Sepsis

4/11/2015
The First 6 Hours of Sepsis

Diagnosis and Management-2015-Part I
Emanuel P. Rivers, MD, MPH
Vice Chairman and Research Director
Emergency and Surgical Critical Care Medicine
Henry Ford Hospital
Clinical Professor, Wayne State University
Detroit, Michigan
Institute of Medicine, National Academies
4/11/2015
The First 6 Hours of Sepsis Diagnosis and

Management-2015-Part I
8:00 AM - 8:30 AM
(4/11)
Starting a Sepsis Program: Practice, Politics and

Performance
10:30 AM - 11:20 AM
(4/11)
The First 6 Hours of Sepsis Diagnosis and

Management-2015-Part II
1:30 PM - 2:00 PM
(4/11)
Resuscitating Sepsis: After ProCESS, ARISE and

ProMISE
4:25 PM - 5:15 PM
(4/11)
Steroid Use in Critical Illness - Update 2015
8:00 AM - 8:30 AM
(4/12)
What is Sepsis?:
The Early Pathogenesis
Sepsis: A Complex and Dynamic Landscape

Systemic Inflammation
or Inflammatory
Organism
Source
Sepsis
Response
Systemic Inflammatory
Response Syndrome (SIRS)
A clinical response arising from a nonspecific insult,
including 2 of the following:
Diffuse endothelial
oC
disruption and
Temperature 38oC or 36
microcirculation defects
OR
General
Intensive
At
Emergency
OutHome
Patient
Practice
Care
or
HR 90 beats/min
and
Recovery
Global Tissue
Department
Residence
Setting
Floors
Unit
Respirations
20/min
Hypoxia and
Organ
WBC
count 12,000/mm3 Severe
or Sepsis
Dysfunction
4,000/mm3 or >10% bands
PaCO2 < 32mmHg
Septic Shock
Multiple Organ
Dysfunction and
Refractory Hypotension
4/11/2015
5-10%
10-20%
20-30%
30-50%
Chronic Lung
Disease (ARDS)
Disabilities
(Amputations)
Neuromuscular
Disorders
Chronic Heart
Failure
Morbidity or
Disabilities
Psychiatric
Disease
Kidney Failure
and Dialysis
Cases per year Mortality (%)

Sepsis
859,858
15-20
Severe Sepsis
791,000
27-40
Septic Shock
200,000
36-47
Pneumonia
1,187,180
5-9
Stroke
591,996
6-7
Acute Myocardial Infarction
540,891
10
Trauma
697,025
5-16
4/11/2015
A Need to Change the

Paradigm of
Current Sepsis Management
Time Sensitive Diseases

Changing the Paradigm of Practice
AMI
Stroke
< 10%
7%
Trauma
< 5%
4/11/2015
What About
Guidelines for Sepsis?
4/11/2015
2004, 2008, 2012
4/11/2015
The Evolution of Early Sepsis Care
NEJM, 2014
NEJM, 2014
Whats is Early Sepsis Care in 2015?
The Fundamental Evidence

for the Bundle Components
The Origin of SIRS
4/11/2015
Roger Bone
JAMA, 1992
SIRS in the Emergency Department

Ander, AEM, 1996
The Timing of Antibiotics
4/11/2015
1.
Natanson C, Danner RL, Reilly JM, et al. Antibiotics versus
cardiovascular support in a canine model of human septic shock. Am J
Physiol 1990;259:H1440-7.
Dogs with septic shock induced by an

intraperitoneal clot containing E. coli.
No
Therapy
Antibiotics
(cefoxitin
and
gentamicin)
0%
13%
Survival
CV support
(fluids &
dopamine
to
hemodynamic
end points.
CV support
and
antibiotics
43%
13%
Crit Care Med,

2014
4/11/2015
Crit Care Med,

2014
8.5% Increase in Mortality
Importance of Blood Cultures and

Adequacy of Antibiotics
5,715 patients,
Retrospective,
Multicenter
10
4/11/2015
10.3%
52%
9.45
11
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The Importance of
Source Control
Crit Care Med, 2004
12
4/11/2015
Every hour of delay from admission to surgery was associated with an adjusted
2.4% decreased probability of survival compared with the previous hour.
Patients who had surgical source control delayed for

more than 6 hours had a significantly higher 28-day
mortality (42.9% vs. 26.7%, P <0.001)
This delay was independently associated with an
increased risk of death
13
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14
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Risk Stratification for

Early Detection of High
Risk Patients:
Changing the way we
detect
illness severity
Systolic
Blood Pressure
Diastolic
Blood Pressure
Stephen Hales - 1733
A Subtle and Deadly Disease Transition

Using a 279 year old definition
ER or Ward
ICU
MAP ~ SVR X CO
15
4/11/2015
Global Tissue Hypoxia:

A More Sensitive Measure of Shock
OXYGEN
DEMAND
OXYGEN
DELIVERY
Global Tissue
Hypoxia
OXYGEN
BALANCE
Lactic Acid
> 4 mM/L
Seminal Lactate Studies

Where did a Lactate cut point of 4 come from?
Broder G, Weil MH.
Science 1964;143:1457-1459
56 patients with clinical signs of shock:

Hypovolemia (17), Sepsis (9), cardiac failure (7),
neural dys. & endocrine def. (4), vascular obs. (2),
mixed (9), unclassified (8)
Screening for Severe Illness in the ED

Infection and Lactate (LA > 4 mM/L)
#SIRS
2 of the following is SIRS:
Temperature 38oC or 36oC
HR 90 beats/min
Respirations 20/min
WBC count 12,000/mm3
or 4,000/mm3
or >10% bands
PaCO2 < 32mmHg
0
1
2
3
4
SIRS SIRS + LA SIRS + LA

Ward (%) Ward (%)
ICU
11.6
14.7
34.6
55.4
70.0
33.3
15.4
40.0
84.6
100
0
0
62.5
94.5
100
Aduen, JAMA, 1994; Grzybowski, Chest, 1999
16
4/11/2015
Crit Care Med, 2014
Outcome Impact of
Lactate Measurements
51.4 to 29% (11.4%) - No Hypotension

58.6 to 44.5% (12.1%) - Hypotension
What patients are at high risk for

global tissue hypoxia?
SvO2
4 mM/L
Case
78 year old female
2 weeks after AAA
T 39o C
Cough
Brown sputum
Right sided chest
pain
17
4/11/2015
The importance of
early detection of high risk
patients
18
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12.1% of All
Cardiac Arrests
Are pnuemonia
Importance of the Fluid Challenge
19
4/11/2015
2.5 3.5 Liters for 70 kg

20 - 40cc per kg fluid challenge
20
4/11/2015
Is Fluid Administration Within Six Hours Early Enough for

Better Patient Outcomes in Sepsis Septic Shock
Results:
594 patients, median age was 70 (58-80) years.
Adjusted for chronic co-morbidity, acute illness, age and fluid given in
the first 6 hours.
In fluids within the first 3 hours:
Survival at discharge 2085 ml (940-4080)
Death at discharge 1600 ml (600-3010), p=0.007.
In the latter 3 hours, median was 660 ml (290-1485) vs. 800 ml (3601680), p=0.09.
Earlier fluid resuscitation (within the first 3 hours) reduces

mortality. [odds ratio 0.34 (95% CI, 0.15 to 0.75), p=0.008].
Lee, Sarah; Li, Guangxi; Jaffer-Sathick, Insara; Valerio-Rojas, Juan Carlos;
Cartin-Ceba, Rodrigo; Kashyap, Rahul, Crit Care Med, 2012
Repeat Lactate:
The Implications of
Lactate Clearance
21
4/11/2015
Initial Lactate minus Later Lactate

Initial Lactate
Bad
Good
Quartiles of Lactate Clearance
22
4/11/2015
Lactate Clearance
Excellent Predictor when elevated
MSOF
Mortality
Resuscitation endpoint
Alactemia is common
Relative changes
An adjunct with other parameters
23
Care of the Hospitalized

Patient with Advanced Liver
Disease
William T. Browne, MD
Disclosures
I have no conflict of interest to disclose
Objectives
By the end of this session participants
will:
Recognize the HIGH risk of mortality in
these patients
Remember at least 3 tips for managing the
common complications of cirrhosis
encountered by hospitalists
Consider early referral for transplant
evaluation in patients with decompensated
cirrhosis
Clinical Case
56 yr old male with a history of Hepatitis C
presents with confusion and dyspnea and is
admitted to the Hospital Medicine Service.
Family reports hes just not himself but
has left by the time he arrives on the floor.
Medications: lactulose, omeprazole,
furosemide, spironolactone, simvastatin
Physical Exam
Vitals: T 99.6, BP 87/45, HR 98, RR 20, O2 sats 91% on RA

Jaundiced, confused, somnolent but responds to loud or noxious stimuli
OP with poor dentition, dry mucous membranes; scleral icterus
No adenopathy
Cor RRR, Nl S1, S2, 2/6 SEM without radiation
Lungs clear anteriorly, dullness to percussion half way up on right
No obvious trauma, Moves all extremities but has asterixis
Abdomen distended with bulging flanks, fluid wave present, no rebound
or guarding, caput medusae
Extremities with 3+ pitting edema bilaterally, palmar erythema
Skin with some petechia where BP cuff compresses arm and spider
angiomata on chest
Labs / Images
BMP remarkable for Na 126, HCO3 18 with anion gap of 6, Cr 2.2 (0.9)
CBC remarkable for Hgb 9 (11.8), WBC 12, Plts 64k
ALT/AST normal, Alk Phos nl, T. Bili 9
INR 2.4
NH3 64
UA- SG 1.031, LE/nitrite/protein -, 1 WBC, 1 RBC
CXR- Right pleural effusion, no other acute cardiopulmonary pathology
Abdominal U/S- large ascites with thickened and distended gallbladder,

shrunken nodular liver c/w cirrhosis, reversal of flow in portal vein with
collateralization.
Assessment/Plan
Pathophysiology of Cirrhosis
Adapted from Hepatitis C Education Society: http://hepcbc.ca/stages-of-liver-disease/
Increased
Splanchnic
Vasodilation
Complications
__of Portal HTN___
Variceal Bleeding
Jaundice
Hepatic Encephalopathy
Ascites / SBP / HH
Increased
Hepatic
Resistance
Hepatorenal Syndrome
Hepatopulmonary Syndrome
Portal Vein Thrombosis
Portopulmonary HTN
Hepatocellular Carcinoma
The splanchnic circulation. (Redrawn with permission from Gelman S, Mushlin PS: Catecholamine induced changes
in the splanchnic circulation affecting systemic hemodynamics. Anesthesiology 100:434439, 2004.)
Natural History and Prognosis

Portal HTN
Clinically
Significant
Portal HTN
HVPG >5
mm Hg
Compensated
Cirrhosis
7% new
varices/yr
HVPG >10
mm Hg
12% variceal
bleed/yr
HVPG >12
mm Hg
Decompensated
Cirrhosis
75% progress
within 10 years
Median Survival
2 years
Compensated
Baveno IV International Consensus Workshop Staging

System for Cirrhosis: 1-Year Outcome Probabilities
NO VARICES
NO ASCITES
VARICES
NO ASCITES
7%
1%
4.4%
3.4%
Decompensated
6.6%
4%
ASCITES
VARICES
DEATH
20%
7.6%
BLEEDING
ASCITES
57%
DAmico G et al. J Hepatol. 2006;44:217-231.
Classification of Cirrhosis Severity

Determinants for Child-Turcotte-Pugh (CTP)
Points
1
Encephalopathy
None
Grade 1 - 2
(or precipitant-induced)
Grade 3 - 4
(or chronic)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
<2
2-3
>3
>3.5
2.8 - 3.5
<2.8
<4
4-6
>6
Bilirubin (mg/dL)
Albumin (g/dL)
Prothrombin Time
(seconds prolonged)
Total Numerical
Score
Child-Pugh
Class
5-6
7-9
10 - 15
Patients in Class A are considered

compensated
Patients in Classes B and C are
considered decompensated
Adapted from Garcia-Tsao G et al. Am J Gastroenterol. 2009;104:1802-1829.
Classification of Cirrhosis Severity

Model for End Stage Liver Disease score
MELD - determines the severity of liver disease based on:
serum bilirubin,
serum creatinine
international normalized ration (INR)
developed in 2002 by UNOS
Calculation:
[0.957 x (Serum creatinine mg/dL) + 0.378 loge (Total
bilirubin mg/dL) + 1.12 loge (INR) + 0.64] x 10
Range: 6 40
equates to estimated 3-month survival rates from 90% to
7%respectively
Most Common Causes of Death

Renal failure increases mortality 7X
50% mortality within one month
Sepsis
Infections common- SBP, UTI, CAP, Skin
30% mortality at 1 month, 60% at 1 year
Variceal Hemorrhage
12% incidence of bleed per year, then
57% mortality at one year
Hepatocellular Carcinoma
4-30% incidence over 5 years depending on etiology of cirrhosis
and origin of patient
Lefton HB et al. Med Clin N Am. 2009;93:787-799.
DAmico G et al. J Hepatol. 2006;44:217-231.
Assessment: Decompensated
cirrhosis with MELD 32 complicated by
1) Overt hepatic encephalopathy
6) Coagulopathy
2) Ascites
7) Hyponatremia
3) Right pleural effusion
8) Hypotension
4) Acute kidney injury
9) Hypoxia
5) Anemia
6) Distended gallbladder
6) Coagulopathy
Overt Hepatic Encephalopathy

(OHE)
Associated with a poor prognosis
Retrospective review of 111 cirrhotic patients for
1217 months following first episode of acute OHE:
82 (74%) died during follow-up period

Survival probability
42% at 1 year
23% at 3 years
Bustamante J et al. J Hepatol. 1999;30(5):890-895.
Treatment Goals for OHE

Provision for supportive care
Identification and removal of precipitating factors
Infection, GI bleed, dehydration
Reduction of nitrogenous load from gut

Correction of electrolyte abnormalities
Long-term therapy assessment
Control of potential precipitating factors
Higher likelihood of recurrent encephalopathy
Assessment of need for liver transplantation
Adapted from Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976.
Lactulose
Currently the mainstay of therapy of HE; ~70% to 80% of
patients with acute and chronic HE improve with lactulose
treatment
Mechanism of action:
A non-absorbable dissacharide that is fermented in the
colon
Metabolism by the bacterial flora in the colon to lactic acid
lowers the colonic pH
Cathartic effect can increase fecal nitrogen excretion with
up to a 4-fold increase in stool volume
Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Ferenci P. Semin Liver Dis. 2007;27(suppl 2):10-17.
Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.
Rifaximin
Minimally absorbed (<0.4%) oral antibiotic
Broad-spectrum in vitro activity against aerobic and
anaerobic enteric bacteria
No clinical drug interactions reported
No dosing adjustment required in patients with liver
disease or renal insufficiency
Approved for overt recurrent HE risk reduction in
patients 18 years of age
Bass NM. Semin Liver Dis. 2007;27(suppl 2):18-25.

Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.
Proportion of Patients Without

Breakthrough HE (%)
Rifaximin Trial: Time to First Breakthrough HE Episode

Primary End Point
Rifaximin*
(77.9%)
Placebo*
(54.1%)
*Rifaximin 550 mg or placebo twice daily

Hazard ratio with rifaximin, 0.42 (95% Cl, 0.280.64)
P<0.001
Days Since Randomization
Bass NM et al. N Engl J Med. 2010;362:1071-1081.
Key Points
Always look for and correct inciting factors:
infection, bleeding, dehydration,
constipation, portal vein clot, porto-systemic
shunt, medications
1st Line Rx: Lactulose 45-90 gm/d (NNT 4)
Nurse driven protocol (oral, NG, or PR)
If on lactulose, add Rifaximin 550 mg bid

DO NOT check Ammonia levels daily
Ascites
Most common complication of cirrhosis
~60% of patients with compensated cirrhosis develop ascites
within 10 years
50% mortality rate within 3 years
Hepatic hydrothorax may be seen with minimal abdominal ascites
SBP a risk in patients with high SAAG (serum albumin ascites
albumin = > 1.1) PPIs increase risk > 4X
Patients should generally be considered for liver transplantation
referral
Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89.
European Association for the Study of the Liver. J Hepatol. 2010;53:397-417.
Illustration from: http://www.hepatitis.va.gov/vahep?page=cirrh-06-02. Accessed 02/15/11. (illustration??)
Management of Ascites
First-Line Therapy
Second-Line Therapy
Tense ascites
Paracentesis
Sodium restriction
(<2 Gm/24 Hrs)
and diuretics*
Refractory
Ascites 10 %
Repeated large volume

paracentesis (LVP)
TIPS
Liver Transplantation
Non-tense ascites
*Diuretics: Spironolactone 100 mg/day,
furosemide 40 mg/day or bumetanide
1 mg/day; uptitrate stepwise to
spironolactone 400 mg/day, furosemide
160 mg/day or bumetanide 4 mg/day as
tolerated
Albumin
infusion of 8-12 gm/liter of fluid

removed is a consideration for repeated
LVP; post-paracentesis albumin infusion
may not be necessary for < 5 liters removed
Adapted from Runyon BA. Hepatology. 2009; 49:2087-2107.
Systematic Review of
Safety of Paracentesis
Nine cases of severe bleeding were identified among
4729 procedures. The occurrence of severe hemorrhage
represented 0.19% of all procedures with a death rate of
0.016%. Bleeding was not related to operator
experience, elevated international normalized ratio or
low platelets. It occurred in patients with high model for
end-stage liver disease and Child-Pugh scores.
Furthermore, some degree of renal failure was present
in all but one patient.
Pache, I., and M. Bilodeau. "Severe haemorrhage following abdominal paracentesis for ascites in patients with liver
disease." Alimentary pharmacology & therapeutics 21.5 (2005): 525-529.
Needle Entry Points
AASLD Practice Guidelines:

Ascitic Fluid Analysis
Routine
Optional
Unusual
Cell count and

differential
Culture in blood
culture bottles
Acid-fast bacteria
smear and culture
Albumin
Glucose
Cytology
Total protein
Lactose
dehydrogenase
Trigylceride
Amylase
Bilirubin
Grams stain
Runyon BA. Hepatology. 2009; 49:2087-2107.
Spontaneous Bacterial Peritonitis: Diagnosis

Diagnosis of SBP:
Positive ascitic fluid bacterial culture
Elevated ascitic fluid absolute PMN count (ie, 250
cells/mm3 [0.25 x 109/L])
No evident intra-abdominal source of infection
Runyon BA. Hepatology. 2009; 49:2087-2107.
Prevention of SBP
Prophylaxis
DrugTherapy
Dose/Duration
Norfloxacin
400mg/dayorally
Ceftriaxone
1g/dayIVfor7days
Doublestrength
trimethoprim/sulfamethoxazole
5doses/week
Ciprofloxacin
750mgassingleoraldose/week
Intermittent dosing of prophylactic antibiotics may select resistant

flora; daily dosing preferred
Key Points
Always perform a diagnostic paracentesis
Always give 8 gm/l albumin when taking over 5
liters of ascites
Always give 1.5 gm/kg albumin on Day 1 and
1.0 gm/kg albumin on Day 3 for SBP
Always start SBP prophylaxis after first episode
Avoid chest tubes in a hepatic hydrothorax
Avoid PPIs in patients with ascites without PUD
Renal Injury in Cirrhosis

Hospitalized patients with cirrhosis
Chronic renal failure
1%
Pre-renal
68%
Intra-renal (ATN, GMN)

