Ventilator
in Mechanically Ventilated Patients Weaning Protocol: ABC Trial
Intervention group Control group P value DSI with SBT n = 167
25.
(n=68) (n= 60) SBT alone n = 168 p = 0.04
median (interquartile range) 19.2
20.
p = 0.02 p = 0.01
Mean Time (days)
Midazolam subgroup 37 29 14.7 14.9

15.
Total dose of midazolam (mg) 229.8 (59‐491) 425.5 (208‐824) 0.05 12.9
11.7
Total dose of morphine (mg) 205 (68‐393) 481 (239‐748) 0.009 p = 0.002
10. 9.1
Propofol subgroup 31 31
Total dose of propofol (mg) 15,150 (3983‐34,125) 17,588 (4769‐35,619) 0.54
5.
Total dose of morphine (mg) 352 (108‐632) 382 (148‐1053) 0.33 3.
2.
0.
% days patients were awake 85.5 9 <0.001 Coma Ventilator free days ICU LOS Hospital LOS
CNS diagnostic tests 6 16 0.02 Four center trial of 336 mechanically ventilated patients randomized to management with a daily sedation
interruption (DSI) followed by an spontaneous breathing trial (SBT) or with sedation per usual care plus a
Patients needing reintubation 12 18 0.17
daily SBT.
Kress et al. N Engl J Med. 2000 May 18; 342(20):1471‐7. Girard TD et al. Lancet. 2008 Jan 12; 371(9607):126‐34.
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Agitation Choice of Sedative: Non‐Cardiac
Recommendations Surgery ICUs
• General takeaway points from MENDS, SEDCOM, MIDEX, PRODEX studies:
• Suggest using propofol over a benzodiazepine for – Benzodiazepine sedation strategies may:
sedation in mechanically ventilated, post‐cardiac — Increase likelihood of coma
— Increase duration of mechanical ventilation
surgery patients — Increase percentage of patients with delirium at specific time points
– conditional recommendation, low quality of evidence – Benzodiazepine sedation strategies have not been shown to:
— Increase ICU length of stay
• Suggest using either propofol or — Increase overall incidence of delirium
dexmedetomidine over benzodiazepines for — Significantly change time spent in goal sedation range
– No significant differences between propofol and dexmedetomidine:
sedation in critically ill mechanically ventilated
— Time spent in goal sedation range
patients — Duration of mechanical ventilation
– Conditional recommendation, low quality of evidence — Hospital and ICU length of stay
Pandharipande PP, et al. JAMA. 2007;298:2644‐2653.
— Mortality
Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation, Riker RR, et al. JAMA. 2009 Feb 4;301(5):489‐99.
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. Jakob SM, et al. JAMA. 2012 Mar 21;307(11):1151‐60.
2018 SCCM PADIS Guideline Agitation 2018 SCCM PADIS Guideline Delirium
• BIS monitoring appears best suited for sedative • Modifiable risk factors (ungraded)
titration during deep sedation or neuromuscular – Benzodiazepine use
– Blood transfusion
blockade, though observational data suggest
• Non‐modifiable risk factors (ungraded)
potential benefit with lighter sedation as well. – Age, dementia, prior coma, pre‐ICU emergency surgery or
– ungraded trauma, increasing Acute Physiology and Chronic Health
Evaluation (APACHE) score and American Society of
• Sedation that is monitored with BIS compared to Anesthesiology (ASA) score
subjective scales may improve sedative titration • Delirium may be able to be predicted through
modeling (ungraded)
when a sedative scale cannot be used
• Critically ill adults should be regularly assess for
– ungraded delirium (good practice statement)
Pathophysiology of Delirium in Probability of Transitioning to Delirium in
Critically Ill Patients Mechanically Ventilated Patients
Subtype Mechanism Etiologies
Probability of transitioning to delirium
100 %
Toxic Metabolic Hypercarbia Respiratory Failure
Hypoxia Cardiopulmonary bypass
Encephalopathies Organ failure: Liver, renal, heart
Elevated Ammonia Overdose
Elevated BUN Toxin Ingestion
Hyperthermia Intoxification of Alcohols (ethanol ethylene
Electrolyte abnormalities glycol, methanol)
Toxin mediated Sepsis
Infection/Inflammation
Alteration of GABA and Glutamate Ethanol abuse
neurotransmitters Dopamine Excessive or inappropriate tapering of
benzodiazepines/ barbiturates/ opioids
60%
Norepinephrine
Serotonin Sleep deprivation and circadian rhythm
0 mg 10 mg 20 mg 30 mg 40 mg
NMDA alteration
Lorazepam Dose (mg)
Acetylcholine Pain
Most cases are Multifactorial!! = Treatment is Multi‐Modal!!
Bongard FS, Sue DY (Eds): Current Critical Care Diagnosis & Treatment. 2nd edition. 2002 Pandharipande P, et al. Anesthesiology. 2006 Jan;104(1):21‐6.
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Delirium
2018 SCCM PADIS Guideline Delirium
Recommendations
• Delirium is associated with (ungraded) Recommendations
– Cognitive impairment at 3 and 12 months
– Longer ICU length of stay • Level of arousal may influence delirium
• Delirium is NOT associated with (ungraded) (ungraded)
– Post‐traumatic stress disorder or post‐ICU distress • Rapidly reversible delirium is associated with
• Delirium is NOT consistently associated with (ungraded)
– ICU length of stay outcomes that are similar to patients who
– Discharge disposition to place other than home never experience delirium
– Depression – Ungraded
– Functionality dependence
– Mortality
Effect of Sedation Level on the Prevalence of Delirium Rapidly Reversible, Sedation‐Related Delirium
Delirium assessment: prior to (pt RASS ‐2/‐3) and 2 hours after SAT
Rapidly Reversible Delirium
No Delirium
Mixture
Persistent Delirium
Mortality
1.0
%
0.75
0.50
0.25
0.0
0 100 200 300 400
Time from enrollment (days)
Single center in Switzerland, prospective, double‐blind trial of 104 mixed medical/surgical ICU. 80 patients enrolled Single center, prospective, cohort of 102 intubated adult medical ICU patients at the University of
(467 patient days) and delirium assed via the ICDSC and CAM‐ICU during SAT. Chicago. CAM‐ICU assessed before and after SAT daily. Rapidly reversible delirium defined by CAM‐ICU
assessment abated within 2 hours of an SAT.
Haenggi M, et al. Intensive Care Med. 2013 Dec;39(12):2171‐9. Patel SB, et al. Am J Respir Crit Care Med 2014;189(6):658‐665.
Question 8: JM currently is receiving IV norepinephrine 20 mcg/min, 2018 SCCM PADIS Guideline Delirium
vasopressin 0.04 units/min, epinephrine 5 mg/min, and propofol 75
mcg/kg/min, with fentanyl IV bolus doses prn CPOT >2. Recommendations
Which of the following would be the best recommendation based on current
medication therapy, hemodynamics and vital signs? • Medications should not be used to prevent
MAP = 66 mmHg delirium
HR = 91 bpm
CPOT 0, RASS ‐3, CAM‐ICU positive – Haloperidol, atypical antipsychotic, dexmedetomidine,
statins, ketamine
A. Replace propofol with a dexmedetomidine infusion titrated to achieve a – Conditional recommendation, vey low to low quality
goal RASS of 0 to ‐1 and negative CAM‐ICU of evidence
B. Replace propofol with a midazolam infusion titrated to achieve a goal RASS • Medications should not be used to treat
of 0 to ‐1 and negative CAM‐ICU
subsyndromal delirium
C. Titrate down the propofol infusion to achieve a goal RASS of 0 to‐1 and
negative CAM‐ICU – Conditional recommendation, vey low to low quality
D. Add quetiapine 50 mg NG every 12 hr to achieve a goal of negative CAM‐ of evidence
ICU
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Delirium Quetiapine for the Treatment of Delirium
in Mixed ICU Patients
Recommendations
30 p = 0.32
• Not routinely using haloperidol, an atypical Quetiapine n = 18
Placebo n = 18
26
antipsychotic or HMG‐CoA reductase inhibitor to 25 24 Quetiapine Placebo P value
treat delirium 20
p = 0.28 SAS 5, hr* 6 36 0.02
Median Time (days)

– Conditional recommendation, low quality of evidence 16 16
SAS 2, hr* 0 0 0.54
Haloperidol 1.9 4.3 0.26
• Dexmedetomidine for treating agitated delirium 15
mg/day*
p = 0.006
for mechanically vented patients where agitation 10
Midazolam
equivalents
5.3 26 0.32
is precluding weaning/extubation 5
mg/day*
– Conditional recommendation, low quality of evidence 5
1.5
*Data presented in median
†Data presented as n (%)
• Not using bright light therapy to reduce delirium 0
Time in Delirium ICU LOS Hospital LOS
– Conditional recommendation, low quality of evidence Three Center, prospective, double‐blind trial of 36 mixed medical/surgical ICU patients with delirium
via ICDSC scale and tolerating tube feeds, randomized to quetiapine 50mg BID (titrated up to 200mg
BID) or placebo with open label IV haloperidol in both groups. 258 screened, 36 enrolled.
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. Devlin JW, et al. Crit Care Med. 2010 Feb;38(2):1‐9.
Olanzapine vs. Haloperidol for the Treatment HOPE ICU‐ Effect of Early Treatment with IV

of Delirium in SICU Patients Haloperidol on Duration of Delirium
Mean ICDSC Score Mean lorazepam dosage (MG) over time p=0.88
8
Haloperidol 1.6
Olanzapine
6 p=0.53
1.3
4 1
1 2 3 4 5 1 2 3 4 5
Day Day
Mean olanzapine dose: 4.5mg/day Mean haloperidol dose: 6.5mg/day Single center, randomized, double‐blind, placebo controlled trial in mixed medical/ surgical ICU. Early
Single center, prospective, open label trial of 73 mixed medical/surgical ICU patients with delirium via treatment of critically ill MV patients with IV haloperidol for duration of ICU stay or until delirium‐free and
ICDSC scale tolerating tube feeds, randomized to olanzapine 5mg QD or haloperidol 2.5–5 mg every coma‐free for 48 hours. Patients were included if mechanically ventilated within 72 hr of ICU admission.
Patients in intervention arm were administered haloperidol 2.5 mg IV q 8hr within 72 hours of ICU admission
Q8hrs “titrated per response,” with rescue haloperidol. Patients > 60 yrs received a lower initial
to the ICU regardless of their delirium or coma status.
dosage (haloperidol 0.5–1 mg, or olanzapine 2.5 mg).
Skrobik YK, et al. Intensive Care Med. 2004;30:444–9. Page V, et al. Lancet Respir Med. 2013 Aug; 1:515‐523.
MIND Feasibility Trial Dexmedetomidine for the Treatment of Hyperactive
Delirium Refractory to Haloperidol in Nonintubated
Patients alive without delirium or coma (%)
100
ICU Patients: A Nonrandomized Controlled Trial
80
• Nonrandomized , controlled, single center in Barcelona,
60 Spain
Haloperidol
40 Ziprasidone
• Agitated delirium
Placebo • Dexmedetomidine added for non‐responders to
20 haloperidol (n = 47) vs. resonders haloperidol (n= 86)
– Dexmedetomidine patients had a higher percentage of time at
0.0 satisfactory sedation level 92.7% vs. 59.3% p= 0.0001
5 10 15 20
Time (days) • Dexmedetomidine may be useful as a rescue drug for
Randomized, double‐blind, placebo‐controlled trial. Six centers in USA. 101 Mechanically ventilated treating agitation due to delirium in patients who fail to
mixed medical/surgical ICU patients with delirium diagnosed by positive CAM‐ICU. Haloperidol, respond to haloperidol
ziprasidone or placebo ever 6 hours for up to 14 days. Number of days alive without delirium or coma
at day 21 primary endpoint.
Girard TD, et al. Crit Care Med. 2010 Feb;38(2):428-37. Carrasco G, et al. Crit Care Med. 2016 Jul;44(7):1295‐306.
___________________________________________________________________________________________________
Effect of Dexmedetomidine 2018 SCCM PADIS Guideline Delirium
Added to Standard Care for Agitated Delirium
p=0.61 Other Metrics Recommendations
16
Dexmedetomidine Dex Placebo P value
• Suggest using a multicomponent, non‐
14
14 n=39 n=32
Median Duration ‐ Days
Placebo 12.5
12 Any day 36.8 65.6 0.02
10
p=0.29 antipsychotic % pharmacologic intervention that is focused on
Study day with any 26.3 40 0.08
8 p=0.01 7.5 antipsychotic % (but not limited to) reducing modifiable risk
6 5.9 Underwent 17.9 6.3 0.14
6 5.3
tracheostomy % factors for delirium, improving cognition, and
4 Time to 41.9 71.1 < 0.01
2
tracheostomy optimizing sleep, mobility, hearing, and vision
Median hours
0 Any day Propofol 980 5390 <0.001 in critically ill adults
Vent Free ICU LOS Hospital LOS Median (mg)
– conditional recommendation, low quality of
Multicenter RCT in New Zealand and Australia in mixed medical/surgical evidence
ICUs. Dex (39) or placebo (32) added to standard of care in agitated
delirious patients. Devlin J, Skrobik Y, Gelinas C et al. Clinical practice guidelines for the management of pain, agitation/sedation,
Reade MC, et al. JAMA. 2016 Apr 12;315(14):1460‐8. delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73.
Management of Delirium Early PT and OT in Mechanically
• Non‐Pharmacologic Ventilated ICU Patients
– Correct any know precipitating cause (toxic metabolic) 17.5 PT/OT with DSI n = 49 p = 0.93
– Early mobilization DSI alone n = 55 All patients