32%
AKI
19%
Post-renal (obstructive)
<1%
Not volume-responsive
Volume-responsive
66%
Infection
Hypovolemia
Vasodilators
Other
HRS type 1
25%
Garcia-Tsao G et al. Hepatology. 2008;48:2064-2077.
HRS type 2
9%
Survival Is Decreased With Renal Dysfunction

Survival Among Patients
With Cirrhosis and
Survival in Cirrhosis
Based on Level
of Renal Dysfunction
1.0
1.0
0.8
0.8
0.6
0.4
Creatinine 1.2-1.5mg/dL
0.2
Creatinine >1.5mg/dL
0.0
0
0.6
Creatinine <1.2 mg/dL
Survival
Survival
P<0.001
3
Years
0.4
Refractory ascites
0.2
0.0
0
Type 1 hepatorenal syndrome

1
Months
Blackwell: Science, Oxford, UK.

Gines et al. N Engl J Med. 2004;350:1646-1654.
Prevention of Acute Renal Injury in Cirrhotics

Prevent/treat volume depletion or vasodilatation
Careful use of diuretics
Avoidance of diarrhea with use of lactulose
Use of albumin after large-volume paracentesis
Avoid use of aminoglycosides and NSAIDs

Aggressively treat hypovolemia/hypotension
occurrence
Volume Challenge
1 gm/kg body weight up to 100 gm
albumin infusion for at least 2 days
Withdrawal of antibiotics
Failure of improvement in renal function
is concerning for hepatorenal syndrome
(part of diagnostic criteria)
Hepatorenal Syndrome: Risk Factors

Development of bacterial infections, particularly
SBP, is the most important risk factor
Hepatorenal syndrome develops in ~30% of patients
with spontaneous bacterial peritonitis
Treatment with albumin infusion/antibiotics reduces
the risk of developing hepatorenal syndrome and
improves survival
Hepatorenal Syndrome: Prognosis

The prognosis of hepatorenal syndrome is poor
Average median survival ~ 3 months
High MELD score and type 1 hepatorenal syndrome
are associated with very poor prognosis
Median survival of patients with untreated type 1
hepatorenal syndrome is ~ 1 month
Key Points
Always closely monitor renal function in
hospitalized cirrhotic patients
Always correct volume depletion in the
setting of a rising creatinine
Gastroesophageal Varices
Gastroesophageal varices present in ~50% of
patients with cirrhosis
Presence correlates with severity of liver disease
40% of Child A patients have varices
85% of Child C patients have varices
Cirrhotic patients without varices develop them

at a rate of 7-8% per year
Patients with small varices develop large varices at a
rate of 8% per year
Gastroesophageal Variceal Hemorrhage

Occurs at a yearly rate of 5% to 15%
Most important predictor of hemorrhage is size of
varices
Other predictors of hemorrhage are:
Decompensated cirrhosis (Child B/C)
Endoscopic presence of red wale marks
Associated with a mortality of 20% at 6 weeks

Bleeding ceases spontaneously in 40% of patients
Cirrhosis Screening and Surveillance Management

Esophagogastroduodenoscopy
No
varices
Repeat endoscopy in
3 years (well
compensated);
in 1 year if
decompensated
Small varices (<5 mm),

Child B/C, red wales
Beta-blocker
prophylaxis
No beta-blocker
prophylaxis
Adapted from Garcia-Tsao G et al. Hepatology. 2007;46:922-938.
Medium or
large varices
Child Class A, no red

wales: Beta blockers
Child class B/C, red
wales: Beta blockers,
or endoscopic band
ligation
Management of Acute Hemorrhage

Patients with suspected acute variceal hemorrhage
require intensive-care unit setting for resuscitation and
management
Acute GI hemorrhage requires:
Intravascular volume support
Blood transfusions
Maintaining hemoglobin of ~7-9 g/dL
Institute short-term (5-7day) antibiotic prophylaxis

Initiate therapy with somatostatin (or its analogs)
Perform esophagogastroduodenoscopy within 12
hours; treat with endoscopic band ligation or
sclerotherapy
Acute Hemorrhage: Role of Early TIPS
Garca-Pagn, Juan Carlos, et al. "Early use of TIPS in patients with cirrhosis and variceal bleeding." New England Journal of
Medicine 362.25 (2010): 2370-2379.
Bacterial Infection and Variceal Bleeding

Variceal bleeding associated with increased risk of
bacterial infection
SBP (spontaneous bacterial peritonitis), urinary tract infection,
pneumonia or bacteremia
Develops in 20% of patients within 48 hours and in

35% to 66% of patients within 2 weeks
Compared to patients without infection, presence of
infection is associated with
Failure to control bleeding (65% vs 15%)
Early rebleeding
Mortality (40% vs 3%)
Vivas S et al., Dig Dis Sci. 2001;46:2752-2757.
Antibiotic Prophylaxis During/After

Acute Variceal Bleeding
Prophylatic ofloxacin vs
antibiotics only at
diagnosis of infection
Less rebleeding within

7 days
blood transfusions
for rebleeding
Rebleeding
infections (2/59 vs 16/61)
1.0
Prophylactic antibiotics (n=59)
0.8
On-demand antibiotics (n=61)
0.6
0.4
0.2
Prophylactic antibiotics
recommended in
management of acute
variceal hemorrhage
0.0
0
3 12 18 24 30
Follow-up (Months)
Hou M-C et al. Hepatology. 2004;39:746-753.
Key Points
Always consider variceal bleeding in the
differential for anemia in a cirrhotic
Always give prophylactic antibiotics in
setting of a variceal bleed- they save lives
Always manage in the ICU and get an EGD
for therapy and risk stratification
Always consider beta blocker prophylaxis
on discharge to prevent or delay rebleed
Liver Transplantation Options
Cirrhosis Was the Most Common

Reason for Liver Transplant in 2007
Non-cholestatic
cirrhosis
Cholestatic liver
disease/cirrhosis
Acute hepatic necrosis
Biliary atresia
Metabolic diseases
Malignant neoplasms
Other/unknown
N = 6223 Recipients of Deceased Donor Livers
Available at: http://optn.transplant.hrsa.gov/ar2008/904a_rec-dgn_li.htm. Accessed 10/05/10.
Contraindications - Absolute
Extrahepatic malignancy unless tumor free for >2
years and probability of recurrence <10%
Alcoholic hepatitis /untreated alcoholism /
chemical dependency
Extrahepatic sepsis unresponsive to medical
therapy
High dose or multiple pressors
Severe multiorgan failure
Severe psychological disease likely to affect
compliance
Extensive portal vein and mesenteric vein
thrombosis
Pulmonary HTN (mean PAP >35mmHg)
Contraindications - Relative
General debility
Portal vein thrombosis
HIV infection
Extensive prior abdominal
surgery
social isolation
Listing for Transplant

Once evaluation is completed and
contraindications excluded must meet
minimum listing criteria: CPT=7
Currently a MELD score of 15
UNOS: organs allocated locally then
nationally
Organs are matched by blood type and size
Priority is based on MELD score
Wait List and Transplant Activity for Liver

19992008
26,407
Number
of
Patients
20,965
On Waiting List Annually

Received Transplants Annually
Died While on Waiting List Annually
6,069
4,49
8
1,894
1,554
Year
US department of Health and Human Services OPTN. Available at: http://optn.transplant.hrsa.gov/data/.
Accessed 02/12/11.
Patients Awaiting Transplantation

Management
Close follow-up with primary GI MD

Preparation/support of family and patient
Treat promptly complications
Avoid therapies/interventions that would make
transplantation more difficult
-Nephrotoxins
-RUQ surgery/shunts
-Anesthesia
Consider living donor transplant
cumulative percent
Patient survival by era

100
90
80
70
60
50
40
30
20
10
0
1968-1970
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
1996-
years posttransplant
Patients on waiting list have highest risk

of death in USA with poor availability of
organs
Where does your state stand?
LDLT survival 83% at 5 years

INTENTION TO TREAT ANALYSIS:
Risk of Death is 40% lower compared
to
No living donor
On the wait list for DDLT
HCC patients MELD>15 risk of death
is 29% lower with LDLT
NO benefit of LDLT in HCC MELD<15
(due to allocation points)
Assessment: Decompensated
cirrhosis with MELD 32 complicated by
1) Overt hepatic encephalopathy
Treat infection, bleed, correct
hyponatremia, give lactulose, rifaximin
6) Anemia variceal bleed
2) Ascites
Tap regardless of INR/plts, treat
SBP, give albumin d1 and d3 and
for LVP, home on SBP
prophylaxis but NO PPI
3) Right pleural effusion Hepatic Hydrothorax. No chest

tube.
4) Acute kidney injury

Likely pre-renal. Hold diuretics.
Volume challenge with 100 gm
albumin X 2 days
ICU, EGD, octreotide, ?early TIPS,

prophylactic abx NOW, beta
blocker on d/c.
7) Coagulopathy
Cant assume auto-anticoagulated,

low risk of bleed with paracentesis
8) Hyponatremia
SIADH and diuretics- hold

diuretics, volume repletion
9) Distended gallbladder
VERY HIGH SURGICAL RISK.

Percutaneous gallbladder drainage
if acute choly is confirmed.
Suspect simply related to ascites.
Objectives
By the end of this session participants
will:
Recognize the HIGH risk of mortality in
these patients
Remember at least 3 tips for managing the
common complications of cirrhosis
encountered by hospitalists
Consider early referral for transplant
evaluation in patients with decompensated
cirrhosis
Special Thanks
Mohamed Hassan
Coleman Smith
Julie Thompson
Jack Lake
Brad Benson
Questions?
brow2110@umn.edu
Surgery in the Liver Patient

30 Day
Mortality by
MELD
Score
Teh, Swee H., et al. "Risk factors for mortality after surgery in patients with cirrhosis." Gastroenterology 132.4 (2007):
1261-1269.
Anticoagulation in the
Cirrhotic Patient
Cannot assume auto-anticoagulation

If bleeding risks are low the balance can shift to prothrombotic state.
Anticoagulation may be safely managed in cirrhosis
Case by case risk-benefit assessment required
4 am Cross-Cover Call: Can I get a

Tylenol order for Mr. Johnson?
Acetaminophen at usual doses (650 mg orally, max 3

gm/d < 1 week) may be used safely in compensated
cirrhosis
May give inpatient at 650 mg dose < 2 gm / 24 hrs for
short term use in more severe liver disease
2 am Cross-Cover Call:
Lab called and the Na is 128
Common: 50% of hospitalized cirrhotics with
Na < 135, 20% < 130
Associated with worse prognosis: MELD-Na
Hyponatremia in Cirrhosis
Renal water retention >>
Sodium retention related to
SIADH
Fluid restriction/ low Na diet
for most patients
Minimally effective
Reduction or d/c of diuretics

often required
Aquaresis with vaptan
drugs available and
effective but EXPENSIVE
Optimizingoxygendeliveryinthe
microcirculation:
Implicationsforbloodtransfusion
Erik B. Kistler, M.D., Ph.D.

Department of Anesthesiology & Critical Care
VA San Diego/University of California, San Diego
Ihavenodisclosures
Oxygendelivery(DO2)inhealthandcriticalillness
Theroleofinspiredoxygeninthemicrocirculation
Implicationsforredbloodcelltransfusioninthe
microcirculation
O2 Delivery:DO2 =CO*CaO2
ArterialO2 content:CaO2 =SaO2*1.39*Hb+0.0031*PaO2
DO2 =CO*(SaO2*1.39*Hb+0.0031*PaO2)
Assumption:
IncriticalillnessinadequateO2 deliverytotissuesis
theproblem(cellularhypoxia)
Iftrue,DO2 shouldimproveoutcomes
ShoemakerWC,etal.Chest1988;94:1176
Boyd,etal.JAMA 1993;270:26992707
Gattinoni L,etal.NEngl JMed,1995;333(16):102532
HayesMA,etal.NEngl JMed1994;330(24):171722
RiversE,etal.NEngl JMed2001;345(19):136877
AlKhafaji A,etal.JCriticalCare2008;23,603606
Macrocirculation andGoalDirectedTherapy
Cellularhypoxiaisthoughttoarisefrom:
Barcroft,J.LancetII:485,Sept4,1920
Hypoxemia:PaO2 insufficientO2 inspired
Stagnation:cardiacoutput inadequatebloodflow
tocarryO2 totissues
Anemia:hemoglobin insufficientO2 transported
Microvascularperfusion
Histotoxic:tissuescannotuseO2,evenifavailable
Histotoxichypoxia
(Cytopathichypoxia)
Organdysfunctionincriticalillnessattissueandcelllevel
Cellsexhibitderanged(oxidative)functionbutdont
necessarilydie(necrosisvs apoptosis)
Organsmaytransition
tohibernationstate
FinkMP.Crit Care.2002;6(6):4919
Reviewofthevasculature
Arteries:
Capillaries:
Veins:
20%ofcirculatingbloodvolume
5%
75%
Capillariescontaingreatestsurfacearea(1200m2)
Smallarteriolesarethemostimportantdeterminantsof
vascularresistance
Tissueperfusionoccursat
themicrocirculation
Oxygendelivery
Kroghcylindermodel:Assumption:allunloadingofO2 occurs
atthecapillarybedalongalongitudinalaswellasradialgradient
PaO2 (mmHg)
100
80
60
40
20
ArteriesArterioles
Capillaries
Venules
Veins
Oxygendelivery
PaO2 (mmHg)
Newmodel:UnloadingofO2 predominantlyatthearteriolarlevel
Nomenclatureformicrocirculation
Intaglietta,M,etal.Cardiovasc.Res.32:632643,1996.
DistributionofO2 inhamsterskinfoldpreparation
Intravascular
Extravascular
TissuePO2
~820mmHg
Minimumtissue
PO2 needed
probably~2.3
2.8mmHg
SafetyMargin
O2 distributionatthevesselwall
60
Vessellumen
PaO2 (mmHg)
50
40
Hamsterskinfold
arteriole
O2 diffusionintissueislimited:
30
Assumingischemicthreshold~35mmHg,
diffusionislimitedtoamaximumof6070m
20
10
10
Vesselwall
20
40
60
80
Distance fromVesselWall(m)
WhyisthereanO2 gradientatthevesselwall?
HighO2 consumptionbyarteriolesandendothelium:Active
metabolism smoothmusclecontraction
venousPO2 necessaryformetabolism,safetymargin(?)
Longitudinaldifferencesdependingontissuestudied:
Brain:considerablelongitudinalgradient,minimalarteriolarvessel
wallgradient
Skeletalmuscle:lessofalongitudinalgradient,greaterarteriolar
vesselwallgradient
Whathappenswhensupplementaryoxygen
isaddedtohealthytissue?
Oxygenextractionby
vesselwallsasthey
contract
Functionalcapillary
density(FCD)
Shunting
IsthistopreventO2
toxicitytotissues?
TissuePO2 maybe
theregulatedvariable
Wagner,P.Eur Respir J2008;31:887890
SchematicofMicrocirculation
HighPaO2 maylimit
O2 deliverytotissues
Limitedshunting:
O2 tovenouscirculation
safetyfeature:
vasodilates withPaO2,
vasoconstricts withPaO2
regulatestissueO2?
Tissueperfusionincriticalillness
Orthogonalpolarizationspectralimagingunderthetongue(human)
Healthyvolunteer
BP120/80
SaO2 96%
Ptinsepticshockafter
resuscitationwithcrystalloids/
colloid,lowdosedopamine
HR82
BP90/35
SaO2 98%
CVP25mmHg
Taken from sepsis.com
MicrocirculationinSepsis
Capillarybedconstricts
(eNOS?)
Thismaybeexacerbated
bypressors
Shuntvasoconstriction
isinhibited(iNOS?)
MicrocirculationinSepsis
DO2 =CO*(SaO2*1.39*Hb +
0.0031*PaO2)
DO2micro DO2
O2 consumption:VO2 ~SvO2
FCD
Oxygendeliveryinthemicrocirculation
Stokesflow
Highlynonlinear
WBCsticking,RBCstiffening,
Endothelialcellswelling
flow~dp/dx*1/
Hb
Fahraeus effect
SaltzmanDJ,etal.Microsurgery.2013 Mar;33(3):20715
Howcanweperfusiontothemicrocirculation?
Isitpossiblethat
FiO2 mightmakeup
for flow??
Changesintissueoxygentension
80
inducedbyhyperoxiaatdifferentHcts
Hct 48%
60
Microvascularoxygentensionsat21%FiO2
Hematocrict
Arteriolar
mmHg
Venular
mmHg
Tissue
mmHg
48%(BL)
48 8
34 6
21 2
28%
51 9
27 6
20 2
11%
30 6
10 4
2 1
Valuesaremeans SD.
Hyperoxiainducedchange, %
40
20
0
20
Arteriolar
Venular
80
Tissue
Hct 28%
60
40
20
0
20
40
Arteriolar
Venular
Tissue
80
Hct 11%
60
40
20
0
FiO2 to100%
20
Arteriolar
Venular
Tissue
Cabrales,P(2013)
ShouldweFiO2 incriticalillness?
FiO2 asnecessarytoachieveadequateSaO2
PaO2 deliveredtotissues:
Inanemia ButtotalDO2
Inexercisingmuscle
Note:COfrom~520L/min
Criticalillness?
Generally,NO
Focusshouldprobablybe
onperfusionnotO2 perse
KnightDR,etal.Jappl Physiol.81(1):246251.1996
Microcirculatory
responseto
changing
systemicHb
MicrovascularHb
WhatistherelationbetweenHbinthe
systemicversusthemicrocirculation?
SystemicHb
Microcirculatory
responseto
changing
systemicHb
Resistancetoflow
HH Lipowsky andJC Ferril,AJP,1986
SystemicHb
Microvascularflow
Microcirculatory
responseto
changing
systemicHb
SystemicHb
Microcirculatory
responseto
changing
systemicHb
DO2
SystemicHb
O2 Delivery:DO2 =CO*CaO2
ArterialO2 content:CaO2 =SaO2*1.39*Hb+0.0031*PaO2
DO2 =CO*(SaO2*1.39*Hb+0.0031*PaO2)
Howdoeschangingtheseparametersaffect
oxygendeliverytothemicrocirculation?
Hb normal
IncreasePaO2
IncreaseHb
IncreaseCO
Hb =7
IncreasePaO2
IncreaseHb
IncreaseCO
Hb =7
14%inDO2
IncreaseHb
1UPRBC
Hb =7
IncreaseHb
Saugel etal.ScanJofTrauma,
ResuscitationandEmergencyMed
2013,21:21
0.5U
1U
2U
0.5U
1U
2U
Tsai,etal2014
Hb =7
IncreaseHb
Hb =7
~3UPRBCs
IncreaseHb
Whatexplainsthisresult?
DO2 =CO*(SaO2*1.39*Hb+0.0031*PaO2)??
ButDO2 DO2micro
CalculatedDO2micro aftertransfusionneverachieves
normalO2 delivery
BloodtransfusionaffectssomethingotherthanHb!
Inflammatoryresponse!!
Endresult:SVRmicro andmicrovascularperfusion
Ramifications:
>50%ofbloodtransfusedisin12UPRBCs
Nonbleedingpatientsmightbeabletobe
effectivelytreatedwithfewertransfusions
Novelbloodsubstitutesimprovingmicrovascular
flow (ratherthanO2 carryingcapacity)could
potentiallybeeffectiveinterventions.
Summary
Macrovascularhemodynamicscorrelateonly
weaklywithmicrovascularperfusion
FiO2 >thannecessarytomaintainSaO2 isprobably
oflimitedefficacyexceptinlowHb states
TransfusionwithlimitednumbersofPRBC (<2U)in
nonbleedinganemicpatientsisprobablyoptimal
Transfusionof2UPRBCs DO2micro >>predicted
Thanks!
MarcosIntaglietta
AmyTsai
PedroCabrales
Microhemodynamics Laboratory
DeptofBioengineering
UC SanDiego
Thanks
O2 distributionatthevesselwall
O2 measurementresolution:
Palladiumporphyrin phosphorescencequenching:10m
TissueO2 probes:250>1000m
Bloodoxygendependent(BOLD)fMRI:10005000m
PETscan:>3000m
NIRS >10000m
60
Vessellumen
PaO2 (mmHg)
50
40
30
Hamsterskinfold
arteriole
O2 diffusionintissueislimited: Assumingan
ischemicthresholdof~35mmHg,undernormal
conditionsdiffusionislimitedtoamaximumof6070m
20
10
10
Vesselwall
20
40
60
80
Distance fromVesselWall(m)
Preload Optimization in Sepsis and