14. 13.5 12.9
– Use of sedation scales
Median Time (days)
p = 0.08
– Use of scheduled pain management protocols and pain scales 10.5 p = 0.02
p = 0.02 7.9
– Reorientation of patients
7. 6.1 5.9
– Timely removal of catheters and restraints 4. 3.4
– Early correction of dehydration 3.5 2.
– Minimizing unnecessary stimuli 0.
– Adjusting ventilator settings ICU Delirium Mechanical Ventilation ICU LOS Hospital LOS
Two ‐center trial of 104 adult patients on mechanical ventilation for less than 72 hr, randomized to
early exercise and mobilization (PT and OT) during periods of daily interruption of sedation or to daily
interruption (DSI) of sedation with therapy as ordered by the primary care team.
Schweickert WD et al. Lancet. 2009 May 30; 373(9678):1874‐82.
Transitions of Care Considerations in Pharmacogenetic Considerations for
the ICU PADIS in ICU
• Medications added to patients in the ICU for ICU • Cytochrome (CYP) P‐450 gene is responsible for
indication are often continued post‐ICU metabolism of many opioids and sedatives
– Antipsychotics • In one analysis 93% of patients were categorized as
– Sedatives “non‐normal” metabolizers of 5 common enzymes
– Stress ulcer prophylaxis and many more (CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5)
• Efforts to align indications with the active problem • CYP gene polymorphisms result in altered effects of
list at transition is warranted midazolam, fentanyl, morphine and likely more
– ICU to the ward
• More research needed
– Ward to home/rehabilitation facility
• Not ready for clinical practice
Terry K, et al. SAGE Open Med. 2015 Dec 15;(3): 1‐7.
Farrokh S, et al. J Pharm Pract. 2017 Jun;30(3):342‐346. Hocum BT, et al. Am J Health Syst Pharm. 2016 Jan 15;73(2):61‐7.
Marshall J, et al. J Crit Care. 2016 Jun;33:119‐24. MacKenzie M, Hall R. Can J Anaesth. 2017 Jan;64(1):45‐64.
___________________________________________________________________________________________________
2018 SCCM PADIS Guideline Sleep 2018 SCCM PADIS Guideline Sleep
• Suggest not routinely using physiologic sleep • Suggest using either an NIV‐dedicated ventilator or a
monitoring clinically in critically ill adults standard ICU ventilator for critically ill adults requiring
– conditional recommendation, very low quality of evidence NIV to improve sleep
• Suggest using assist‐control ventilation at night (versus – conditional recommendation, very low quality of evidence
pressure support ventilation) for improving sleep in
critically ill adults • Suggest not using aromatherapy, acupressure, or music
– conditional recommendation, low quality of evidence at night to improve sleep in critically ill adults
• No recommendation regarding the use of an adaptive – conditional recommendation, low quality of evidence
mode of ventilation at night (versus pressure support [aromatherapy and acupressure]); very low quality of
ventilation) for improving sleep in critically ill adults evidence [music]
– no recommendation, very low quality of evidence
2018 SCCM PADIS Guideline Sleep
Low‐dose Nocturnal Dexmedetomidine
Recommendations
1.0
• Suggest using noise and light reduction strategies to improve sleep
in critically ill adults
Cumulative proportion of patients
0.8
– conditional recommendation, low quality of evidence
• No recommendation regarding the use of melatonin to improve
without delirium
0.6
sleep in critically ill adults Dexmedetomidine
– no recommendation, very low quality of evidence 0.4
• No recommendation regarding the use of dexmedetomidine at
night to improve sleep 0.2 Placebo
– no recommendation, low quality of evidence
• Suggest not using propofol to improve sleep in critically ill adults 0
Dexmed.
Number of patients remaining in the ICU still free of delirium
50 24 8 4 2 2 1 1
– conditional recommendation, low quality of evidence placebo 50 20 4 3 1 1 10 0
14 28 42 49
• Suggest using a sleep‐promoting multicomponent protocol in 0 7 21
Follow‐up days
35
critically ill adults
– conditional recommendation, very low quality of evidence Two‐center RCT general medical/surgical critically ill adults. Dexmedetomidine initiated at 0.2 mcg/kg/hr, titrated by 0.1
mcg/kg/hr every 15 min to goal RASS score of ‐1 or maximum rate of 0.7 mcg/kg/hr
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. Skrobik Y, et al. Am J Respir Crit Care Med. 2018 May 1;197(9):1147‐1156.
Melatonin and Melatonin Receptor Agonists Ramelteon
• May help promote sleep
– Very little evidence in ICU patients
• Single‐center RCT in Japanese medical ICU
• Pilot study of ramelteon (melatonin receptor agonist) Variables Ramelteon (n = 45) Control (n = 43) p
– 67 patients (24 ICU patients)
– Prevalence of delirium 3% in ramelteon group vs. 32% in placebo ICU length of stay, median (range), 4.56 (2.1‐7.07) 5.86 (2.97‐14.16) NS
group in medically ill patients days*
Hospital mortality, n (%) 3 (6.7) 3 (7.5) NS
• More evidence is needed to support routine use of melatonin
Occurrence of delirium, n (%) 11 (24.4) 20 (46.5) 0.044
or ramelteon in the ICU
Length of delirium, mean (SD), days 0.78 (1.81) 1.40 (2.30) 0.048
*primary endpoint
Hatta K, et al. JAMA Psychiatry. 2014:71(4);397‐403.
Mo, Y et al. J Intensive Care Med. 2016 Aug;31(7):451‐5. Nishikimi M, et al. Crit Care Med. 2018 Jul;46(7):1099‐1105.
___________________________________________________________________________________________________
Recommendations ‐ Ungraded Recommendations ‐ Ungraded
• Total sleep time and sleep efficiency are often normal • Subjective sleep quality is reduced
• The presence of delirium may not affect total sleep time, • The presence of delirium may not affect total sleep time,
sleep efficiency, or sleep fragmentation sleep efficiency, or sleep fragmentation.
• Sleep fragmentation, the proportion of time spent in light • The influence of delirium on the proportion of time spent in
sleep (stages N1+N2), and time spent sleeping during the day light (N1 + N2) versus deeper (N3) sleep is unknown
(versus night) are higher • REM sleep is lower if delirium is present
• The proportion of time spent in deep sleep (stage N3 sleep
and REM) is lower
Recommendations ‐ Ungraded Recommendations ‐ Ungraded
• Delirium is associated with greater circadian sleep‐cycle disruption and
increased daytime sleep • Patients who report poor quality sleep and/or use of a pharmacologic
sleep aid at home are more likely to report poor quality sleep in the ICU
• Whether delirium affects reported subjective sleep quality remains
unclear • Pain, environmental stimuli, healthcare‐related interruptions,
psychological factors, respiratory factors and medications each affect sleep
• The use of mechanical ventilation in critically ill adults may worsen sleep
quality in the ICU
fragmentation, architecture, and circadian rhythm (daytime sleep)
compared to normal sleep, but these effects are often variable and have • While an association between sleep quality and delirium occurrence exists
not yet been fully investigated in critically ill adults, a cause‐effect relationship has not been established
• The use of mechanical ventilation (versus periods without mechanical • An association between sleep quality and duration of mechanical
ventilation) in patients with respiratory failure may improve sleep ventilation, length of ICU stay and ICU mortality in critically ill adults
efficiency and reduce fragmentation, but data are limited remains unclear
• The prevalence of unusual or dissociated sleep patterns is highly variable • The effects of sleep quality and circadian rhythm alterations on outcomes
and depends on patient characteristics in critically ill patients after ICU discharge are unknown
2018 SCCM PADIS Guideline
ABCDEF Bundle Via PADIS
Mobilization Recommendations
• Performing rehabilitation or mobilization in ICU • For every 10% increase in total bundle
– Conditional recommendation, low quality of evidence
• Serious safety events or harms do not occur commonly during physical compliance, patients had a 15% higher
rehabilitation or mobilization
– Ungraded hospital survival
• Major indicators for safely initiating rehabilitation/mobilization include
stability in cardiovascular, respiratory, and neurologic status
– Vasoactive infusions or mechanical ventilation are not barriers to initiating
rehabilitation/mobilization, assuming patients are otherwise stable with use of
these therapies.
– Ungraded
• Major indicators for stopping rehabilitation/mobilization include
development of new cardiovascular, respiratory, or neurologic instability.
– Other events, such as a fall or medical device removal/malfunction, and
patient distress
– ungraded
delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825‐73. Barnes‐Daly MA, et al. Crit Care Med. 2017 Feb;45(2):171‐178
___________________________________________________________________________________________________
ASHP Core Therapeutic Module Question 9: JM is now POD 3 and with a progressively decreasing
platelet count from 210 cells/mm3 on admission to 72 cells/mm3 on
POD 3. She is currently on day 8 of unfractionated heparin (UFH)
• Select topics in prevention and supportive exposure. Lab results include: SRA is negative, 4T score is medium
care in critical care patients and heparin PF4 antibody test is positive, with no thrombosis
detected. The ICU surgical intern ask you about discontinuing
– Stress ulcer prophylaxis (SUP) heparin and starting direct thrombin inhibitor infusion (DTI). Along
– Venous thromboembolism (VTE) prophylaxis with continued monitoring of continue platelets, which is the best
recommendation for medication management?
– Bowel regimens
– Ventilator associated pneumonia (VAP) prevention A. Initiate DTI therapy and discontinue UFH
B. Do not initiate DTI, and continue UFH
C. Do not initiate DTI, and initiate fondaparinux
D. Initiate DTI and initiate bridge therapy with warfarin
Heparin‐Induced Thrombocytopenia (HIT) Pathophysiology of HIT
• Immune‐mediated IgG antibody response to • Platelet factor 4 (PF4) forms a complex with
heparin/platelet factor 4 (PF4) complex heparin
– Cardiovascular surgery > general surgical > medical – Conformational change in PF4
patients
– Antigenic
– Unfractionated heparin (UFH ‐ bovine>porcine) >> low
molecular weight heparin (LMWH) • IgG antibodies are formed
• 8% of UFH treated patients develop antibodies • The Fc receptor of the Ab binds platelets