Other Hemodynamic Crises
53nd Annual Weil/UC San Diego Symposium on
Critical Care & Emergency Medicine
(April 11, 2015)
Ral J. Gazmuri MD, PhD, FCCM

Resuscitation Institute
at Rosalind Franklin University
and
Captain James A. Lovell Federal
Health Care Center
(Section of Critical Care Medicine)
Conflicts
Funding for research on various aspects of

resuscitation from cardiac arrest and
hemorrhagic shock and role of mitochondria
(DoD, VA Merit Review, Zoll, Baxter, Friends
Medical Research Institute, DePaul-RFU, and
ALGH)
None related to the current presentation
Outline
Definition of preload optimization and its
necessity
Blood delivery is inadequate
How to assess adequacy of blood delivery

Clinical (signs of perfusion and organ function)
Metabolic (lactate and SvO2, perhaps)
Concept of preload
How to assess and guide its optimization
Upstream effects
PRELOAD OPTIMIZATION
The concept of preload optimization
applies primarily to states of
inadequate blood delivery and
circulatory shock
Circulatory shock can be defined as the
sustained failure to deliver and/or
utilize the oxygen required to meet
metabolic demands as a result of
circulatory (macro or micro) deficits
Why is oxygen needed?
500 nm
B
100 nm
CYTOSOL
OMM
H+
H+
H+
H+
ADP
C
IMM
e-
III
IIeNADH
H+
FADH2
H+
IV
O2
H+
ANT 180 mV
ATP
H2 O
ATP
ADP+Pi
MATRIX
FoF1 ATP
synthase
CYTOSOL
MITOCHONDRIA
Cr
ATP
ATP
ATP
CK
ADP
ATP
CK
CK
ADP
CK ATPase
ADP
pCr
Glycolysis
Cytosolic
ATP/ADP ratio
ADP
Cytosolic
ATP consumption
Oxidative
Phosphorylation
32 ATP
2 ATP
Somepeoplemayrecognizethename,butfewcancomprehendhow
muchthismanhasdoneforthefieldsoftraumaandcriticalcare.Dr.
Weilwasaworldclassclinician,teacherandresearcher,andisbelieved
tohavecoinedthephrasecriticalcaremedicine.
Someofhismanynotableaccomplishments:
In1955,Dr.Weilcreatedthefirstbedsideshockcart,whichisnow
knownasthecrashcart.
Inthelate1950s,heandhiscolleaguesrecognizedthatsomepatients
whowereseriouslyillorwhohadundergonemajorsurgeryhada
propensitytodieatnight.Hehitupontheconceptthathavinganarea
forclosermonitoringofthesepatientsmightallowforearlierrecognition
ofacuteproblemsandearlierinterventiontocorrectthem.Thisledto
thecreationofafourbedshockward.Thiswastheprecursortothe
firstintensivecareunit,whichopenedin1968.
Introducedautomatedvitalsignsmonitorsin1961.
Createdthefirstcomputerassisteddiagnosistoolsin1976.
DevelopedtheSTATlabconceptforrapidresultsincriticallyillpatientsin
1981.
Hewasthecoinventorfor22patenteddevicesincluding:
Resuscitationblankettoprotectmedicalpersonnelfromelectricshocks
whendefibrillatingpatients(2002).
Capnometer forassessingtheseverityofshockwhichcanbeplacedin
theupperGItractorunderthetongue(2001).
TheWeilMiniChestCompressor(2006)
AnIVpumpsystem(1981),detectionforocclusionorinfiltration(1985)
Osmoticpressuresensor(1977)
Highfrequencyventilator(1983)
AmethodforidentifyingcardiacrhythmevenwhileCPRisinprogress
(2006)
Dr.WeilestablishedtheInstituteforCriticalCareMedicinein1961,and
workedtherefulltimeafterhelefttheUniversityofSouthernCalifornia.
Theinstitutetrainsphysiciansandengineerstodiscoveranddevelop
conceptsandmethodsformorebeneficiallifesavingmedical
management.Hesteppeddownasthepresidentoftheinstitutein2006,
butcontinuedtoworktherefulltimeuntiltwoweeksbeforehedied.
Theworldhaslostatruephysician,teacherandinnovator.
MaxHarryWeilMD,PhD
(Feb9,1927July29,2011)
O2
CcO2
CvO2
10
10
CcO2
1.39
0.003
1.39
0.003
0.25
75
50
0.75
20 ml/dl 25
0
0
O2
SO2 (%)
100
CaO2
15 ml/dl
25 50 75 100
pO2 (mmHg)
2
2
2
20
0.25
15
20
0.75
Inabilitytoconsumeoxygen(e.g.,microcirculatoryshunt)
20
0.25
15
SYSTEMIC OXYGEN DELIVERY

DO2 = CO x 10 x CaO2
AL
CO = HR x SVf
SV = EF x EDV
PL
CTR
CaO2 = 1.39 x SO2 x Hb + PaO2 x 0.003
ADEQUACY OF PERFUSION
Bedside assessment of perfusion
Reduced peripheral skin blood
flow (pulse, temperature, refill)
Reduced urine output
Tachycardia
Hypotension (supine orthostatic)
Altered mentation
CARDIAC LOOP: DIASTOLIC DYSFUNCTION
mmHg
150
End of
systole
Diastolic
dysfunction
For a given enddiastolic volume
(preload), there is a
greater end-diastolic
pressure
50
End of
diastole
100 mL
50
CARDIAC LOOP: SYSTOLIC DYSFUNCTION
mmHg
150
End of
systole
Systolic
dysfunction
Dilation is
accompanied by
decreased compliance
and increased enddiastolic pressure
50
End of
diastole
50
100 mL
PRELOAD AUGMENTATION
Stroke Volume
Increased
contractility
Normal
Depressed
contractility
End Diastolic Pressure
TRANSMURAL PRESSURE
5 - (-1) = 6
9-5=4
12
-1
12 - 12 = 0
12
PRELOAD ASSESSMENT
Fluid challenges are considered the
cornerstone for preload optimization
However, not all hemodynamically unstable
patients are volume responsive
Increasing evidence suggests that excess fluid
is associated with poor outcomes
Thus, assessment of fluid responsiveness
might be appropriate before embarking on fluid
loading
Static measurements (CVP, PAOP, IVC diameter,
LVEDA) may not be optimal for predicting
volume responsiveness
PRELOAD ASSESSMENT
Bedside assessment of jugular veins
Simple but requires skills; useful when
substantial volume deficit is present
correlates with IVC diameter and collapse
Central venous pressure

Poor correlation with RV preload and fluid
responsiveness
Pulmonary artery occlusion pressure

Similar limitations as CVP but useful to
titrate therapies
PRELOAD ASSESSMENT
Passive leg raise
Rapid (and reversible) translocation of 300 to 500 cc
of blood centrally
LV stroke volume changes during mechanical

ventilation
High sensitivity and specificity for fluid
responsiveness
SVC and IVC diameter changes with

respiration
High sensitivity and specificity for fluid
responsiveness
Passive Leg Rising
Alexander Levitov and Paul E. Marik. Cardiol Res Pract. 2012; 2012: 819696
IVC distensibility recorded with TTE during mechanical ventilation.

Expiration
Inspiration
IVC collapsibility recorded with TTE in a spontaneously breathing patient.

Early Goal-Directed Therapy in the Treatment of Severe

Sepsis and Septic Shock
Emanuel Rivers, M.D., M.P.H., Bryant Nguyen, M.D.,
Suzanne Havstad, M.A., Julie Ressler, B.S., Alexandria
Muzzin, B.S., Bernhard Knoblich, M.D., Edward Peterson,
Ph.D., and Michael Tomlanovich, M.D. for the Early GoalDirected Therapy Collaborative Group
N Engl J Med 2001; 345:1368-1377
Of the 263 enrolled patients, 130 were randomly assigned to
early goal-directed therapy and 133 to standard therapy; there
were no significant differences between the groups with respect
to base-line characteristics. In-hospital mortality was 30.5
percent in the group assigned to early goal-directed therapy,
as compared with 46.5 percent in the group assigned to
standard therapy (P=0.009).
H.J.C. "Jeremy" Swan

(1 June 1922 7 February 2005)
William Ganz
(January 7, 1919 - November 11, 2009)
Catheterization of the Heart in Man with Use of a Flow-Directed Balloon-Tipped

Catheter
H. J. C. Swan, M.B., Ph.D., F.R.C.P., William Ganz, M.D., C.Sc., James Forrester,
M.D., Harold Marcus, M.D., George Diamond, M.D., and David Chonette
N Engl J Med 1970; 283:447-451August 27, 1970
Pressures in the right side of the heart and pulmonary capillary wedge can
be obtained by cardiac catheterization without the aid of fluoroscopy. A No.
5 Fr double-lumen catheter with a balloon just proximal to the tip is inserted
into the right atrium under pressure monitoring. The balloon is then inflated
with 0.8 ml of air. The balloon is carried by blood flow through the right
side of the heart into the smaller radicles of the pulmonary artery. In this
position when the balloon is inflated wedge pressure is obtained. The
average time for passage of the catheter from the right atrium to the
pulmonary artery was 35 seconds in the first 100 passages. The frequency
of premature beats was minimal, and no other arrhythmias occurred.
From the Department of Cardiology, Cedars-Sinai Medical Center and the
Department of Medicine, University of California, Los Angeles
Hemodynamic Monitoring
Shock
RA
PA
PAOP
CO
Hypovolemic
Cardiogenic
Obstructive
Distributive
Starlings Equation
Net Flow = K[(Pc - Pi) + s(i - c)] - L
K = membrane permeability
coefficient
P = hydrostatic pressure
= colloid oncotic pressure
s = Staverman reflection coefficient

L = lymph flow
Case
76 year old male with multiple comorbidities
was found unresponsive with low O2 in the
medical floor and was transferred to ICU
CXR showed right lower lobe pneumonia &
pleural effusion. Started on BiPAP and
treated with antibiotics & fluids
Several days later hypercarbic acidosis on
BiPAP prompted intubation for mechanical
ventilation (PS 17, PEEP 5, FiO2 0.60)
Peripheral edema and large right pleural
effusion noted; serum albumin 1.7 g/dl.
Case
Thoracocentesis drained 2 liters of
transudate but patient remained on
mechanical ventilation
CXR showed significant pulmonary edema
not responding to diuretics
Recent echocardiography showed normal LV
size, walls, and systolic function, reversal of
E to A ratio, and estimated pulmonary artery
systolic pressure of <35 mmHg
A pulmonary artery catheter was placed 4
days later
Case
Cardiac index was 3.5
l/min/m2, pulmonary
artery occlusive pressure
12-15 mmHg, diastolic
pulmonary artery
pressure 22 mmHg, and
systolic pulmonary artery
pressure 60 mmHg;
consistent with precapillary pulmonary artery
hypertension
Case
Furosemide infusion started at 10 mg/h
monitoring pulmonary artery diastolic pressure
and cardiac index to avoid drop in preload
96 h
48 h
prominent diuresis without hemodynamic

compromised PAOP 10-12 mmHg and CI 3.5-4.0
l/min/m2
Case
PofC5
Hypovolemic
Cardiogenic
Obstructive
Distributive
Combination
HEMODYNAMIC INSTABILITY
Goal: Hemodynamic Stability
Hemodynamic
Instability
Yes
Assess
Continue/Modify
Treatment
Elevated Lactate (type A)

Infusion Vasoconstrictive
Agent
Skin/Kidney
Hypoperfusion
Preload
Cardiac Function
Vasoactive Drugs
Inotropic Drugs
Underlying Condition
Summary (II)
Have a goal and reassess at

frequent intervals
Exercise the various choices
available
Develop and trust your team
Measure outcomes and institute
new approaches as needed
Summary (I)
Preload optimization and its necessity
Blood delivery is inadequate
Risk of fluid accumulation
How to assess adequacy of blood delivery

Clinical (signs of perfusion and organ function)
Metabolic (lactate)
Concept of preload
Abnormalities in myocardial distensibility
Upstream effects and safety factors
Upstream effects to be avoided and treated

when they occur
MANAGEMENT OF
PATIENTS WITH ACUTE
EXACERBATION OF COPD
James Runo, MD
Pulmonary & Critical Care Medicine
University of Wisconsin-Madison
Financial Disclosures
None related to this topic
Objectives
Basic review on COPD including treatment
modalities
Pharmacologic therapies for COPD
exacerbations
Non-pharmacologic treatments for COPD
exacerbations
Preventive measures
Definition of Acute Exacerbation

Global Initiative for Chronic Obstructive
Lung Disease (GOLD) and WHO
One or more of the following cardinal
symptoms
Cough increases in frequency and severity
Sputum production increases in volume and/or
changes character
Increase in dyspnea
Chest radiograph usually unchanged
Implications
Often occur 1-3 times per year

50% not reported to physicians
3-16% require hospitalization
Hospital mortality 3-24%
Need for ICU admission increases mortality to 1530%
Adverse effects on functional status and QOL with
very slow recovery
May contribute to accelerated loss of FEV1
Mortality after Hospitalization

49%
33%
Connors, AJRCCM 1996; 154:959
Risk Factors For Exacerbations
Advanced age
Severity of FEV1 impairment
Chronic sputum production
Frequent prior exacerbations
Hospitalization w/in past year
Comorbidities
CAD
CHF
DM
Association of Disease Severity with the

Frequency and Severity of Exacerbations during
the First Year of Follow-up in Patients with COPD
Hurst, NEJM 2010; 363:1128
Differential Diagnosis
Pneumonia
Pneumothorax
CHF
Pulmonary embolism
Pleural effusion
Others
Recurrent aspiration
Upper airway obstruction
Arrhythmia
Diagnostic Studies
Chest radiography (for ED or hospital admits)
15-25% have abnormalities that will change rx
Spirometry not clinically useful

ABG
Mainly for hypercarbia assessment
Sputum cultures
Mainly for hospitalized patients
Outpatient empiric therapy effective
+/- Respiratory viral PCR panel

BNP
D-dimer
Procalcitonin utility still unclear
Soler, Eur Respir J 2012; 40:1344
Thorax 2004; 59 (supp I)

Snow, Chest 2001; 119:1185
Etiology
Infectious 80%
Bacterial 25-30%
Viral 25-30%
Co-infection 25-30%
Atypical bacteria 5-10%
Noninfectious 20%
Environmental exposures (NO2,
SO2, ozone, particulates)
Noncompliance
Sethi, Chest 2000; 117 (suppl):380S
New Bacterial Strain Acquisition

Sputum samples from 81 COPD (chronic
bronchitic) pts monthly and during exacerbations
Performed molecular typing
1,975 clinic visits with 374 exacerbations
Exacerbations occurred in 33% of clinic visits
with new isolate compared with 15.4% with
absence of new strain
Relative risk for exacerbation with new strain 2.15
Sethi, NEJM 2002; 347:465
Sethi, S. Proc Am Thorac Soc 2004; 1:109
Admission Considerations
Comorbidities
Frequent exacerbations
Severe COPD
New Arrhythmias
Diagnostic uncertainty
Older age
Insufficient home support
Rapidly progressing or sudden onset symptoms
Failure of outpatient treatment
GOLD, AJRCCM 2007; 176:532
Worrisome Signs
Accessory muscle usage

Paradoxical respirations
Little or no air movement
Cyanosis
Peripheral edema
Hypotension
Signs of right heart failure
Altered mentation
Treatment Options
Removal of irritants
Corticosteroid therapy
dust, pollutants,
cigarette smoke
oral, IV, or inhaled
AE-COPD
Bronchodilators
-agonists,
anticholinergics
Antibiotics
Low-flow oxygen
Ventilatory support
Pharmacotherapy
Bronchodilators Reduce Hyperinflation

and Thereby Reduce Work of Breathing
Sutherland, NEJM 2004; 350:2689
2-Agonist Agents
Sympathomimetic activation through 2 receptors
in lung
Side effects common
Tremor
Tachycardia
Anxiety
Albuterol sulfate
2.5 mg diluted in saline by nebulizer every 1-4 hrs
4-8 puffs by MDI every 1-4 hrs
Oral agents not recommended due to systemic side

effects
Anticholinergic Agents
Parasympathetic tone causes
bronchoconstriction at the level of the
smooth muscle cells
Ipratropium bromide
0.5 mg by nebulizer q4hrs
2-4 puffs by MDI q4hrs
Combination Therapy More Effective

Test Day 85
40
% Change in mean FEV
Albuterol (N=165)
35
Ipratropium (N=176)
Ipratropium + Albuterol
(N=173)
30
25
20
15
10
5
0
0
Hours After Test Dose
Chest 1994;105:1411
Metered Dose Inhalers vs Nebulizers
MDI
Nebulizer
Metered Dose Inhalers

Must be used with spacer device
for optimal drug delivery
Shake canister
At beginning of inspiration
actuate the MDI
Breathe in slowly to full
capacity and hold 4-10 secs
Wait 15-60 secs before next
dosage
Antibiotics in Acute Exacerbations

Overall Clinical Status
favors placebo
-1.0
favors antibiotics
-0.5
0.5
1.0
1.5
Effect size (SD)

Saint et al. JAMA. 1995;273:957
Antibiotics in Outpatient Setting
Sethi, Infect Dis Clin Am 2004; 18:861
Treatment Failures
32%
35
Relapse Rate (%)
Retrospective analysis of
ED outpatient treatment of
362 exacerbations at a
VAMC
95% of severe episodes
were treated with Abx
Relapse defined as return
visit w/in 14 days
30
25
19%
20
15
10
5
0
Abx
No abx
Adams, Chest 2000; 117:1345
Treatment Failures
Does choosing the correct antibiotic matter?
Relapse Rate (%)
60
50
40
30
20
10
0
Adams, Chest 2000; 117:1345
Antibiotic Summary
Outpatient
No Antibiotics
Mild COPD exacerbation w/o sputum production
Antibiotics
Mod-severe COPD exacerbation
Severe disease
Low risk doxycycline, bactrim, clarithromycin, azithro
Avoid amoxicillin as not effective against most H. influenzae and M.
catarrhalis
High risk quinolone, augmentin, cipro (Pseudomonas)

>65 yo, recent antbx, severe COPD, frequent exacerbations, cardiac dz
5-7 day duration
Inpatient studies show antbx helpful
Corticosteroids
No definitive evidence of improvement in
stable COPD patients
Only indication is acute COPD exacerbation
40 mg/day for 5-7 days outpatient
5-14 days for inpatient
Inhaled corticosteroids not indicated for

acute exacerbations
May prevent exacerbations
Corticosteroids Improve Outcomes in