• 1‐5% of UFH treated patient develop HIT – Platelet Activation  Arterial and/or venous
– 30‐50% of these develop thrombosis thrombosis
– 20‐30% morbidity and mortality – Thrombocytopenia
Linkins LA et al. Chest. 2012 Feb; 141(2 Suppl):e495S‐530S.
Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392. Baroletti SA et al. Circulation. 2006; 114:e355‐6.
Type I and II HIT HIT Natural History
• HIT ‐ I • HIT ‐ II • Development of antibodies/platelet activation
– Heparin‐associated – Antibody‐ mediated takes 5‐10 days
thrombocytopenia – Develops within 5‐10
• May also occur with re‐exposure to heparin after
– NOT immune‐mediated days
– Develops within 1‐4 – High risk of thrombotic
a recent course (within 100 days)
days complications – Be careful of products/devices with heparin in them
– NOT associated with —Catheters
thrombotic events —Blood products (4‐factor prothrombin complex concentrate)
– Mild, self‐limited • Once started, continued exposure to heparin
HIT discussion will refer to HIT‐II propagates the cycle
Arepally GM, Ortel TL. N Engl J Med. 2006; 355:809‐17.
___________________________________________________________________________________________________
Incidence of HIT According to Patient
HIT with Thrombosis ‐ HITT Population and Type of Heparin
Population Incidence of HIT %
• Major cause of HIT morbidity Post‐op
UFH prophylaxis 1 ‐ 5
• Thrombosis may be initial presentation UFH treatment 1 ‐ 5
• Venous >arterial thrombosis (3:1 or 4:1) UFH flush 0.1 ‐ 1
Low Molecular Weight Heparin 0.1 ‐ 1
• Severe complications: PE, MI, CVA, Cardiac surgery 1 ‐ 3
Medical
amputation
Patients with cancer 1
• May also present with skin necrosis UFH prophylaxis or treatment 0.1 ‐ 1
Low Molecular Weight Heparin 0.6
Intensive Care 0.4
Heparin flush < 0.1
Obstetrics < 0.1
Guidelines for Diagnosis and
Overview of HIT Diagnosis
Management on HIT
• 2012 ‐ Treatment and prevention of HIT: • Clinical suspicion?
Antithrombotic therapy and prevention of • Does patient have new‐onset thrombosis?
thrombosis, 9th ed: American College of Chest • What is the 4T score?
Physicians evidence‐based clinical practice
guidelines • What is the result of platelet factor 4 (PF4)
immunoassay antibody testing (if indicated)?
• 2018 ‐ American Society of Hematology
guidelines for management of venous • What is the result of the serotonin release
thromboembolism: HIT assay (SRA) functional assay (if indicated)?
Linkins LA et al. Chest. 2012 Feb; 141(2 Suppl):e495S‐530S. Linkins LA et al. Chest. 2012 Feb; 141(2 Suppl):e495S‐530S.
Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392. Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392.
4Ts Score: HIT Assessment Tool Clinical Suspicion for HIT
• Clinical role • Agent used: UFH>>LMWH
– Clinical diagnosis
— Sensitivity ~ 81% • Extent of Thrombocytopenia
— Specificity ~ 100% – Counts of 20,000‐100,000 × 109/L or 50% fall
– Determine the need for laboratory diagnosis
• Scoring system ( 0 to 2 points for each category) • Timing of thrombocytopenia
– Degree of Thrombocytopenia – After 5‐10 days of heparin, or recent re‐exposure
– Timing of platelet drop
– Thrombosis
• New onset Thrombosis
– OTher etiologies of thrombocytopenia • oTher causes of thrombocytopenia
• Probability of HIT diagnosis – Medications: antibiotics, antiarrhythmics
– High: 6‐8 points
– Medium: 4‐5 points – Disseminated intravascular coagulation, sepsis, indwelling
– Low: < 3 points devices, idiopathic thrombocytopenic purpura, surgery
Janatpour KA et al. Am J Clin Pathol. 2007; 127:429‐33.
Lo GK et al. J Thromb Haemostasis. 2006; 4:759‐65.
___________________________________________________________________________________________________
Sample 4T Score Sheet Laboratory Diagnosis of HIT
• 2 major tests:
1. Antigen assays detect the presence of HIT antibodies
— Enzyme‐linked immunosorbent assay (ELISA) testing for
antibodies that are reactive against PF4/heparin
— Typically fast turn‐around time (same day or next day)
— High risk of false positives because:
– Sensitive high
– Specificity is low
2. Functional assays detect evidence f platelet activation in
the presence of HIT
— Serotonin release assay (SRA) or heparin‐induced platelet
activation (HIPA)
— Typically have a slow turn‐around (days or longer)
— More specific than the ELISA because SRA and HIPA only detect
antibodies capable of activating platelets
Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392.
Laboratory Diagnosis of HIT PF4 ELISA: Nonspecific vs. IgG‐Specific
Serotonin Release Assay (SRA) Nonspecific ELISA (PF4)
Type of Test Functional Assay Immunoassay
• IgG‐Specific ELISA detects anti‐PF4/Heparin
Platelet activation Detects antibodies against
Evaluation and aggregation Heparin‐PF4 complex antibodies of the IgG class only
Requirements Freshly prepared donor platelets Donor serum – IgG‐Specific ELISA
Gold Standard
Standard Clinical Practice Operating Characteristics of the Nonspecific ELISA and IgG‐
Role in – Usually a send‐out lab
– Usually done in house specific ELISA
– Requires radioactive isotopes
Clinical Practice – Fast turnaround time
– Slow turnaround time
– Relatively Inexpensive Sensitivity Specificity NPV
Sensitivity
– Expensive
88 ‐ 100% 95‐99%