Outpatient COPD exacerbations
Randomized 147 COPD
patients released from ER
to 10 days of placebo or
40 mg/day prednisone
10 days antibiotics
Bronchodilators
30 day f/u with relapse
primary endpoint
Aaron, NEJM 2003; 348:2618
Corticosteroids Improve Outcomes in

Hospitalized COPD exacerbations
271 patients with acute COPD exacerbation admitted to VA hospitals

randomized to placebo, 2 weeks, or 8 weeks of prednisone therapy
Methylprednisolone 125 mg IV q6hrs x 3 days then taper from 60 mg/day oral
Niewoehner, NEJM 1999; 340:1941
Oral Versus Intravenous

Retrospective study of 414 hospitals w/ AE-COPD, non-ICU
hospitalizations in 2006-7
79,985 pts total, 92% initial IV versus 8% oral
Median total dose 1st 2 days 600 mg IV vs 60 mg oral (prednisone)
Hospital mortality 1.4% (IV) vs 1.0% (oral)
Composite endpoint 10.9% (IV) vs 10.3% (oral)
Mechanical ventilation after 2nd day, death, readmission for AE-COPD
w/in 30 days
No differences after multivariable adjustments

Lower failures, LOS, and cost in orals in propensity-matched analysis
Lindenauer, JAMA 2010; 303:2359
Methylxanthines
Theophylline and Aminophylline
Possible mechanisms
Bronchodilator
Improvement in diaphragmatic function
Respiratory stimulant
Pulmonary vasodilator and cardiac inotrope
Narrow therapeutic window

Keep levels in 8-12 ug/ml range
Studies have failed to show benefit above that

obtained with bronchodilators and steroids
Hospitalized COPD Exacerbation

High doses of 2-agonists
Albuterol MDI 4-8 puffs q1-4 hrs or nebulizer
Ipratropium
MDI 2-4 puffs or nebulizer q4 hrs
Corticosteroids (5-14 days)

IV if severely ill, otherwise oral fine
Antibiotics (5-7 days)

Broad-spectrum IV if severely ill/pneumonia
Antivirals if influenza suspected

Hold on aminophylline/theophylline
Non-Pharmacologic
Therapies
Oxygen Therapy
Only therapeutic intervention that
impacts mortality in COPD long-term
Want to keep PaO2 60-70 mm Hg or
SaO2 88-92%
Never withhold oxygen due to CO2
concerns
Nocturnal Oxygen Therapy Trial

203 hypoxemic
COPD patients
Randomized
nocturnal or
continuous oxygen
Followed at least 1
year
Mortality 1.94 times
higher in nocturnal
group
Ann Intern Med 1980; 93:391
Medical Research Council Study

87 COPD patients
with hypoxemia, CO2
retention, and CHF
Randomized to
oxygen (> 15 hrs/d) or
not
Mortality 45% vs
67%
Lancet 1981; 1:681
Oxygens Effects on PaCO2

Oxygen therapy increased PaCO2 due to
Worsened V/Q mismatch from pulmonary vasodilator
effect (reversal of hypoxic vasoconstriction)
Haldane effect- increased SaO2 causes release of CO2
from Hb
Slight decrease (15%) in minute ventilation (drive to
breath)
Milic-Emili
Am Rev Respir Dis 1980;122:191
Am Rev Respir Dis 1980;122:747
Oxygen Parameters
General
PaO2 < 55 mm Hg or SaO2 < 88%
In the presence of cor pulmonale
PaO2 < 59 mm Hg or SaO2 < 89%

ECG evidence of P pulmonale
Hct > 55%
Clinical right heart failure
Air Travel
General estimate is PaO2 > 70 mm Hg
High altitude stimulation test (FiO2 = 0.15)
Nocturnal amount should be same as needed for exercise
Chest Physiotherapy
Chest percussion and vibration
Intermittent positive pressure breathing
(IPPB)
Postural drainage
Bronchoscopy
None have proven efficacy and may worsen
an exacerbation
Noninvasive Ventilation
Biphasic positive airway pressure
(BiPAP) most effective
Hypercarbia
Pressure support 5-15 cm H20
CPAP 3-5 cm H2O
Allows time for pharmacotherapy to
work
15
Pressure
IPAP
Pressure support
5
CPAP/PEEP/EPAP
0
Time
Brochard, NEJM 1995; 333:817
Intubation occurred usually in 1st 12

hours in both groups
More complications in control group

48% vs 16% (p = 0.001)
More pneumonia
Hospital LOS
35 days vs 23 days (p = 0.02)
Mortality
29% vs 9% (p = 0.02)
No difference in mortality after adjusting

for intubation
When to Use/Not Use NIPPV

Selection criteria
Mod-severe dyspnea w/ accessory muscle usage and/or paradoxical
abdominal motion
Mod-severe acidosis (pH < 7.35) and/or hypercapnia (PaCO2 > 45 mm
Hg)
Respiratory rate > 25
Exclusion criteria
Respiratory arrest
CV instability (hypotension, arrhythmias, MI)
Poor mentation, uncooperative
High aspiration risk
Heavy secretions
Recent facial/gastroesophageal surgery
Craniofacial trauma or nasopharyngeal abnormalities
Burns
GOLD, AJRCCM 2007; 176:532
Intubation Criteria
Unable to tolerate NIPPV or failure
Severe dyspnea w/ usage of accessory muscles and paradoxical
abdominal motion
Respiratory rate > 35
Life-threatening hypoxemia
Severe acidosis (pH < 7.25) and/or hypercapnia (PaCO2 > 60 mm Hg)
Respiratory arrest
Declining mentation
Cardiovascular collapse (shock, arrhythmias)
Other complications
Metabolic abnormalities, sepsis, pneumonia, PE, barotrauma, massive pleural
effusion
GOLD, AJRCCM 2007; 176:532
Preventive
ICS Do Not Slow Disease

Progression
912 mild COPD patients
actively smoking
Randomized placebo vs
800 mcg/d budesonide
Initial improvement in
FEV1 with ICS but after 9
months slopes same
End of 3 yrs placebo
group lost 180 ml and
ICS group lost 140 ml (P
= 0.05)
Budesonide Group
Placebo Group
Pauwels, NEJM 1999; 340:1948
ICS May Reduce Exacerbations and

Improve Symptoms
The Lung Health Study
ISOLDE Trial
1116 COPD pts

Placebo or 1200 mcg
triamcinolone for 40 months
No change FEV1 decline
Fewer lung Sxs (21.1 vs 28.2
per 100 person yrs)
Fewer physician visits (1.2 vs
2.1 per 100 person yrs)
Significantly lower BMD of
lumbar spine and femur
751 COPD pts

Placebo or 1000 mcg
fluticasone for 3 yrs
No change in FEV1 decline
Median exacerbation rate
decreased by 25%
Health status deterioration
significantly less
Small but significant decrease
in serum cortisol levels
NEJM 2000; 343:1902
BMJ 2000; 320:1297
TORCH Trial
3 yr study of 6,112
COPD pts
Reduction in
exacerbation rates for
LABA, inhaled steroid,
and combination
Annual exacerbation
rate was 0.85 in combo
group and 1.13 in
placebo
Higher pneumonia rates
with inhaled steroid
(alone and combo) and
mortality (inhaled
steroids alone, combo
lower)
Calverley, NEJM 2007; 356:775
Uplift Trial
5993 COPD pts given
Tiotropium or placebo for 4 yrs
Improvement in FEV1 pre and
post bronchodilator maintained
for Tiotropium long-term
No difference rate of FEV1 loss
Quality of life improved
Reduction in COPD
exacerbations
No mortality difference (p =
0.09)
Tashkin, NEJM 2008; 359:1543
Tiotropium vs Salmeterol
Tiotropium reduced risk of acute exacerbations in

moderate-severe COPD by 17% compared with salmeterol
Vogelmeier, NEJM 2011; 364:1093
Treatment Escalation
GOLD, AJRCCM 2007; 176:532
Azithromycin
1577 COPD pts randomized
placebo vs 250 mg/day azithro
AE-COPD
Azithro - 266 days 1st exacerbation,
1.48/yr
Placebo 174 days 1st exacerbation,
1.83/yr
Hearing decline by audiograms

25% azithro, 20% placebo
No cardiac differences
Albert, NEJM 2011; 365:689
Phosphodiesterase-4 Inhibitors
Roflumilast oral
PDE-4 inhibitor
1411 COPD pts
24 week trial
Improved FEV1
Trend for improved
symptoms
Slight decline in
exacerbations
Rabe, Lancet 2005; 366:563
Pulmonary Rehabilitation
Needs to have structured exercise training
w/wo educational classes
Benefits wane over time
Definite Improvements
Dyspnea
Exercise capacity
+/- Reduced exacerbations
Quality of life & Psychosocial
No mortality or spirometry benefits
Vaccinations
Influenza vaccinations
proven to prevent
acute respiratory
illness in COPD
patients
Pneumococcal
vaccination should be
given to those with
COPD
Wongsurakiat, Chest 2004; 125:2001
Influenza Vaccination
10 year observational
study 1990-2000
Elderly patients
~300,000 unvaccinated
~415,000 vaccinated
15-19% pts with lung dz

70%+ vaccination rate
Results:
27% reduction admits for
influenza & pneumonia
48% reduction in risk of
death
Nichol, NEJM 2007; 357:1373
Pneumococcal Vaccination
596 COPD pts followed over 979 days and
divided whether received pneumococcal
vaccination (PV)
Efficacy of PV in preventing infection
76% in pts < 65 yo (p = 0.013)

91% in pts < 65 with severe obstruction (p = 0.002)
48% in pts with FEV1 < 40% predicted (NS)
24% in all pt groups (NS)
Alfageme, Thorax 2006; 61:189
Age-related Decline in FEV1

FEV1 (% of value at age 25 y)
Never smoked or not susceptible to smoke

Stopped at 45 y
Stopped at 65 y
Smoked regularly and susceptible to its effects
100
75
50
Disability
25
Death
0
25
50
75
Age (y)
Tobacco Cessation
Nicotine replacement
Gum, patch, nasal, or inhaler
Doubles quit rate
Bupropion
Seizure d/o contraindication
Addition of nicotine little benefit
Varenicline
Partial agonist of nicotinic
acetylcholine receptors
Superior quit rate than buproprion
Insomnia and nausea
Neuropsychiatric effects
Gonzales, JAMA 2006; 296:47
Psychiatric and Palliative Care

Estimated 58% of COPD pts with psychiatric d/o
16% depression and 34% anxiety
SSRI or bupropion
Cautious usage of benzodiazepines
Palliative care of dyspnea

Oxygen therapy
Narcotics best agents
Benzodiazepines not effective
Yellowlees, Med J Aust 1987; 146:305
Lung Volume Reduction Surgery

Resection of nonfunctional lung
National Emphysema Treatment Trial (NETT)
Mortality benefit for Upper Lobe disease and poor
exercise capacity after pulmonary rehab
Worse mortality for FEV1 < 20% and either
homogenous dz or DLCO < 20%
All others may receive symptomatic benefit
Difficult to decide who to perform on

Fishman, NEJM 2003; 348:2059
Lung Transplantation
Consider once
FEV1 < 25%

Hypoxemia/Hypercarbia
Pulmonary HTN
Rapid decline or
complications
About 50% survival at

5 yrs with transplant
Unclear if survival
advantage
Algorithm for Management of Patients With AE-COPD
Celli, B. JAMA 2003;290:2721
Assessment of Pulmonary Gas Exchange

and Adequacy of Systemic Oxygen delivery
(April 11, 2015)

and
Health Care Center
Conflicts
ALGH)
500 nm
B
100 nm
CYTOSOL
OMM
H+
H+
H+
H+
ADP
C
IMM
e-
III
IV
IIeNADH
H+
H+
O2
FADH2
H+
ANT 180 mV
-
ATP
H2 O
ATP
ADP+Pi
MATRIX
FoF1 ATP
synthase
CYTOSOL
MITOCHONDRIA
Cr
ATP
ATP
ATP
CK
ADP
ATP
CK
CK
ADP
CK ATPase
ADP
pCr
Glycolysis
Oxidative
Phosphorylation
Cytosolic
ATP/ADP ratio
ADP
Cytosolic
ATP consumption
32 ATP
2 ATP

DO2 = CO x 10 x CaO2
AL
CO = HR x SVf
SV = EF x EDV
PL
CTR
CaO2 = 1.39 x SO2 x Hb + PaO2 x 0.003
MEASURING OXYGEN CONTENT

CaO2 = 1.39 x SO2 x Hb + PaO2 x 0.003
0.97
18.9
98
0.3
100
75
SO2 (%)
19.2 ml/dl
14
50
25
0
0
25
50
75
pO2 (mmHg)
100
MEASURING OXYGEN CONTENT

Functional O2 saturation
O2Hb
SaO2 % =
x 100
O2Hb+HHb
Fractional O2 saturation
O2Hb % =
O2Hb
O2Hb+HHb+COHb+MetHb
x 100

CaO2 = 1.39 x SO2 x Hb + PaO2 x 0.003
100
SO2 (%)
75
50
25
0
0
25
50
75
pO2 (mmHg)
100
OXYGENATION OF ARTERIAL BLOOD

Alveolar Gas Equation
PAO2 = FiO2 x (PB-PH2O) - PaCO2/RQ
0.21
760 - 47
40/0.8
100
75
SO2 (%)
99.7
50
25
0
0
25
50
75
pO2 (mmHg)
100

100
75
SO2 (%)

PA-a O2 gradient = 10 mmHg
50
25
0
0
25
50
75
pO2 (mmHg)
100
Normal
FiO2 x (PB-PH2O) - PaCO2/RQ = PAO2
0.21
760 - 47
40/0.8
PaO2
99.7
89.7 (96.8)

100
75
SO2 (%)

50
25
0
0
25
50
75
pO2 (mmHg)
100
Low FiO2 + Hyperventilation

PaO2
0.12
760 - 47
40/0.8
35.6
25.6 (47.2)
0.12
760 - 47
20/0.8
60.6
50.6 (93.5)

100
75
SO2 (%)

50
25
0
0
25
50
75
pO2 (mmHg)
100
Mount Everest + O2
0.21
236 - 47
40/0.8
1.00
236 - 47
40/0.8
-10
PaO2
-10
138.9 128.9 (98.5)

100
75
SO2 (%)

50
25
0
0
25
50
75
pO2 (mmHg)
100
Mount Everest + Hyperventilation

PaO2
0.21
236 - 47
40/0.8
-10
-10
0.21
236 - 47
12/0.8
25
15

100
75
SO2 (%)

50
25
0
0
25
50
75
pO2 (mmHg)
100
Acute Hypercarbia + O2
PaO2
0.21
760 - 47
80/0.8
49.7
39.7 (56.4)
0.30
760 - 47
80/0.8
113.9 103.9 (95.5)

100
75
SO2 (%)

50
25
0
0
25
50
75
pO2 (mmHg)
100
Chronic Hypercarbia + O2
PaO2
0.21
760 - 47
90/0.8
37.2
27.2 (43.9)
0.30
760 - 47
80/0.8
101.4
91.4 (95.9)

100

SO2 (%)
75
50
25
0
0
25
50
75
pO2 (mmHg)
100

100

SO2 (%)
75
50
25
0
0
25
50
75
pO2 (mmHg)
100
V/Q mismatch + O2
PaO2
0.21
760 - 47
40/0.8
99.7
0.40
760 - 47
40/0.8
235.2 175.2 (99.2)
O2
CcO2
CvO2
10
10
CcO2
1.39
0.003
1.39
0.003
0.25
75
50
20 ml/dl 25
O2
SO2 (%)
100
CaO2
15 ml/dl
39.7 (73.8)
25 50 75 100
pO2 (mmHg)
0.75
2
2
2
20
0.25
15
20
0.75
Inabilitytoconsumeoxygen(e.g.,microcirculatoryshunt)
20
0.25
15
O2
CcO2
20
0.25
15
20
0.50
10
20
0.75
50
25
0
O2
25 50 75 100
pO2 (mmHg)
1.39
SO2 (%)
100
CcO2
0.003
10
10
2
2
75
CaO2
50
25
CvO2
O2
25 50 75 100
pO2 (mmHg)
2
2
SO2 (%)
100
CcO2
20
0.25
15
20
0.50
10
20
0.75
75
CaO2
50
25
CvO2
0
0
O2
25 50 75 100
pO2 (mmHg)
1.39
SO2 (%)
100
CcO2
0.003
10
10
2
2
75
CaO2
50
25
CvO2
25 50 75 100
pO2 (mmHg)
2
2
75
50
25
0
0
SO2 (%)
100
CaO2
CvO2
CvO2
75
CaO2
CcO2
2
2
CvO2
O2
25 50 75 100
pO2 (mmHg)
SO2 (%)
100
CcO2
CvO2
10
CvO2
20 ml/dl 25
0
CvO2
10
50
O2
CvO2
0.003
75
CaO2
15 ml/dl
1.39
SO2 (%)
100
CcO2
CvO2
25 50 75 100
pO2 (mmHg)
20
0.25
15
20
0.50
10
20
0.75
CAPNOMETRY IN SUSPECTED PULMONARY EMBOLISM

WITH POSITIVE D-DIMER IN THE FIELD
Crit Care. 2009; 13(6): R196
Patients total
131
No 31
PETCO2 > 28 mmHg and

low clinical probability is a
potentially safe method for
excluding PE in patients
with suspected PE and
positive D-dimer test
Inclusion criteria
Di-dimer +
Yes 100
Clinical probability of PE (Wells criteria)

Unlikely 55
PETCO2
nasal
> 28 mmHg < 28 mmHg

35
20
PE 0
PE 14
Likely 45
> 28 mmHg < 28 mmHg

17
28
PE 3
PE 24
The combination of
PETCO2 < 28 mmHg and
high clinical probability is
a potentially safe method
for confirmation of PE in
patients with suspected
PE and positive D-dimer
SUMMARY
Oxygen is required to sustained electron transport at

the mitochondrial levels; which provides the energy
for establishing the proton-motive force that drives
ATP synthesis
Oxygen delivery is function of cardiac output and

arterial oxygen content
Most of the oxygen travels bound to hemoglobin and

therefore measuring the % of oxygen bound to
hemoglobin is more important than measuring PaO2
(SpO2)
Because hemoglobin uptakes oxygen as blood passes

through the pulmonary capillaries, knowing the
alveolar gas equation helps determine mechanism of
hypoxemia
SUMMARY
Widening of the alveolar-arterial oxygen gradient

caused by areas of low V/Q or zero V/Q (shunt)
venous admixture is a common mechanism of
hypoxemia
The oxygen content of venous admixture which is

determined by tissue oxygen extraction influences
arterial oxygen content
Mechanical ventilation with use of PEEP is intended to

reduce venous admixture
When PEEP fails, VV-ECMO should be considered.

Identification of areas of dead space ventilation (high
V/Q) could be useful in the diagnosis of pulmonary
embolism.
4/11/2015
Starting a Sepsis Program

Practice, Politics and Performance
Emanuel P. Rivers, MD, MPH
Vice Chairman and Research Director
Emergency and Surgical Critical Care Medicine
Henry Ford Hospital
Clinical Professor, Wayne State University
Detroit, Michigan
Institute of Medicine, National Academies
The Size of the Problem
4/11/2015
HealthGrades analyzed over 5 million Medicare

records of patients admitted through the emergency
department at 4,907 hospitals from 2006 through
2008, to identify the top 5% of the best-performing
hospitals in emergency medicine.
Changing the Landscape of Sepsis

Diagnosis and Treatment
4/11/2015
Pre-Hospital
ICU
General IPD Floors
ED
115 million visits/year.