• Purpose of this % %
PPV %
%
Nonspecific
Specificity 89 ‐ 100% 86% enhanced ELISA ELISA
98.1 89.4 38.7 99.9
Positive Predictive
Value
89 ‐ 100% 10 ‐ 93 %, depending on population – Increase specificity IgG specific
95.8 93.5 49.6 99.1
ELISA
Negative Predictive – Maintain sensitivity PPV = positive predictive value; NPV = negative predictive
81% > 95%
Value value
Arepally GM et al. N Engl J Med. 2006; 355(8):809‐17.
Bowman M et al. J Thromb Haemost. 2010; 8:216‐8. Cuker A, et al. Hematology. 2009:250‐2.
PF4 ELISA: Nonspecific vs. IgG‐Specific IgG‐Specific PF4 Optical Density Cut Offs
Percent of Patients with a Positive PF4 Test Result
Optical Density Sensitivity Specificity PPV NPV
(95% CI) (95% CI) (95% CI) (95% CI)
Patients with Positive PF4 (%)
12 11.3 p = 0.044
PF4 Elisa >0.4 91.3% 61.5% 31.8% 97.3%
10 (72.6‐98.8) (52.5‐69.9) (21.8‐43.8) (90.1‐99.8)
8 6.9
PF4 Elisa >0.8 82.6% 87.2% 55.9% 96.2%
6 (62.3‐93.6) (79.8‐92.2) (39.4‐71.1) (90.4‐98.8)
4
PF4 Elisa >1 73.9% 91.5% 63.0% 94.7%
2 (53.2‐87.7) (84.8‐95.5) (44.2‐78.5) (88.7‐98.5)
0
Nonspecific (n = 336) IgG Specific (n = 336)
An increased antiheparin–PF4 ELISA threshold of 0.8 or 1.0 OD units enhances
specificity, PPV, and accuracy while maintaining NPV with decreased sensitivity
Implementation of an IgG specific ELISA was associated with a lower rate
of positive PF4 diagnoses
Sylvester KW, et al. Pharmacotherapy. 2013 Nov;33(11):1191‐8. Ritchie BM, et al. Clin Appl Thromb Hemost. 2017Apr;23(3):282‐286.
___________________________________________________________________________________________________
Diagnosis and Initial Management
5 phases of HIT HIT Suspected
Calculate
4T score
Intermediate/high
Phase Platelet count Functional assay Immunoassay
Low clinical clinical probability
probability (4T score >3)
Suspected HIT Decreased No result yet No result yet (4T score <4)
Discontinue heparin
Acute HIT Decreased Positive Positive and start non‐heparin
Subacute HIT A‐ following Normal Positive Positive anticoagulant
acute HIT with platelet
recovery
Subacute HIT B‐after Normal Negative Positive (‐) Immunoassay (+) Immunoassay
functional assay becomes
negative
HIT unlikely; HIT lab testing should not
Remote HIT Normal Negative Negative be ordered; continue/resume heparin HIT likely‐ continue
if indicated; discontinue non‐heparin to management of
anticoagulant (if applicable) acute HIT
Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392. Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392.
Question 9: JM is now POD 3 and with a progressively decreasing Management
platelet count from 210 cells/mm3 on admission to 72 cells/mm3 on
POD 3. She is currently on day 8 of unfractionated heparin (UFH)
• Clinical suspicion key based on 4T score
exposure. Lab results include: SRA is negative, 4T score is medium • High‐probability 4T score/intermediate‐
and heparin PF4 antibody test is positive, with no thrombosis
detected. The ICU surgical intern ask you about discontinuing
probability 4T score
heparin and starting direct thrombin inhibitor infusion (DTI). Along – Stop heparin immediately, choose alternative anti‐
with continued monitoring of continue platelets, which is the best coagulant
recommendation for medication management?
– Start non‐heparin anticoagulation
A. Initiate DTI therapy and discontinue UFH
• Low‐probability 4T score
B. Do not initiate DTI, and continue UFH
– Continue heparin
C. Do not initiate DTI, and initiate fondaparinux
D. Initiate DTI and initiate bridge therapy with warfarin
Linkins LA et al. Chest. 2012 Feb; 141(2 Suppl):e495S‐530S0.
Management of Acute HIT
HIT Treatment Data
• Stop Heparin product (and warfarin)
• Randomized controlled trials have proven – If patient on warfarin, reverse with Vitamin K
difficult to conduct in HIT • Treat with therapeutic‐intensity non‐heparin
– only two direct comparison trials have been anticoagulant
published – Argatroban, bivalirudin, danaparoid, fondaparinux,
—danaparoid versus dextran 70 or a direct oral anticoagulant (DOAC)
—desirudin versus argatroban
– terminated early due to poor accrual after only 16 subjects
– Life‐ or limb‐threatening thromboembolism
had enrolled —Parenteral preferred
• Rest are single arm trials or case reports
Linkins LA et al. Chest. 2012 Feb; 141(2 Suppl):e495S‐530S. Cuker A, et al. Blood Adv. 2018 Nov 27;2(22):3360‐3392.
___________________________________________________________________________________________________
Management of Acute HIT Question 10: You’ve noticed that your institution has been spending much