2.9% of hospital admits are
severe sepsis and septic shock.
600,000 admissions per
year through the ED.
ED waiting times (5-6 hours)
approaching 24 hours.
67 minute delay to
ICU arrival.#
3 fold increase in
mortality.
After ICU Admission:

2 hour delay for PA catheter*
> 6 hour total delay for
hemodynamic optimization.
Shock outcome:
ICU - 24%
ED or GPU - 70%.
McCaig: MMWR, 2001, Angus DC et al. CCM, 2001,

Varon, CCM, 1997, Lundberg, 1998, CCM, Lefrant, 2000*, CCM
How can I do this at my Hospital?
The Problem:
Changing The Current Paradigm
4/11/2015
Cases per year Mortality (%)

Sepsis
859,858
15-20
Severe Sepsis
791,000
27-40
Septic Shock
200,000
36-47
Pneumonia
1,187,180
5-9
Stroke
591,996
6-7
Acute Myocardial Infarction
540,891
10
Trauma
697,025
5-16
Time Sensitive Diseases

Changing the Paradigm of Practice
AMI
Stroke
Trauma
< 10%
8-25%
< 5%
4/11/2015
Developing a program is not

as painful as it seems!
4/11/2015
Make it Entertaining
Fear?
Castor Bean
Ricin
Bacillus
Anthracis
Ebola
4/11/2015
Disaster Planning
215,000 Deaths/Year
A Sepsis Pilot
Recognizes trouble before it starts
Follows standard operating
procedures (SOP) for managing
sepsis.
Does not take little things for granted.
Understands the consequences:
Immediate
Long term
Holds everyone accountable

takes personal responsibility for
outcomes.
4/11/2015
The Devil is in the Details of a Sepsis Program
Epidemiology
3 Concepts
Understanding
the
Pathogenesis
6 hour
of
Documentation
and
Bundle
Teams
Standard Operating Procedures
Recognizing
one has a
problem?
Early Staging
of Illness
Severity
Timely
Interventions
Upon Arrival
Definitive
Care
ED or ICU?
Current Sepsis
Management
Early Markers
24 hour
Bundle
Documentation
And Orders
NAME
5 Page Order Set
Quality
Assurance
Improved
Outcomes
And Costs
CME
and
Peer
Uniformity
DRAFT
PORTER
INSULIN INFUSION PROTOCOL FOR THE INTENSIVE CARE UNIT
ACCT #
NAME:
ACCOUNT #:
PORTER
Item # 12339
Form # 645014
Revised 1/2006
SEVERE SEPSIS MANAGMENT

Corticosteroids
ITEM # 13081
PORTER
XIGRIS (DROTRECOGIN
ALFA) PROTOCOL
DATE:
Name:
Acct #:
Date:
REVISED 4/05
GENERAL CONSIDERATIONS
Insulin
Rev 1/05
infusion will be considered if a patient is in the Intensive Care Unit (ICU) and blood sugar is greater than 110 mg/dl.
The insulin infusion will be titrated to maintain the blood glucose levels in the range of 80-110 mg/dl.
Intensive Insulin Protocol is to be discontinued on discharge from the ICU.
All IVPBs
in 0.9%
when
possible.
FOR
USENSIN
CRITICAL
CARE AREAS ONLY
Maximum infusion rate is 50 units per hour.

PREPARATION OF IV INSULIN INFUSION
F orm #730022
Item #11909
ROOM #:
DATE
PORTER
NAME:
ACCOUNT #:
FORM # 640012
ROOM #:
PHYSICIAN ORDERS
IMPORTANT: PLEASE USE BALL POINT PEN
Infusion should be mixed at a concentration of 1 unit of regular insulin per ml of 0.9% NS

SEVERE SEPSIS MANAGEMENT
Corticosteroids
and
Infuse
intomanage
an IV line using an infusion pump to control the rate.
The prescribing of Xigris is limited
to those
knowledgable
its use and in the care of critically ill patients with sepsis
who
Early
Goal
Directed inTherapy
Screening for Severe Sepsis:
Room #:
NAME:
ACCOUNT #:
mechanical ventilation. This therapy is to be initiated only in a critical care unit or in a patient waiting to be transferred
GLUCOSE
toMONITORING
a critical care unit.
DURING IV INSULIN INFUSION
11. Any other condition in which bleeding
a significant
hazard
constitutes
Blood glucose
monitored
Patient
every
meets
1 hour
the on
three
initiation
following
and aftercriteria
a rate change.
Xigris Therapy Inclusion
ITEM # Criteria:
13080
FORM # 640011
REVISED
4/05
Inclusion
criteria
or would be difficult to manage because of its
location
Blood
glucose
monitored
every
2 hours
glucose level is between 80-110 mg/dl
SIRS
Criteria:
Two
or more
ofonce
the blood
following
Suspect
infection
12. Age
less than 18 years
Blood glucose
monitored
hoursorif greater
glucose level
Temp
lessevery
than496.8
thanremains
100.4 between 80-110 for 24 hours
13. criteria
Pregnant
breastfeeding
SIRS
(3orout
of 4)
poorly
Bloodcontrolled
glucose
monitored
PRN
14. Uncorrectable
condition (e.g.
HR
neoplasm
greater
orthan or equal to 90
Patient
is receiving medical
vasopressors
other end-stage disease)
RR
greater than or equal to 20, or PCO2 less than 32
Patient
is mechanically ventilatedcount of less than
3 DRIP
OF INSULIN
15. HIV in association with a CD4 INITIATION
50/mm
WBC less than 4,000 or greater than 12,000
Cosyntropin16.Stimulation
Testlung, Iiver, pancreas
Bone marrow,
BloodorGlucose
small bowel transplantation
Insulin infusion rate
Perforated viscus
#: ITEM # 13079 FORM # 640010 REVISED 4/05
Bands
greater than 10%
17. Chronic
renalCortisol
failure requiring
hemodialysis
or peritoneal
dialysis
Baseline
Random
level Greater
than 110
mg/dl
Initiate insulin infusion @ 2 units per hour
18. Recent250
(within
7 days)
toSystem
increaseFailure:
the risk One or more of the following
PHYSICIAN ORDERS Modified SIRS Criteria
FOR(Three
USEorIN
CRITICAL
CARE AREAS
Organ
ONLY
Cosyntropin
mcg
IVP use of medications
Greater than known
220
mg/dl
Initiate insulin infusion @ 4 units per hour
more
of the following):
of
bleeding
including
aspirin,
NSAIDS,
COX-2
inhibitors,
clopidogrel
Temp less than or equal to 96.8F or greater than or equal to
level
Respiratory
Random
cortisol level 30 minutesIfand
next60
blood glucose
is between 110-140 mg/dl
Increase insulin infusion rate by 1 unit per hour
(Plavix), ticlopidine (Ticlid), and cilostazol (Pletal)
100.4F
IMPORTANT: PLEASE USE BALL POINT PEN
If next blood
glucose
level
Cardiovascular
is greater than 140 mg/dl
Increase insulin infusion rate by 2 units per hour
minutes
after cosyntropin
19. Concurrent
use of anyadministration
of the following
treatment
regimens:
HR greater than or equal to 90 bpm
OF INSULIN
a. treatment
doses after
of unfractionated
Renal
than orDRIP
equal
and Florinef
60MAINTENANCE
minute heparin (greater
Early Goal Directed Therapy Resp rate greater than or equal to 20 bpm or PaCO 2 less than Start Hydrocortisone
to 15units/kg/h) or until aPTTreturns
to baseline
Check
blood
within 60 minutes of starting insulin infusion and titrate according to table below. Use the lower rates for patients
glucose
Hematologic
Screening for Severe Sepsis:
cortisol level is drawn
or equal to 32mmHg
Inclusion Criteria
3
b. treatment doses of enoxaparin (Lovenox)
withinglucose
hours
before
is decreasing
rapidly (greater than 30mg/dl); the higher rate for those decreasing slowly (less than 30mg/dl). Infusion
WBC less than or equal to
4,000/mm
or greater
than following
or equal
12
Metabolic
Hydrocortisone
mg IVP every 6 hours whose blood
Patient
meets
the three
criteria
Suspect infection
Xigris50
infusion
may be titrated in increments of 0.5 units/hour.
to 12,000/mm3 or greater than 10% bands
Hepatic
Florinefc.50 treatment
mcg PO/NG
every
day (Angiomax), lepirudin
SIRS Criteria: Two or more of the following
doses
of bivalrudin
(Refludan)
SIRS
(2 out of 4)
FORUSE
INcriteria
CRITICAL
CARE AREAS ONLY
Blood Glucose
Insulin Infusion Rate
Argatroban
4 hours before Xigris infusion
CNS
or until
(altered
aPTTlevel of consciousness)
Stop hydrocortisoneorand
florinefwithin
if cortisol
Temp
lessone
than
than 100.4
SBP less than 90 mmHg after Organ
2-3 liters
of FailureCriteria
System
(Any
or 96.8
moreor
ofgreater
the following):
Stop insulin infusion and administer 25 ml dextrose 50% and check blood glucose in 1 hour.
Less than
returns
to baseline
change is greater than
or equal
to 9
Sepsis-induced
respiratory
HR greater
distress
than or
syndrome
equal torequiring
90
IMPORTANT:
fluid
PLEASE USE BALL
POINT PENacute
Infection:
Onethan
or
more
If greater
or
equaloftothe
80,following
resume infusion @ 50% of previous rate. If less than or equal to 80 recheck blood glucose in 1 hour.
60 mg/dl
d. warfarin, if INR is elevated due
to warfarin use,
warfarin
should
mechanical
ventilation
Continue
and florinef
for INR
761-79
days
RR greater than or equal to 20, or PCO2
less thanhydrocortisone
32
Lactate level greater than 4
Documented
Decrease infusion by 50% and recheck glucose in 60 minutes.
mg/dl
be discontinued
and the
should
be rev ersed
prior to starting
Septic shock requiring vasopressors despite fluid resuscitation
if Cortisol change isXigris
less than 9
WBC less than 4,000 or greater than 12,000
No change.
Place
Venous
O 2 Catheter Any 2 sepsis-induced
80-110 mg/dl
Anti-infective therapy
dysfunctional organs
Screening
forCentral
Severe
Sepsis:
e. thrombolytic therapy within
3 days mg/dl
(excluding
for catheter
greater than 10%
increase infusion by 0-1 units/hour
111-150
Place arterial line
usePneumonia
Respiratory Bands
Cardiovascular
Patient meets the three following
criteria
clearance) before Xigris infusion
151-180 mg/dl WBCs
increase infusion by 0.5-1.5 units/hour
RenalOrgan SystemHematologic
Fluid replacement:
Failure: One or more of the following
f.
glycoprotein IIb/IIIa antagonists within 7 days
before Xigris
SIRS Criteria: Two or more of the following
Metabolic
Hepatic
181-200
mg/dl
increase
infusion
by 1-3 units/hour and bolus with 2 units
CVP of less than or equal to 8
Perforated viscus
Respiratory
infusion.
100.4
CNS (altered level of consciousness)
Temp less than 98.6 or greater
than
201-250 mg/dl
increase infusion by 1-3 units/hour and bolus with 4 units
500 ml bolus of 0.9% sodium
chloride
Cardiovascular
Patient is not a candidate increase

for corticosteroids.
HR greater than or equal to 90
251-300 mg/dl
infusion by 1-3 units/hour and bolus with 6 units
every 30 minutes
Renal
Patient IS a candidate for Xigris therapy. Proceed with administration.
Xigris should be startedwithin
the first 24 hours of the first sepsisGreater than
Notify physician
RR
greater
than
or fluid
equalreplacement
to 20,induced
or PCO2
less than 32 Hematologic
MAP
less
than 65
after
organ dysfunction.
300
mg/dl due to :

WBC
less than 4,000
greatercc,than
12,000
Patient IS NOT a candidate for Xigris
therapy
Norepinephrine
16 or
mg/250
titrate
to
Metabolic
_______________________________________________________
Bands greater than 10%
Contraindications to the Use of Xigris (per package insert):
PORTER
Infection Criteria (One or more of the following):

Documented
SEVERE SEPSIS MANAGEMENT
Pneumonia
Early Antibiotics
WBCs
ROOM
DATE
ROOM #:
DATE
PHYSICIAN ORDERS
Inclusion Criteria
SIRS criteria (2 out of 4)
Organ System Failure (1 or more)
Infection (1 or more)
Cultures (prior to antibiotic administration):
Blood cultures
UA C & S
Sputum gram stain, C & S
Wound C & S
Early antibiotics (initial regimen should include 1
antibiotic from all 3 groups A, B, C):
A: Gram Negative Rod coverage (choose one)
Piperacillin/tazobactam (Zosyn) 3.375 g
IVPB every 6 hours
Imipenem/cilastatin (Primaxin) 500 mg
IVPB every 6 hours
Aztreonam (Azactam) 2 gram IVPB every 8
hours (for Penicillin allergy only)
B: MRSA coverage (choose one)
Vancomycin 1 gram IVPB every 12 hours
Linezolid (Zyvox) 600 mg IVPB every 12
hours
C: Quinolone or Aminoglycoside (choose one)
Gentamicin 5 mg/kg IVPB every day
Amikacin 15 mg/kg IVPB every day
Levofloxacin 750 mg IVPB every day
De-escalate initial antibiotic regimen at 72 hrs
1) No MRSA DC Vancomycin/Zyvox
2) No MDR pseudomonas select
appropriate regimen based on culture data or
clinical setting.
*Pharmacy will follow for antibiotic dosing
maintain a MAP equal to 65

Hepatic
SPECIAL CONCERNS
1. Active internal bleeding
MAP greater than 90
CNS (altered level of consciousness)
If the patient leaves the ICU without an ICU RN present, DC protocol and resume when patient returns to the ICU.
(within 3 months) hemorrhagic stroke
Organ System Failure: One or more of 2.
theRecent
following
Medication Order
Nitroglycerin 50 mg/250 cc,3.titrate
to (within 2 Infection:
One or or
more
of the surgery,
following
When tube feeding or TPN infusions are briefly interrupted, start D 10W @ 50cc/hr and continue to titrate the drip as above.
Recent
months) intracranial
intraspinal
or severe
Respiratory
Patient Wt:___________________________ (Please fill in)
maintain a MAP equal to 90head trauma
Discontinue the protocol when the patient resumes a P.O. diet.

Documented
Cardiovascular
4. Trauma with an increased
of life-threatening
bleeding
ScvO2 less than 70
Call physician for orders in patients with increased ICP.

risk
Anti-infective
therapy
IV Infusion Administration
Renal
of an epidural catheter
When
insulinweighing
infusion is
stopped for a non-protocol interruption, follow INITIATION OF INSULIN DRIP when resumed.
Dobutamine 500mg/250 cc 5.
IV,Presence
start at 2.5
Pneumonia
1. Mix drotrecogin alfa 10mg in 125mL0.9%NS
forthe
patients
less
6. Intracranial neoplasm
or mass
lesion or evidence of cerebral herniation
Hematologic
0.9%NS
Insulin requirements
may increase in patients receiving glucocorticoids or IV vasopressors.
mcg/kg/min, increase by 2.5 mcg/kg/min
than 154 pounds (70kg) or 20mg in 250mL
for patients weighing
WBCs
Metabolic
o shake.
When weaning vasopressors, check blood glucose every 30-60 minutes depending on the rate of weaning.
greater than or equal to 154 pounds (70kg). Do not
every 30 minutes until ScvO2
greater to the Use
Precautions
of Xigris
(per package
Perforated
viscusinsert and Prowess
2.
Infuse
through
a
dedicated
central
line
at
a rate of 24 mcg/kg/hour x 96
Hepatic
study of
criteria):
than or equal to 70, or maximum
20
hours total
3
Patient
notisaincreased
candidate
Early Goal Directed
Physician Signature:________________________________________________
Date/Time: _______________________________
CNS
(altered level of consciousness)
1. Plts less than 30,000/mm
, even ifiscount
afterfor
transfusions
mcg/kg/min.
3. If any bleeding occurs during infusion, stop infusion and inform
White Chart
Canary - Pharmacy
2.
PT-INR
greater
than
3,
aPTT
greater
than
100
Infection: One
or Dobutamine
more of the following
Therapy.
Hold
if:
physician immediately
3. Recent (within 6 weeks) GI bleeding
Documented
4. Note any time that infusion is interrupted and restarted. When infusion
Heart rate greater than 120
4. Recent (within 3 months) ischemic stroke
is
restarted,
resume
at
rate
of
24mcg/kg/hour.
Dose
escalation
or
bolus
5. Intracranial AVM or aneurysm
MAP less than 65 on nor-epinephrine
Pneumonia
6. Known bleeding diathesis
PHYSICIAN doses are not recommended.
DATE/TIME
5. Stop Xigris infusion 2 hours prior to undergoing any invasive surgical
If hematocrit less than 30%,
transfuse
7. Chronic
severe hepatic disease
WBCs
SIGNATURE: procedure or procedure with an inherent risk of bleeding. Once adequate
8. Acute pancreatitis with no established source of infection
PRBC
Perforated
viscus
hemostasisWHITE:
has been achieved,
be reconsidered
12
CHART initiation of Xigris may
CANARY:
PHARMACY
9. Patient with suspected meningitis and plts less than 45,000/mm 3
Measure lactate level in 4 hours
hours after major invasive procedures or surgery or restarted immediately
10. Surgery with general or spinal anesthesia within 12 hours before
Xigris infusion or the potential need for such surgery during infusion
Date / Time:
White - Chart
PHYSICIAN
SIGNATURE:
Canary - Pharmacy
DATE/TIME
WHITE: CHART
PHYSICIAN
SIGNATURE:
after uncomplicated less invasive procedures.