more on direct thrombin inhibitors (DTIs) for the management of heparin‐
induced thrombocytopenia (HIT) over the past year than in previous years.
• Do not initiation of vitamin K antagonist (VKA) You conduct a chart review and determine that most patients with negative
results from heparin/PF4 antibody tests are kept on DTIs for several days post
before platelet count has returned to 150,000 × result. Which of the following practice guideline for patients with suspected
109/L or baseline HIT would be most appropriate to create and implement at your institution?
• If using VKA, overlap VKA with non‐heparin A. A practice guideline recommending earlier transition of patients from DTIs to
anticoagulation for at least 5 days and at least 2 fondaparinux based on a consensus among clinical leaders at the institution
B. A practice guideline recommending serial testing heparin/PF4 antibodies in all patients
days with therapeutic INR on heparin based on consensus among clinical leaders at the institution
• Provide adequate duration of therapy C. A practice guideline recommending transition from DTI to heparin based results of
heparin/PF4 antibody test results based on consensus among clinical leaders at the
– No active venous thromboembolism (VTE)‐ typically institution
less than 3 months D. A practice guideline recommending continuing heparin in all patients until positive
heparin/PF4 antibody test results are obtained unless the 4T score exceeds 5 based on a
– With active VTE – treat for 3‐6 months consensus among clinical leaders at the institution
Sample Local Guideline for HIT Management
Based on Level of Suspicion (4T score)‐ Sometimes Differ Management
• Negative heparin/PF4 antibody test typically
discontinue non‐heparin anticoagulant with
low to intermediate 4T score
• Negative SRA typically discontinue non‐
heparin anticoagulant
BWH Hemostatic and Antithrombotic DTI for Management of HIT
(HAT) Stewardship Program
Mission Statement
To promote the appropriate and optimal use
of hemostatic and antithrombotic agents in
order to maximize patient outcomes and
minimize adverse events
Reardon D et al. J Thromb Thrombolysis. 2015; 40: 379‐382. Data on File BWH, Boston, MA; January 2016
___________________________________________________________________________________________________
Bivalirudin Use in Cardiac Surgery for HIT Cumulative PF4s by Month
160
1200
143
1062
140
128 972
113 1000
906
120 876
828
791 766
100 800
Number of PF4s
89 91 708 703
Number of Patients
623 629
80 73 600 582
68 FY13
506 507 FY13
60 FY14 422 429
50 361 FY14
400 338
39
40 30 243 270
185
18 18 200 154
20 75 95
0 0
Total Suspected Diagnosed Total Suspected Diagnosed
HIT CSS HIT
Data on File BWH, Boston, MA; January 2016. Data on File BWH, Boston, MA; January 2016.
Question 10: You’ve noticed that your institution has been spending much
Duration of Treatment of Confirmed more on direct thrombin inhibitors (DTIs) for the management of heparin‐
induced thrombocytopenia (HIT) over the past year than in previous years.
HIT or HITT You conduct a chart review and determine that most patients with negative
• HITT: 3 Months (considered reversible results from heparin/PF4 antibody tests are kept on DTIs for several days post
result. Which of the following practice guideline for patients with suspected
provoking risk factor for VTE) HIT would be most appropriate to create and implement at your institution?
• HIT: 4 Weeks A. A practice guideline recommending earlier transition of patients from DTIs to
fondaparinux based on a consensus among clinical leaders at the institution
– due to the high risk of thrombosis that extends for B. A practice guideline recommending serial testing heparin/PF4 antibodies in all patients
2 to 4 weeks after treatment of HIT is initiated, on heparin based on consensus among clinical leaders at the institution
C. A practice guideline recommending transition from DTI to heparin based results of
consideration should be given to continuing heparin/PF4 antibody test results based on consensus among clinical leaders at the
anticoagulant therapy with an alternative agent or institution
D. A practice guideline recommending continuing heparin in all patients until positive
warfarin for up to 4 weeks in patients with heparin/PF4 antibody test results are obtained unless the 4T score exceeds 5 based on a
isolated HIT consensus among clinical leaders at the institution
Linkins LA et al. Chest. 2012; 141(2 Suppl):e495S‐530S.
Pharmacogenetic Considerations for HIT Key Takeaways

HIT
• Human Leukocyte Antigen (HLA) genes may • HIT diagnosis
prevent immune‐related adverse drug – Pre‐existing exposure to heparin
reactions – Clinical suspicion
– 4T score
• Preliminary analysis suggests the HLA‐
– Heparin/PF4 antibody test
DRB3*01:01 allele may be a risk factor for
– SRA
developing HIT
• HIT management
• More research needed – D/C all heparin products
• Not ready for clinical practice – Start non‐heparin anticoagulant
Karnes JH, et al. Pharmacotherapy. 2017 Sep;37(9):1164‐1171.
___________________________________________________________________________________________________
Complex Case:
Summary Complications After Cardiac Surgery –
• Glucose management Glucose, Sedation and
– Hyperglycemia is typically defined as >180 mg/dL
– IV insulin is typically recommended for ICU patients Thrombocytopenia
• Pain, agitation and delirium
– Core management includes assessment and local
guidelines implementation based on recommendations
SCCM guideline
• HIT
Paul M. Szumita, Pharm.D., BCCCP, BCPS, FASHP, FCCM
– Diagnosis is often difficult/complicated and includes Clinical Pharmacy Practice Manager
clinical criteria and laboratory tests Brigham and Women’s Hospital
– Management ‐ D/C all heparin products and use non‐ Boston, Massachusetts
heparin anticoagulant
___________________________________________________________________________________________________

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Complex Case:

No history of diabetes No history of diabetes but History of

Umpierrez GE et al. J Clin Endocrinol Metab. 2002; 87(3):978‐82. Umpierrez GE et al. Endocrine Society. J Clin Endocrinol Metab. 2012; 97(1):16‐38.

A. Increase the low‐dose supplemental insulin to a medium dose < 40 mg/dL 0.9% 57.4% 2.6 (2.1-3.2)

Median Time (days)

p < 0.01 Propofol/hr, 0 (0‐0.5) 0.77 <0.001

60 Mechanical 120 65 0.01 mg/kg* (0.1‐1.6)

Delirium† (34.2) (34.7) 0.9 can communicate reliably

0.01 0.1 1 10 100 ‐ Favors Light 0 Favors Deep

Midazolam subgroup 37 29 14.7 14.9

antipsychotic or HMG‐CoA reductase inhibitor to 25 24 Quetiapine Placebo P value

Median Time (days)

Olanzapine vs. Haloperidol for the Treatment HOPE ICU‐ Effect of Early Treatment with IV

– Early mobilization DSI alone n = 55 All patients

88 ‐ 100% 95‐99%

Pharmacogenetic Considerations for HIT Key Takeaways

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