6. A prepared Xigris infusion is stable for 12 hours refrigerated and an
additional 12 hours at room temperature.
Physician Signature:
CANARY: PHARMACY
DATE/TIME
WHITE: CHART
CANARY: PHARMACY
Early Identification
4/11/2015
Annal of Surgery 2010
4/11/2015
15 - 40 Fold Increase in Mortality
10
4/11/2015
Risk Stratification or Early

Detection of High Risk Patients:
The Evidence for the
use of Lactate
11
4/11/2015
Risk Stratification of Sepsis

Hypotension, vasopressors:
Lactate > 4 Only:
SBP < 90 and Lactate > 4:
36.7%
30.0%
46.1%
What patients are at high risk for

global tissue hypoxia?
SvO2
4 mM/L
Case
78 year old female
T 39o C
Cough
Brown sputum
Right sided chest
pain
Crit Care, 2008
12
4/11/2015
MARKER ANALYSIS
Over 150 markers analyzed by immunoassay, including various
pro-forms, variants, and fragments.
Markers of :
Markers of :
Pro-inflammation
(e.g., CRP, TNF,
IL-1, IL-8)
Apoptosis
(e.g., caspase-3)
Vasoregulation
(e.g., BNP, proBNP,
bigET-1, calcitonin)
Anti-inflammation
(e.g., IL-10, IL-6,
soluble TNF
receptors)
Organ and tissue

dysfunction
(e.g., NGAL,
myoglobin, I-FABP,
pulmonary surfactant
proteins)
Coagulation and
fibrinolysis
(e.g., D-dimer, tissue
factor, protein C)
CREATING THE DIAGNOSTIC

MARKER CHECKLIST*
Protein C
Inhibits FV, FVIII, PAI-1, inhibiting
coagulation and promoting
fibrinolysis; reduces monocyte
cytokine production
Myoglobin
Marker of muscle
damage
Tissue hypoxia
CCL-19 / MIP-3b
Chemokine expressed in lymphoid
tissues; chemoattractant for
lymphocytes, macrophage progenitor
cells and NK cells
D-dimer
Coagulation/fibrinolysis disorders
play a major role in organ
dysfunction during sepsis
BNP
Ventricular dysfunction
associated with sepsis;
prognosis and marker of
tissue hypoxia
Myeloperoxidase
Enzyme expressed in neutrophils;
elevated in inflammatory conditions;
exhibits microbiocidal activity
*This list includes preliminary research as of October 2005.
13
4/11/2015
THE SEPSIS MARKER PANEL MMX VALUE

EXHIBITED HIGHER ROC AUC THAN MARKERS
DESCRIBED IN THE LITERATURE
MMX and Marker ROC AUC for Low Risk vs. High Risk on the subpopulations
of patients for which both the MMX and Marker values were determined
Enrollment Blood Draw
Marker
Procalcitonin**
CRP
WBC Count
Serum Creatinine
Lactate*
Number of Patients
Low Risk Hish Risk
101
320
177
748
147
736
147
726
38
310
0.78, Lancet, 2007
ROC AUC
Marker
MMX
0.76
0.83
0.75
0.83
0.66
0.83
0.63
0.83
0.59
0.83
P-value*
0.034
0.002
<0.001
<0.001
<0.001
0.78, Int Care Med, 2002
Low Risk = low risk infection or non infection

High Risk = high risk infection with or without severe sepsis and/or shock at enrollment
Subgroup of patients for which both the Marker and MMX were determined and compared in the paired test
* p-value for MMX Value AUC vs. Marker AUC; p-value and AUC apply to the subgroup listed under Number of Patients
** Procalcitonin was measured with the Brahms LIA assay
Stay Tuned!
Have blood
cultures be
drawn?
Has a lactate
been ordered.
Evaluate the
patient for
sepsis.
Antibiotics
Have blood cultures been drawn?
Has a lactate been ordered?
Evaluate the patient for sepsis.
14
4/11/2015
June 27, 2012 The FDA has approved the first nucleic
acid test capable of quickly detecting sepsis and
identifying markers of microbial resistance.
In less than 2.5 hours, the Gram-Positive Blood Culture
Nucleic Acid Test (BC-GP; Nanosphere Inc) detects:
12 gram-positive bacteria, including methicillinresistant Staphylococcus aureus, vancomycin-resistant
Enterococci, and Listeria.
Identifies antimicrobial resistance, genes that confer
resistance to methicillin/oxacillin and vancomycin.
1642 patient blood samples contaminated with grampositive bacteria:
93% to 100% accuracy compared with blood culture
methods.
A test for gram-negative blood cultures is currently in
development.
15
4/11/2015
The Need for Coordinated Care:

From the ED to the ICU
ED Course
54 year old male

Infected leg
B/P 107/79, HR 76
Base deficit -10 Meq/L
BNP - 4399
Lactate 15.5, ER for 9 hours
Fluids 4 liters, colloids
Antibiotics, Dobutamine
EGDT to ScvO2 of 78%
OR for amputation
16
4/11/2015
Where do you perform EGDT?

Emergency
Department
General
Practice Unit
Intensive
Care Unit
Hospitalist
EICU
CNP
ICU Based Strategy
17
4/11/2015
Transfer to Sepsis
Referral Centers
18
4/11/2015
You have to start somewhere and

you dont have to be perfect!
Crit Care Med, 2007
19
4/11/2015
You need continuous quality

improvement to see the outcome
benefit
How can we over come

the constipation in
sepsis management?
20
4/11/2015
Roberta Mooney
Sepsis Coordinator at HFHS
Daily
Assessment of
all admitted
sepsis patients
Monthly
Meetings and
Reports for all
ICUs and ED
Feed back to all

clinicians
21
4/11/2015
54.336 Billion
183% Increase
over 8 years
The Cost of Non-compliance

Noncompliance
Compliant
512
414
Hospital Length of Stay
20.8
15.95
Cost per admission
$191,468.3
$144,835.4
$12 Million per year
22
4/11/2015
March 6, 2013
Joint Commission
CMS
AHRQ
23
4/11/2015
2012
24
4/11/2015
Multi-center Severe Sepsis & Septic Shock Collaborative

St. Cloud Hospital
Henry Ford Hospital

Northwest Community
Detroit
Hospital
St. Joseph Mercy
Hospital
Christiana Care
Health System
California Pacific
Medical Center
Porter Memorial
Hospital
University of Kansas
Hospital
University Medical Center
at Brackenridge
Barnes Jewish
Hospital
Henry Ford Hospital

Wyandotte
25
4/11/2015
16% ARR
Kaiser, California
Ingredients of a Sepsis Program
Early
Detection
Appropriate
ICU
Disposition
Early and
Rapid
Intervention
Improved
Outcomes
ER
26
Endocrine Emergencies:
Thyroid Cases
Lori B. Sweeney, MD
VCU Health System
Famous golfers with thyroid disease

Ben Crenshaw: 1995 Masters
Winner
Patty Berg: Winner of the first
Womens National Open Golf
Tournament 1946
Pat Bradley: Top player in the
LPGA
Objectives
Review general principles of thyroid disease
Discuss Thyroid Emergencies
Provide some pearls for thyroid function test interpretation
Thyroid Function Tests

Generic term for thyroid blood tests
Used to define the thyroid status of a patient
Normative ranges may be laboratory specific
Normative ranges are different for pregnancy
Normal Physiology
Auto-regulation
Changes in thyroid function related to
changes in circulating iodide concentrations:
Wolf-Chaikoff effect
1. reversible iodide-induced inhibition of
organification (normals will escape from this
effect in around 10 days)
2. Inhibition of Tg proteolysis (clinically the most
significant pharmacologic effect of iodide acutely
inhibiting thyroid hormone release)
TSH
Glycoprotein consisting of alpha and beta
subunits
Binds to specific receptor on thyroid plasma
membrane
Stimulates all steps in thyroid hormone
synthesis and release.
Actions are mediated via cyclic AMP
Increases thyroid size and vascularity
Total T4 (Thyroxine)
99.97% protein bound
Half-life: approximately 1 week
Total T3 (Triiodothyronine)
99.7% of T3 is protein bound
80% comes from conversion of T4 in the
peripheral tissues
Half-life: approximately 1 day
Roughly 10 times more potent than T4
Thyroid Binding Globulin

TBG excess
TBG deficiency
Hypothyroidism
Liver: PBC, Acute
Hepatitis, Hepatoma
Myeloma
HIV
Collagen vascular disease
Estrogen
Drugs: clofibrate, nicotinic
acid, Heroin
Hyperthyroidism
Critical Illness
Starvation
Liver: cirrhosis
Protein losing enteropathy
Drugs: glucocorticoids,
androgens
Calculating the FTI

T4 X T3 Uptake
Free Thryoxine Index
Falsely elevated in heparin therapy

Falsely decreased in phenytoin and valproic acid therapy
Free T3
Discriminates extremely well between hyperthyroid
and euthyroid patients
Discriminates poorly between hypothyroid and
euthyroid patients
Some hyperthyroid patients will have normal serum
free T4 levels but elevated serum T3 levels
(referred to as T3 thyrotoxicosis)
Free T4
Free T4 by equilibrium dialysis (gold standard)
Direct Free T4 immunoassay
Calculated FTI (obtained using the T4 with
Tuptake)
Drugs: Heparin and Furosemide increase free T4
Decreased peripheral conversion

of T4 to T3
Propranalol
PTU
Corticosteroids
Amiodarone
Non-thyroidal illness
Sodium ipodate and iopanoic acid
Thyroid hormone degradation,

clearance, GI loss
Phenobarbitol
Rifampin
Cholestyramine
Carbamazapine
TSH Elevation
Hypothyroidism
Nocturnal TSH surge
Thyroid hormone resistance
Pituitary adenoma secreting TSH
Suppressed TSH
Euthyroid Sick Syndrome
Starvation
Elderly
Hypopitutarism
Hyperthyroidism
Suppressed TSH and drugs

Glucocorticoids
Opiates
NSAIDS
Dopamine and dopaminergic agents
Somatostatin
Amphetamines
Non-thyroidal Illness
Decreased peripheral conversion of T4 to
T3
Reduction in binding to TBG (impaired
hepatic synthesis/binding inhibitors)
Serum T3 is decreased more than T4
TSH is normal to mildly decreased
Free t4 is usually normal to decreased
Reverse T3 is increased
Thyroid Emergencies
Thyrotoxicosis----------------------Thyroid Storm
FEVER, MENTAL STATUS CHANGE, TACHYCARDIA
High mortality if untreated
(30%)
18 y/o
hispanic female
Postpartum x 12 weeks
Admitted for dyspnea
h/o weight loss
Sinus tach 130s
Beta-blockers started
Dyspnea significantly increased
EF 15%
PATHOGENESIS
Underlying pathology: Graves disease > toxic adenoma,
toxic multinodular goiter > hypersecretory thyroid caner
Precipitating events: infection, surgery, RAI, contrast dyes,
withdrawal of antithryoid medication, amiodarone therapy
Less common: exogenous TH ingestion, DKA, CHF,
Toxemia of pregnancy, partuition, severe emotional stress,
PE, CVA, trauma
PATHOBIOLOGY
SARLIS NJ. REV ENDOC & METAB DISORDERS 2003
High serum levels of circulating hormone: often not significantly

different among patients with storm and severe thyrotoxicosis
Acute or rapid increase in TH level: especially post thyroid
surgery, administration of RAI, sudden discontinuation of lithium
or antithyroid RX
Enhancement of cellular response to TH: infection, hypoxemia,
hypovolemia, lactic and ketoacidosi
s
)
Laboratory Findings
Elevated total and free thyroid hormone
Fully suppressed TSH (there is a delay however)
Mild hyperglycemia (catecholamines)
Hypercacemia (TH acute bone resorption,
hemoconcentration)
Leukocytosis with left shift
LFT abnormalities: most commonly elevated ALP
Burch and Wartofsky Scale

Thermoregulatory dysfunction
CNS alteration
GI-hepatic dysfunction
Tachycardia
Congestive cardiac failure
Precipitating event
Cumulative score of 45 highly suggestive
CLINICAL EXAMINATION
Signs of underlying pathology: significant orbitopathyGraves, goiter (smooth vs. nodular)
Tremor
Hyperreflexia
Warm, moist skin
Widened pulse pressure
Tachycardia-sinus tach, a fib
CNS-can have frank psychosis
TREATMENT
All patients with severe thyrotoxicosis should be treated in
the ICU
Reduce TH (secretion/production): both PTU and MMI block
intrathyroidal iodine organification, PTU blocks peripheral
conversion (probably not that significant)
PTU 200-250 mg every 6 hours
MMI 20 mg every 4 hours
Non-oral administration of
antithyroid drugs
Case reports of IV Methimazole (Hodak and colleagues)
Authors prepared IV methimazole by reconstituting 500 mg
methimazole in 0.9% sodium chloride to a final solution of 10
mg/ml
Filtered through a 0.22 mm filter and administered as slow
IV push over 2 minutes
Followed by a saline flush
Non-oral administration of
antithyroid drugs
Rectal suppository
Suppository: Zweig and colleagues prepared 14.4 g of PTU
tablets in 40 mL of light mineral oil and mixed in 36 grams of
cocoa butter solid melted in a hot water bath (maintained at
less than 60 C
Mixture was distributed into thirty-six 1 gram suppository
mold and then frozen until solid
Each contained 400 mg of PTU
Administered every 6 hours
Documented therapeutic blood levels
TREATMENT CONT.
Inhibition of release of preformed thyroid hormone:
Wolff-Chaikoff effect: administer cold stable iodine as SSKI
(8 drops every 6 hours)..remember always at least 1 hour
after PTU or MMI
Sodium ipodate/iopanic acid not generally used
(hyperosmolar), but they also reduce peripheral conversion
to T3, as well as T3 binding (2 gm IV, then 1 gm IV daily)
Lithium carbonate 300mg q 6 hrs po (then aim for level of 1
mEq/L
TREATMENT CONT.
Glucocorticoids: underlying autoimmune disease
(polyglandular type 2), increased cortisol clearance, inability
of adrenals to produce sufficient hormone in hypermetabolic
state.
Hydrocortisone 300mg IV X 1, then 100mg q 8 hrs for a few
days, then a rapid taper (also inhibits TH release and
peripheral conversion)
Inhibit peripheral hormone action: beta blockade with
propanalol (80-120 mg q 6 hrs po or ).5-1.0 mg IV over 10
min, followed by 1-3 mg IV over 10 min every couple of
hours. ? Peripheral conversion effect? (happens over a
week or so)
PEARLS
Dont be afraid to use antithryoid medications with elevated
liver enzymes (up to 4 times ULN)
Please look for a precipitant event
If the patient has heart failure: They will be warm!
Antithyroid medications and vasculitis: pANCA positive, far
more common with PTU: lupus like picture with fever,
palpable purpura, splenomegaly, lymphadenopathy, serositis
of pleura and pericardiumbut dont stop meds for just
pruritic rash
Agranulocytosis: rare treat with G-CSF
PEARLS CONT.
High output cardiomyopathy: who gets this? Generally treated with
digoxin and furosemide (often higher than usual doses),
However..Furosemide at high doses displaces hormone from TGB
leading to increase in free hormone..Rapid metabolism of digoxin in
the early phasebut as patient improves, dig toxicty can ensue
Acetaminophen over ASA (TH binding effects)

Cooling blankets
Fluid requirements: 3-5 liters per day are not uncommon
Hepatic Glycogen storage depletion: dextrose containing fluids, thiamine
Limited Medical Therapy Options

CHOLESTYRAMINE.I USE IT ALL THE TIME!!! 4 GRAMS
EVERY 6 HOURS..TALK TO PHARMACIST ABOUT
TIMING OF OTHER MEDICATIONS.USUALLY AT LEAST
3 HOURS AFTER CHOLESTYRAMINE
(TH binds to the GI tract, and enterohepatic circulation is
blunted)
PLASMAPHARESIS
EMERGENT SURGERY: RAPID PREPARATION:
PROPRANALOL AT LEAST 60 MG TID
DEXAMETHASONE 2 MG IV FOUR TIMES DAILY
CHOLESTYRAMINE 4 GM ORALLY, FOUR TIMES DAILY
SSKI 2 DROPS THREE TIMES DAILY
MYXEDEMA COMA
Severe hypothyroidism-------- Mxyedema
Symptoms along a continuum
Often misdiagnosed in septic patient (altered sensorium,
hypotension..sometimes hypothermia)
Often insidious onset..elderly patient off LT4 therapy
Often precipitating factor (same as thyrotoxicosis)
MULTIORGAN DISORDER
Thyroid hormone receptor is present on virtually every cell
type, is even a neurotransmitter
Cardiovascular system: the hypothyroid heart
(cardiomegally, decreased contractility, bradycardia),
pericardial effusion (SIADH/volume overload), diastolic
hypertension
Renal system: hyponatremia, decreased GFR, resulting in
decreased excretion of water load, and SIADH (urine will be
inappropriately concentrated)
Multi-organ disorder cont.

Respiratory system: Alveolar hypoventilation, hypercapnea,
respiratory muscle myopathy
Can be complicated by OSA (often present with
hypothyoidism..hypogonadism associated with OSA as
well), macroglossia
GI system: decreased motility, bowel wall edema, parlytic
ileus/megacolon
Neurological system: can have frank psychosis and
generalized seizure
LABORATORY FINDINGS
Low free and total TH, markedly elevated TSH (remember
delay)
Hyponatremia
Hypoglycemia
Marked CPK elevation (increased skeletal muscle cell
memebrane permeability)
Low WBC count
Macrocytic anemia (B 12 malabsorption)
Other studies: LP: increased ICP and CSF protein, EEG
alpha wave activity (hyponatremia, hypoglycemia)
TREATMENT
Why dont we treat in all suspicious cases.myocardial
ischemia
300-600 g IV (4 mcg/kg lean body weight), then 50-100 g
daily (supraphysiologic TH for 24 hrs-monitoring crucial),
continue until patient can be transitioned to PO regimen
(usually 125-150 g daily)
PEARLS
Low normal TSH, with frankly low free T4: Central hypothyroidism (rule
out panhypopit), or non-thyroidal illness
Dopamine has most data for hypotension
Get both baseline cortisol and if possible perform ACTH stim
Patient with severe hyponatremia and volume overload: monitory
pulmonary capillary wedge pressure and administer hypertonic saline
but dont correct sodium more than 10mEq/L
What about T3? Controversial.limited outcome data..
Suggested doses range from 2.5 to 25 mcg IV every two hours for up to
48 hours..not in the patient with ASCADsimultaenous with
T4if I use it.upper range is 10 mcg q 12 hours or add after
48 hours if no improvement on LT4 alone
Case 1
62 female vasculopath with history of atrial
fibrillation, ASCAD, PVD, Type II DM admitted
to ED for DOE progressive over several days
Approximately 6 months ago she was admitted
for rapid AFIB and was treated with amiodarone
Case 1
Lab
measure
Total T4
12.0 g/dl (4.6-12)
Free T4
3.5 ng/dl (0.7-1.9)
Total T3
220 ng/dl (80-240)
TSH
<0.01 (0.5-5)
a-TPOab
negative
TSIIab
negative
Case 1
How do you explain the tfts?
Lab
measure
Total T4
12.0 g/dl
Free T4
2.5 ng/dl
Total T3
220 ng/dl
TSH
<0.01
a-TPOab
negative
TSIIab/TRAB negative
Inappropriately normal
Euthyroid sick
component
Inappropriately normal
Diminished type 1-5

deiodinase
Underlying autoimmunity
Likely Type
2 AIT
Case 2
18 y/o female with history of eating disorder is
admitted for sinus tachycardia, fever
She has 10kg weight loss, insomnia, shortness
of breath, irregular menses
Case 2
LAB
MEASURE
Free T4
4.0 (0.7-1.9)
Total T3
260 (80-240)
TSH
<0.10 (0.5-5.0)
TGB
0.5
TPO-ab
negative
Case 3
44 y/o male admitted for bradycardia,
hypotension, altered mental status,
hyponatremia and mild hypothermia
PMH also significant for weight loss,
diminished libido, peripheral visual field deficit
Case 3
Lab
measure
Total T4
2.8 g/dl (4.6-12)
Free T4
0.4 mg/dl (0.7-1.9)
Total T3
83 ng/dl (80-240)
TSH
0.30 U/ml (0.5-5)
a-TPOab
negative
TSII0ab
negative
Why is this
normal?
Case 3
What is the diagnosis?
What if the patient presented with severe
thunderclap headache?
What therapy would you initiate?
Any other tests?
Case 3
Supportive therapy is initiated and
supplemental thyroid hormone is administered
Hypotension worsens?
What test should have been done?
Questions?
Critical Illness
Polyneuromyopathy
H. Erhan Dincer, MD
Associate Professor of Medicine
Director, Interventional Pulmonology & Bronchoscopy
Pulmonary, Critical Care & Sleep Medicine
University of Minnesota
Disclosure
Consultant
Spiration/Olympus
Holaira
Boston Scientific
Outline
Critical illness polyneuropathy and myopathy
Definition
CIP and CIM
Pathophysiology
Risk factors
Diagnosis
Prevention and Treatment
Outcome
Definition/Terminology
Variation in terminology and nosology
Rapid loss of flesh in prolonged sepsis by Osler in

1892
Severe motor dysfunction in septic patients during

convalescence in the 1980s
Neuromuscular diseases in the ICU last 25 years

Critical illness polyneuropathy (CIP), critical illness
myopathy (CIM)
CIPNM, ICU-acquired weakness (ICU-AW)
CIP
Distal axonal sensory-motor
polyneuropathy
Limbs and respiratory muscles,

SPARES facial muscles
Symmetrical
Lower extremity>upper extremity,
distal>proximal
CIP
Clinical features
Difficulty weaning from MV

Independent risk factor for failed weaning and prolonged MV
Only facial grimacing on painful nail bed stimulus

DTR might be preserved or reduced
If alert;
Distal loss of pain/temp/vibration
Medical Research Council (MRC) scale or handgrip
dynamometry for limb and MIP/MEP, VC for respiratory muscle

strength
CIP
MRC combined into a sum
score
A score < 48 defines ICUacquired weakness

Prolongation of MV, ICU stay,
increased mortality, reduced
QOL in ICU survivors
Fletcher et al, CCM 2003;31:1012
CIP
Electrophysiological features
Amplitude reduction or missing
compound motor action potentials
(CMAP) and sensorial neural action
potentials (SNAP)
Reduction in nerve conduction
velocity (NCV)
Muscle EMG; fibrillation potentials
with sharp waves
CIP
Histologic features
Nerve biopsy
Axonal degeneration with
decreased density of myelinated
fibers, rarely indicated
Muscle biopsy
Acute denervation of muscle
atrophy of both type 1 and 2 fibers
Sural biopsy
CIP diagnostic criteria

Multiorgan dysfunction or failure
Limb weakness or difficulty weaning from MV after nonneuromuscular causes excluded (heart or lung)
Electrophysiological evidence of axonal motor or

sensory polyneuropathy
Absence of a decremental response on repetitive nerve

stimulation (e.g. motor neuron disease, MG)
CIM
Clinical features
Primary myopathy, not due to denervation

Difficulty weaning from MV
Flaccid limbs, some reduction in DTRs
Normal sensation, if testable
CIM
Electrophysiological features
Amplitude reduction and duration increase in CMAP, normal

SNAP and abnormal EMG
CMAP in septic patient now
and 3 weeks alter
Needle EMG of tib ant; low amplitude, polyphasic motor unit

potentials
CIM
Histologic features
Muscle biopsy
Selective loss of thick
filaments (myosin) and
varying degrees of necrosis
CIM diagnostic criteria

Multiorgan dysfunction or failure
Limb weakness, difficulty weaning from MV after non-neurologic
causes (heart, lung) excluded
CMAP amplitude < 80% of the lower limit of normal in 2

nerves
SNAP amplitude > 80% of the normal limit of normal

Needle EMG
Low amplitude, polyphasic potentials, CMAP duration
Absence of decremental response to repetitive stimulation

Primary myopathy on muscle biopsy (myosin loss, necrosis)
CIM
Bedside ultrasound of the muscle
28 sepsis/septic shock
First pilot study
26/28 + CIPNM by EP & exam
US echogenicity grading
Muscle edema in early stage
(Day 4)
Fibrosis and fatty degeneration

in late stage (Day 14)
Edema atrophic & fibrous

changes by MRI (1 patient)
Grimm et al, Crit Care 2013;17:R227
Combined CIP + CIM

Can occur
Mild or severe
Mild;
Some features of electrophysiological changes of CIP
and CIM, normal biopsy, good recovery
Severe;
Most features of electrophysiological changes of CIP and
CIM, abnormal muscle biopsy, complete recovery may
not happen and prolonged need of rehab
Pathophysiology
Incidence of CIP & CIM

Patients on MV for 4-7 days or with high risk of
developing MOFS;
25%-30% on clinical assessment
30%-60% on electrophysiological assessment
Patients with ARDS

24%-77% (> 1 week in the ICU)
55%-80% (MOFS and SIRS)
100% (severe sepsis or septic shock)
De Jonghe et al. Intens Care Med, 2004;30:1117
Risk factors of CIP & CIM

Sepsis
SIRS
MOFS
Immobility
Mixed results;
Aminoglycosides
Neuromuscular agents
Corticosteroids
Hyperglycemia

Independent risk factors
Severity of illness
Duration of MOFS (2) with or without SIRS
Duration of vasopressor or catecholamine support
Duration of ICU stay
Hyperglycemia
Female sex
Renal failure or RRT
Hyperosmolarity
Low serum albumin, parenteral nutrition

SIRS, sepsis, MOFS
Prospective studies
Electrophysiology, APACHE III scores and the
presence of SIRS were independently associated with
CIP & CIM
Mechanism: unclear, may be a local phenomena

Ischemia or injury of nerve and muscle via mediators of
local inflammation (cytokines), increased vascular
permeability (expression of adhesion molecules on
vascular endothelium)
IL-6 and TNF are NOT increased

Corticosteroids
Animal models, selective muscle atrophy

Combination of denervation injury + steroids cause
muscle changes identical to CIM
Mechanism:
May activate muscle proteolysis and deplete muscle
proteins
Mixed results on prospective studies
Corticosteroid-induced Myopathy
Pre-existent condition
Excess of external or internal (adrenal tumors) steroids
Upper/lower limbs (proximal) and neck flexors,
Weakness, difficulty weaning from MV
More often with fluorinated steroids (dexamethasone,

triamcinolone) than nonfluorinated (prednisone,
hydrocortisone), prednisone 40-60mg/d for weeksmonths
Acute (high dose, associated with rhabdo) or chronic

Neuromuscular blocking agents
Mixed results
Prolonged use and accumulation in the setting of
renal/liver failure

Immobility
Contributing in presence of other risk factors

Prolonged sedation, bed rest are independent risk factors
for ICU weakness when adjusted for duration of MOFS
Diaphragm atrophy when MV fully controlled

Repeated daily passive mobilization prevents muscle
atrophy in mechanically ventilated patients

Glycemic control
50% reduction in evolution of CIP in surgical patients

who treated with tight glycemic control when compared
to conventional control
Van den Berghe et al. CCM 2003;31:359
Mixed results
Diagnostic algorithm
Myopathy due to electrolyte abnormalities
Hypokalemia, hypophosphatemia, hypocalcemia
Acute or chronic effect of medications

Acute; NMBA, steroids
Chronic; chemotherapy, antiretroviral, statins
Propofol related infusion syndrome

Guillain-Barre syndrome
Post surgical axonal neuropathies
Propofol-related Infusion Syndrome
Severe metabolic acidosis, cardiac failure,

rhabdomyolysis, renal failure, hypertriglyceridemia
Propofol use > 48 hours, > 5mg/kg/h

1% incidence, more common in head trauma and acute
inflammatory syndromes
Rhabdomyolysis (normal muscle biopsy) acute

necrotizing myopathy
Treatment; stop propofol, supportive
Autoimmune polyneuropathy
C. jejuni infection with diarrhea often precedes the
progressive muscle weakness including respiratory

failure
Facial muscles are usually involved (not in CIP)

Clinical and electrophysiological studies can not
differentiate GB from CIP
Serial electrophysiological studies needed

Treatment: IVIG, plasmapheresis
Post surgical inflammatory axonal neuropathies
In the absence of nerve compression, contusion,

stretching or transection
Polyneuropathy away from the surgical site

Focal, multifocal or diffuse forms
Focally increased T2 signal on MRI, nerve biopsy for
definitive diagnosis
Treatment: IV methylprednisone, IVIG

Staff et al. Brain, 2010;133:2866
Prevention & Treatment

Risk factor modifications
Avoid corticosteroids and NMBA

Tight insulin control (surgical patients)
Sedation sparing protocols
Early limb mobilization
Electrolyte management (magnesium, phosphorus)
Optimal nutrition
Ventilator weaning protocols

Avoid corticosteroids
Benefit of corticosteroids in sepsis, ARDS or

pneumonia obscure
Before fibrotic phase of ARDS, severe sepsis (BP<90
mmHg in spite of fluids and pressors)

Avoid NMBA
Depolarizing; succinylcholine (hyperkalemia, malignant

hyperthermia)
Non-depolarizing;
Benzylisoquinolium (cisatracurium, atracurium)
Aminosteoid (Roc, vec, pancuronium)
Use in ICU; early ARDS, improve oxygenation,
decrease inflammatory response, improve mortality

Papazian et al, NEJM 2010;363:1107
Aminosteroids more strongly implicated in CIP/CIM

Tight insulin control
BG 80-110 mg/dl showed fewer cases of CIP by
electrophysiological studies after day 7 (28% vs 52%,

p< 0.001) in surgical and medical patients
Van den Berghe, et al. NEJM2001;345:1359
Hermans, et al. AJRCCM 2007;175:480
Tight insulin control is associated with increased

mortality in the ICU
Finfer, at al. NEJM 2009;360:1283
Target BG 140-180mg/dl

Sedation sparing protocols
Under Sedation
-
Self extubation
Removal of lines
Increased systemic/myocardial O2
consumption
Failure to participate therapeutic
interventions
Over Sedation
-
Increased ICU/hospital stay

Increased time on ventilator
Increased delirium
Increased VAP
Long term psychological problems
Difficult neurologic assessment
Sedation scales (RASS), protocols (nurse directed,

patient directed), daily sedation interruption, new
generation medications (dexamedetomidine)

Early mobilization
Changing paradigm

Early mobility (Prospective cohort study of 165 patients)
All outcomes adjusted for severity of illness

All patients had daily spontaneous awakening and breathing trials
Morris et al, CCM 2008;36:238

Early mobility
104 sedated, vented patients, prospective randomized
Both groups had sedation protocol and daily SAT/SBT
Schweickert et al, Lancet, 2009;373:1874

Feasibility of PT/OT beginning from initiation of MV
49 vented patients received PT/OT a median of 1.5 days
after intubation
Edge of bed (69%), bed to chair (33%), stood (33%) and
ambulated (15-20 ft) (15%) of patients
16% adverse effects (tachycardia, tachypnea)

4% early interruption due to agitation and patientventilator asynchrony
Pohlman et al, CCM 2010;38:2089

Implementing the ABCDE bundle in the ICU
ABC
Awakening &
Breathing Trial
Coordination
Delirium
Assessment &
Management
Early Exercise &

Progressive
Mobility
Balas et al, CCN 2012;32:35

Electrical Muscle Stimulation
140 critically ill (APACHE II>13), a randomized parallel

intervention trial (Daily EMS to lower extremity only)
EMS group (n=68) daily EMS
Control group (n=72)
Routsi et al, Crit Care 2010;14:R74

Electrical Muscle Stimulation
140 critically ill (APACHE II>13), a randomized parallel

intervention trial (Daily EMS to lower extremity only)
EMS group (n=68) daily EMS
Control group (n=72)
P=0.01
P=0.11
Routsi et al, Crit Care 2010;14:R74

IgM-enriched IVIG
38 critically ill patients randomized (MOFS and SIRS/sepsis)
CIPNM score based on electrophysiology and muscle biopsy
IVIG did not mitigate CIP or CIM
Brunner et al, Crit Care 2013;17:R213
ARDS Outcome
Canadian cohort study of 109 ARDS survivors for 1 year

Median age; 45, median APACHE II; 23, median ICU LOS;25 d
ARDS Outcome
At 1 year
49% back to work
ALL described poor function due to weakness, fatigue
PFT improved except for DLCO remained low, 6 MWT limited
due to neuromuscular complaints
Outcome
Survivors of critical illness
Neuromuscular recovery may take years

Long term outcome in patients with CIP and CIM
36 study, 263 patients, follow up 3 to 6 months
Complete functional recovery 68%
Severe disability (quadriparesis or plegia) 28%
Latronico et al, Curr Opin Crit Care, 2005:11:126
CIP/CIM Outcome
Critical illness myopathy and/or neuropathy (CRIMYNE)
1 year prospective cohort study of 92 patients

28 diagnosed CIP and/or CIM while in the ICU
18 had persistent CIP and/or CIM at discharge
Guarneri et al, J Neurol Neurosurg Psych, 2008;79:838
Take Home Messages
CIP and CIM are different entities but may occur together
Both presents as difficulty weaning from MVtoo late!!
CIP (motor-sensory); limbs, resp muscles, not face
CIM; flaccid limbs, normal sensation
Diagnosis: Neurol exam, EP studies, muscle biopsy
Avoid risks as much as possible (drugs)
Implementation of sedation, weaning protocols
Early diagnosis and intervention (mobilization)
Capnography: Basic Concepts And

Clinical Utility
(April 11, 2015)

and
Health Care Center
Conflicts
ALGH)
CAPNOGRAPHY
A Few Basic Concepts
CAPNOGRAPHY
Capnography is a non-invasive technique
whereby the change in partial pressure of

carbon dioxide (PCO2) in the gases
entering and leaving the lungs is
graphically displayed and analyzed
quantitatively and qualitatively.
Capnography can be measured in patients
intubated for mechanical ventilation or in

non-intubated patients using mainstream
or sidestream technology.
CAPNOGRAPHY
CO2 in the respiratory gases can be
measured by:
Mass Spectrometry: For research purposes;

expensive and not clinically practical or necessary
Colorimetric: Chemical reaction; semi-quantitative
and does not provide good temporal resolution
and waveform analysis
Infrared absorption spectroscopy: Preferred
method; quantitative with waveform capabilities,
widely available in stand-alone devices and
incorporated to bedside monitors, defibrillators,
pumps, etc.
BASIC INFRARED TECHNOLOGY

Sample chamber with
CO2 absorbing light
Infrared light
detection
Infrared light
emitter
Filter
Detector
CAPNOGRAPHY
Mainstream
Technique
CAPNOGRAPHY
Sidestream
Technique
To capnograph
(~150 ml/min)
Patient
Ventilator Adaptor
tubing
End-inspiration and beginning of exhalation

Early exhalation
Exhalation and end-tidal PCO2
Inspiration
End-Tidal PCO2
40
Baseline (a-b)
Rapid sharp rise (b-c)
Alveolar plateau (c-d)
Rapid,
sharp descend (d-e)
CAPNOGRAPHY
Production
VCO2
Ventilation
Transport
DCO2
Vd/Vt
CAPNOGRAPHY
Accordingly, end-tidal PCO2 is a
function of:
VCO2
(CO2 production)
DCO2
(CO2 transport)
Vd/Vt
VE
(dead space ventilation)
(minute ventilation)
CAPNOGRAPHY
VCO2
DCO2
Vd/Vt
VE
PETCO2
VCO2 (CO2 production)

Increased
metabolic activity
Fever, malignant hyperthermia, shivering,

exercise, hyperthyroidism, seizure
activity, pain, stress
Decreased
metabolic activity
Hypothermia, hypothyroidism, sedation,

muscle paralysis
CAPNOGRAPHY
VCO2
DCO2
Vd/Vt
VE
PETCO2
DCO2 (CO2 transport)

Decreased
Diversion
blood flow
Cardiac arrest, CPR, severe shock

(hypovolemic, cardiogenic, obstructive)
of blood flow
Extracorporeal circulation
CAPNOGRAPHY
VCO2
DCO2
Vd/Vt
VE
PETCO2
Vd/Vt (dead space ventilation)

Increased
dead space ventilation
Pulmonary embolism (clots, air, tumor,

amniotic fluid), increased zone A, decreased
tidal volume
CAPNOGRAPHY
VCO2
DCO2
Vd/Vt
VE
PETCO2
VE (minute ventilation)
Increased
(hyperventilation)
Mechanical ventilation, anxiety, fever, pain,

metabolic acidosis
Decreased
(hypoventilation)
Mechanical ventilation, respiratory muscle

fatigue, neuromuscular disease, drug
overdose, metabolic alkalosis
CAPNOGRAPHY
Some applications
CAPNOGRAPHY
Confirmation tracheal
intubation
Highlights of 2010 Guidelines

Waveform Capnography
Verification endotracheal tube placement
(Class I, LOE A)
CAPNOGRAPHY
Monitoring ventilation
Non-invasive monitoring of CO2 is standard of care by the ASA

since July 2011 for monitoring moderate and deep sedation
Hyperventilation
Hypoventilation
J Anesth Clin Res. Mar 18, 2013; 4(3): 295
Non-invasive monitoring of CO2 is standard of care by the

ASA since July 2011 for monitoring moderate and deep
sedation
Pulse oximetry in patients

receiving room air or
supplemental oxygen at 2
L/min during an episode of
hypoventilation.
J Anesth Clin Res. Mar 18,

2013; 4(3): 295
CAPNOGRAPHY
Diagnosing diabetic
ketoacidosis
Predictive Value of Capnography for Suspected Diabetic

Ketoacidosis in the Emergency Department
West J Emerg Med. Nov 2013; 14(6): 590594.
Predictive Value of Capnography for Suspected Diabetic

Ketoacidosis in the Emergency Department
West J Emerg Med. Nov 2013; 14(6): 590594.
Sixty-two of 181 patients

had DKA, with significant
differences in pH,
bicarbonate, PaCO2, and
PETCO2 (p0.001)
PETCO2 > 24.5 mmHg could
rule out DKA with a
sensitivity and specificity
of 0.90
PETCO2 < 24.5 mmHg could
not differentiate between
DKA and other disease
entities
CAPNOGRAPHY
Pulmonary embolism
CAPNOMETRY IN SUSPECTED PULMONARY EMBOLISM

WITH POSITIVE D-DIMER IN THE FIELD
Crit Care. 2009; 13(6): R196
Patients total
131
No 31
PETCO2 > 28 mmHg and

low clinical probability is a
potentially safe method for
excluding PE in patients
with suspected PE and
positive D-dimer test
Inclusion criteria
Di-dimer +
Yes 100
Clinical probability of PE (Wells criteria)

Unlikely 55
PETCO2
nasal
> 28 mmHg < 28 mmHg

35
20
PE 0
PE 14
Likely 45
> 28 mmHg < 28 mmHg

17
28
PE 3
The combination of
PETCO2 < 28 mmHg and
high clinical probability is
a potentially safe method
for confirmation of PE in
patients with suspected
PE and positive D-dimer
PE 24
CAPNOGRAPHY
51 year old man had internal fixation of fractured
olecranon
On day 2, he abruptly developed intense dyspnea followed
by apnea and pulseless
CPR reestablished ROSC after 24 min
Chest x-ray unremarkable
EKG RBBB
Arterial pCO2 was 50 mmHg and the PETCO2 was 21 mm Hg
Bedside transthoracic echocardiogram showed RV dilation
Tenecteplase was given and within 75 minutes the RBBB
normalized
A CT angio on day 4 confirmed small filling defect in the a
proximal right pulmonary artery branch
CAPNOGRAPHY
50 year old man admitted for the diagnosis of PE
complained of chest pain
Chest pain intensified developing signs of reduced
peripheral perfusion with altered mentation and
intensification of chest pain
Jugular vein distension
Patient transferred to ICU for intubation and
hemodynamic monitoring/management
Arterial pCO2 was same as PETCO2
Bedside transthoracic echocardiogram showed 4chamber dilation
Patient referred for coronary angiography and CABG
CAPNOGRAPHY
Monitoring CPR efficacy
CPR
Chest compression
Blood flow generation
Ventilation
Oxygenation
Removal of CO2 (?)
Coronary Perfusion
Ao-RA pressure between
compressions
Pressure
Aorta==Flow
COx Resistance
x PVR
CPR
Vasopressors
CHEST COMPRESSION
Forward Blood Flow
120
Venous Return
Cardiac Output, ml/min
100
(n = 7)
80
60
40
20
0
6
Myocardial blood flow, ml/min
5
4
3
2
1
0
BL
CC
PR 15 min
PR 60 min
Kolarova at al AJP 2005; 288:H2904
Depth of Compression Determines

Forward Blood Flow
Normalized CO
Babbs et al. Ann Emerg Med 1983;12:527
1.5
1.0
0.5
0
4
2
Depth, cm
ETCO2 vs CARDIAC INDEX DURING CHEST COMPRESSION IN PIGS

(24 observations in 7 animals)
ETCO2 = 0.038 CI 0.44

r = 0.91 p < 0.001
ETCO2, %
4
3
2
1
0
0
20
40
60
80
CARDIAC INDEX, ml/min/kg
100
End Tidal PCO2 During CPR

Sanders AB et al. JAMA 1989;262:1347-52
p < 0.001
25
mmHg
20
15
10
5
Resuscitated
Non Resuscitated
PETCO2: A Clue on the Mechanism of

Cardiac Arrest
Difference in end-tidal CO2 between
asphyxia cardiac arrest and ventricular
fibrillation/pulseless ventricular
tachycardia cardiac arrest in the
prehospital setting
tefek Grmec, Katja Lah, and Ksenija TuekBunc
Center of Emergency Medicine, Prehospital Unit
Maribor, Maribor, Slovenia
Crit Care 2003; 7: R139R144
PETCO2: A Clue on the Mechanism of

Cardiac Arrest
PETCO2 (mmHg)
Asphyxia
(n = 44)
VF/VT
(n = 141)
Immediate after ET
66 17
17 9
At 1 min of CPR
29 5
24 5
ROSC (yes)
36 9
30 8
ROSC (no)
19 9
14 5
Grmec S et al. Crit Care 2003;7:R139
PORCINE MODEL OF VF AND CLOSEDCHEST RESUSCITATION

LUCAS Device
CAROTID
BLOOD FLOW
AIRWAY PRESSURE
AND FLOW
ECG
PETCO2
VENTILATOR
(PB 840)
PACING
ELECTRODE
(induce VF)
5
0
-10
AORTA
RIGHT ATRIUM
(microtip P-T) (microtip P-T)
Airway flow and airway pressure

during chest compression measured
immediately before delivery of a
positive pressure breath. Data were
averaged from measurements
obtained at minutes 2, 4, 6, and 8 of
chest compression and presented as
mean SEM.
Airway Flow
(L/min)
-20
The top graph depicts mean airway

flow denoting gas movement from the
respirator to the lungs (positive values)
and from the lungs to the respirator
(negative values). *p < 0.05 vs 33/18
by Holm-Sidak method using all
pairwise comparisons after
establishing overall significance by
one-way ANOVA (p = 0.028).
-30
16
12
Airway Pressure (mmHg)
The bottom graph depicts the airway

pressure measured during chest
compression (higher values) and
during chest decompression (lower
values). *p < 0.05 vs 33/18 by StudentNewman-Keuls method using all
pairwise comparisons after
establishing overall significance by
one-way Kruskal-Wallis ANOVA for
pressures during chest compression (p
= 0.023) and for pressures during
chest decompression (p = 0.013).
8
4
*
10/6
-4
10/18
33/6
33/18
RR (min-1)/TV (ml/kg)
60
Respiratory Rate (10-bpm)

Tidal volume (6-ml/kg)
50
PETCO2 (mmHg)
RR = Respiratory rate; TV = Tidal

volume.
Respiratory Rate (33-bpm)

40
30
20
10
PETCO2 = 10.3 + 61.2/minute-volume; R2 0.85, p< 0.0001
0
0
400
8000 12000 16000

Minute-Volume (ml/min)
20000
CAPNOGRAPHY
Return of native circulation
OPEN- CHEST PIG MODEL OF VF

LAD Flow
meter
100% O2
Flow meter
PET CO2
VENT
100% O2
Punch
biopsies
Lactate (Enzyme)
Liquid HEM (HPLC)
Nitrogen Ions (AAS)
Protein (Western blot)
ECG
LV
PA
High-fidelity
Microtip pressure
transducer
LV
Vent
EchoDoppler
AORTA
CAPNOGRAPHY
Changes in waveform
morphology
Normal morphology
Shark fin morphology

in patients with airway
disease (asthma, COPD)
Apnea, disconnection
from mechanical
ventilation
Rebreathing, moisture
and/or secretion in
adaptor
J Anesth Clin Res. Mar 18, 2013; 4(3): 295
Shark fin pattern typical

of patients with airway
disease (e.g., COPD).
Slow expiratory flow
typically interrupted by
inspiration (i.e., leading to
air trapping) with occasional
long expirations allowing
complete exhalation.
Forced Expiratory Capnography and Chronic Obstructive

Pulmonary Disease (COPD)
J Breath Res. Mar 2013; 7(1): 017108.
Natural log transformed slopes

of plateau phase of the exhaled
CO2 during forced exhalation for
1- 6 seconds (p=0.008).
Natural log transformed slopes of

plateau phase of the exhaled CO2
during forced exhalation (1-6 s) for
the COPD subjects vs percent of
voxels below -950 HU by HRCT.
Cardiac Oscillations
EKG (V1)
50-
Capnography
250SpO2
Respirations
1s
Ventilation
Production
VCO2
Transport
DCO2
Vd/Vt
a
Update on Acute Kidney Injury
Kevin K. Chung, MD, FCCM, FACP

U.S. Army Institute of Surgical Research
The opinions or assertions contained herein are the

private views of the author and are not to be construed
as official or as reflecting the views of the Department
of the Army or the Department of Defense.
Grant support from the American Burn Association and

the Air Force.
Overview
Diagnosis
Prevention/treatment
Contrast induced nephropathy
CRRT vs IHD
Crystalloid of choice
True or False?
As little as a 0.3 increase in SCr
results in the diagnosis of AKI.
Acute Dialysis Quality Initiative

2nd International Consensus Conference
AKIN Classification
Mehta et al. Crit Care. 2007 Mar 1;11(2):R31.
NephroCheck
Question
In a patient at risk for post-ischemic ATN,
which of the following preventive
therapies have been shown improve
mortality in prospective RCTs?
A.
B.
C.
D.
Dopamine
Fenoldopam
Atrial Naturetic Peptide
None of the above
Ischemic ATN
Two major mechanisms
Occlusion of tubular lumen by cellular debris
Loss of intact or necrotic tubular cells
Causing backleak
Potential Preventive
Therapies
Dopamine in ATN
Bellomo et al. (Lancet Dec 2000;35:2139-43)
Randomized, double blind, placebo controlled,
multi-center
N=328, ICU patients
Low dose dopamine (2 mcg/kg/min) vs
placebo
No difference in selected outcomes
Dialysis, ICU/hospital stay, mortality
Atrial Natiuretic Peptide

Natriuretic and diuretic hormone
Peripheral vasodilator
Lowers systemic blood pressure (BP)
Causes both afferent dilatation and

efferent constriction
Improves renal blood flow
Beneficial in preventing contrast induced
ARF and ATN in animal models
Atrial Natiuretic Peptide

Allgren et al. (N Engl J Med Mar 1997;336(2):828-34)
Randomized, double-blind, placebo controlled,
multi-center
N=504, ICU patients with ATN
Anaritide vs placebo
Overall, no difference in dialysis free survival
in 21 days
In subgroup of 120 pts with oliguria, better outcome in
anaritide group
In subgroups of 378 pts with non-oliguria, worse
outcome in anaritide group
Atrial Natriuretic Peptide in

oliguric acute renal failure
Lewis et al. (Am J Kidney Dis. 2001 feb;37(2):454-5.)
Randomized, double-blind, placebo controlled,
multicenter
n=222 patients with oliguric renal failure
Atrial natriuretic peptide vs placebo
No difference in dialysis free survival at 21
days
21% vs 15% (p=0.22)
Fenoldopam
A selective postsynaptic dopamine agonist
(D1-receptors)
Exerts hypotensive effects by decreasing
peripheral vasculature resistance with
increased renal blood flow, diuresis, and
natriuresis
6 times as potent as dopamine in producing
renal vasodilitation
Fenoldopam
Morelli et al. (CCM. 2005 Nov)
Prospective, double blind RCT
N = 300 septic patients with normal serum
creatinine
Fenoldopam 0.09 mcg/kg/min vs placebo
continuous drip
Incidence of ARF lower in fenoldopam
group
29 vs 51 patients (p = 0.006)
No mortality benefit
Meta-analysis
Need for RRT
NNT = 25
Death
NNT = 25
Question
In a patient at risk for post-ischemic ATN,
which of the following preventive
therapies have been shown improve
mortality in prospective RCTs?
A.
B.
C.
D.
Dopamine
Fenoldopam
Atrial Naturetic Peptide
None of the above
Question
47 y/o man with a 20 yr hx of DM is admitted
with an STEMI. His Cr is 2.8. An emergent
cath is planned. All of the following has
been shown to decrease the risk of contrast
induced nephrotoxicity EXCEPT.
A.
B.
C.
D.
E.
F.
G.
Nonionic iso-osmolar contrast

Fenoldopam
Oral Mucomyst
IV Mucomyst
Vitamin C
Prophylactic hemofiltration
Sodium Bicarbonate

Reported incidence widely variable
Normal renal function (<1%)

Mild-mod renal insuff alone (4-11%)
CRI + DM (9-38%)
Baseline Cr 4-5 mg/dL (50%)
Elevated Cr within 24 hours

FENa typically very low
Prevention is key
Avoidance in high risk patients

Mechanism
Vasoactive effects
Vasodilation => Intense Vasoconstriction
Patients with impaired compensatory mechanisms
CRI, DM, CHF, cirrhosis
Direct toxic effects

Tubular injury in association with oxygen free radicals
Risk Factors
Preexisting renal dysfunction

Diabetic nephropathy
Severe CHF
Volume depletion
Elderly patient
High total dose of contrast agent
Types of contrast
Ionic hyper-osmolar agent
1500-1800 mosmol/kg
Nonionic low-osmolar agent

600-850 mosmol/kg
Nonionic iso-osmolar agent

290 mosmol/kg
Iso-osmolar BETTER
Aspelin et al (N Engl J Med 2003 Feb 6;348(6):491-9)
Randomized, double-blind, prospective, multi-center
N=129, high-risk patients (DM with CRI) undergoing
angiography
Visipaque [iodixanol] vs Omnipaque [iohexol]
Rate of nephrotoxicity (0.5 mg/dL inc in SCr in 3

days)
17/65 (26%) pts in low-osmolar group vs 2/64 (3%) pts in isoosmolar group
Iso-osmolar better than low-osmolar in high risk pts
Meta-Analysis
Reed et al. JACC: Cardiovascular Interventions. 2009;2:645-54.
16 PRCT, N = 2,763 patients
Visipaque (iodixanol) BETTER than
Omnipaque (iohexol)
Hexabrix (ioxaglate)
No difference
Isovue (iopamidol)
Ultravist (iopromide)
Optiray (ioversol)
Different Contrast Agents

Normal renal function non-issue
Patients at high risk (DM and/or CRI)
Nonionic, iso-osmolar better than

Nonionic, low-osmolar better than
Ionic, high-osmolar
Or few select non-ionic, lowosmolar (Isovue, Ultravist, Optiray are OK)

At our hospital
Radiology/Cardiac Cath/IR
Optiray (nonionic low-osmolar) OK
Visipaque (nonionic iso-osmolar)
BOTTOM LINE
NOT ALL CONTRAST
ARE CREATED
EQUAL!
Acetylcysteine
Thiol-containing antioxidant
Reactive oxygen species may be involved
in pathogenesis of contrast nephropathy
Prevention of Radiographic-contrast-agentinduced Reductions in Renal Function by

Acetylcysteine
Tepel et al. (N Eng J Med 2000;343:180-184.)
Randomized, placebo controlled, single center
N= 83, patients with renal insufficiency
undergoing radiographic contrast study
Non-ionic, low-osmolar contrast
Incidence of contrast nephropathy
significantly lower in NAC group
2% vs 21%; p=0.01
PO Acetylcysteine
Cheap
Easy to use
Minimal side effects
Potential benefit
IV Acetylcysteine
Used in acetaminophen toxicity
Minimal toxicity
Viable option in certain clinical
scenarios?
Off label use?
Intravenous Acetylcysteine
Baker et al. (J Am Coll Cardiol 2003:41(12);2114-2118.)
Prospective, randomized, open label
N=80, patients with renal dysfunction undergoing
cardiac cath
IV NAC (150 mg/kg in 500 cc NS over 30 mins followed by 50
mg/kg in 500 cc NS over 4 hours) vs NS (1 ml/kg/h 12 hrs pre
and post)
Non-ionic, iso-osmolar contrast

Incidence of contrast nephropathy significantly
less in NAC group (25% increase in SCr)
5% vs 21%; p=0.045
NAC infusion stopped in 3 patients (itching, rash)
BOTTOM LINE
NAC only helpful if given
PO >24 hours prior
or
IV immediately before
Vitamin C
Spargias K. et al. Circulation. 2004;110:2837-2842.
PRCT
N = 231 patients with SCr >1.2 undergoing CATH
Ascorbic acid 3 grams 2 hrs before and 2 grams
in the AM vs PLACEBO
9% vs 20%
Prophylactic Hemofiltration
Marenzi et al (N Eng J Med Oct 2003;349(14):1333-40)
Randomized, single center
N=114, patients with CRF (Cr>2) undergoing cardiac
cath
Hemofiltration vs control (NS, 1 ml/kg)
Both interventions 6-8 hrs prior and 24 hrs after
procedure
Non-ionic, low-osmolar contrast
None in control group received mucomyst
Prophylactic Hemofiltration
Less likelihood of increased Cr (>25%
from baseline)
Less likelihood of requiring temporary RRT
Decreased in-hospital mortality (2% vs
14%)
Decreased one year mortality (10% vs

30%)
Patients with Cr > 4 benefited most
How about Hemodialysis?

Vogt et al. (Am J Med 2001;111:692)
Randomized, prospective
N=113, high risk patients
Hemodialysis group more likely to need more
hemodialysis
Lehnert et al. (Nephrol Dial Transplant 1998;12:358)

Randomized, prospective
N=30, high risk patients
No benefit, possible harm

Sodium Bicarbonate
Free radicals postulated to mediate
contrast induced nephropathy
Promoted by acidic environment
More protective than sodium chloride in
animal models
Alkalinization of urine may be protective
Merten et al (JAMA May 2004;291(19):2328-2334)

Randomized, single center
n=119 pts with CRI (Cr >1.1) undergoing cath, CT
scan, or angiogram
D5W + 154 mEq/L NaCl vs D5W+3 Amps bicarb
(Bolus 3cc/kg 1 hour prior then 1cc/kg/hr for 6 hrs)
Nonionic low-osmolar, No acetylcysteine

Incidence of contrast nephropathy less in Sodium
Bicarb group (25% increase in SCr)
1.7% vs 13.6% (p=0.02)
Brar et al. JAMA 2008

N = 353 patients with CRI (GFR<60) undergoing
cardiac cath
Low-osmolar contrast, 48% in each group got
acetylcysteine
Incidence of CIN NO DIFFERENT!

BICARBONATE
for
Prevention
of
Contrast Induced Nephropathy
Fenoldopam
Stone et al. (JAMA 2003;290(17):2284-91)
Randomized, double-blind, prospective,
multicenter
N=315, high risk patients undergoing
cardiac cath
No difference in incidence of CIN
Lit Search
Question
47 y/o man with a 20 yr hx of DM is admitted
with an STEMI. His Cr is 2.8. An emergent
cath is planned. All of the following has
been shown to decrease the risk of contrast
induced nephrotoxicity EXCEPT.
A.
B.
C.
D.
E.
F.
G.
Nonionic Iso-osmolar contrast

Fenoldopam
Oral Mucomyst
IV Mucomyst
Vitamin C
Prophylactic hemofiltration
Sodium Bicarbonate?
Why dont we just get an MRI?
Nephrogenic Systemic Fibrosis
Gadolinium
Nephrogenic systemic fibrosis
NEW fibrosing disorder with strong
association with GAD (first cases reported in
1997 now over 300 cases)
Anyone with a GFR<15 mL/min
High doses (or repeat doses)
Vast majority with Gadodiamide (Omniscan)
FDA black box warning for ALL GAD
Gadolinium
Nephrogenic systemic fibrosis
Majority involve the skin
Contractures in severe cases
Fibrosis of other organs (lungs, myocardium,
pericardium, diaphragm, etc)
Consider IHD in patients at high risk who

need gadolinium
True or False?
Continuous Renal Replacement Therapy
is associated with better outcomes
than Intermittent Hemodialysis
CRRT or IHD?
CRRT
SCUF
CVVH
CVVHD
CVVHDF
C-SLED
SCD
Intermittent
IHD
SLED/SLEDD
SLEDD-f
EDD
SLED/SLEDD/SLEDD-f/EDD
Sustained Low-Efficiency Daily
Dialysis/Diafiltration or Extended Daily Dialysis
Various hybrid techniques reported in the late
90s
Retrofitted outpatient machines used for chronic
HD to allow slower dialysate/blood flow rates
Treatment over 4-12 hours
C-SLED/SCD
Continuous Sustained Low Efficiency
Dialysis
Slow Continuous Dialysis
Continuous vs Intermittent
Lancet 2006;368:379-85.
Mortality = No Difference
N Engl J Med 2008; 359:E1.
ATN Trial: Largest RCT

High-dose CVVH/IHD
UNSTABLE - CVVH 35 cc/kg/hr (or SLED)
STABLE - IHD 6x/week
Low-dose CVVH/HD
UNSTABLE - CVVH 20 cc/kg/hr (or SLED)
STABLE - IHD 3x/week
N Engl J Med 2008; 359:E1.

KDIGO
How about long term (renal)

outcomes?
KDIGO
13 year retrospective study across Canada

2004 CRRT patients matched with 2004 IHD
patients
ATN Trial vs RENAL Trial
Of survivors 25% needed long

term dialysis
Of survivors 5% needed long term dialysis
A CRRT-based strategy may lead

to superior renal outcomes
among survivors compared to
IHD.
True or False?
High chloride containing
crystalloids (NS) are associated
with increased AKI and Death and
should be used with caution.
Thank You!
kevin.k.chung.mil@mail.mil
Respiratory Muscle Physiology and

Bedside Assessment of Work of
Breathing
(April 11, 2015)

and
Health Care Center
Conflicts
ALGH)
Outline
Respiratory muscle physiology (overview)
Work of breathing
Loads to overcome
Elastic load (ARDS, pneumonia, pneumothorax)

Resistive load (epiglottitis, tracheal stenosis, IAC)
Inspiratory threshold load (intrinsic PEEP)
Inertial load (obesity)
Recognizing increased work of breathing and

risk of respiratory muscle fatigue
Clinical clues
Utility of arterial blood gases
WOB Scale
Diaphragm
Contraction lowers the
dome by l-2 cm during
normal breathing and up to
l0 cm during deep
inspiration
Costal and crural parts; the
costal also expands the rib
cage.
Responsible for 60-75% of
the lung volume increase.
Motor innervation is
through the phrenic 3rd, 4th,
and 5th cervical segments.
Ventilation
The relationship between

alveolar pressure and
intrapleural pressure and the
volume of air moved
RESPIRATORY MUSCLE PHYSIOLOGY

For gas to enter the lungs, a
negative pressure gradient is
required between the alveoli and
atmosphere (or source of gas).
Normal inspiration is active.
For gas to exit the lungs, a
positive pressure gradient is
required between the alveoli and
atmosphere (or source of gas).
Normal expiration is passive.
WORK OF BREATHING
WOB (
represents the work
performed by the respiratory muscles to mobilize
gases in and out the lungs to ensure that CO2
removal and oxygen delivery appropriately meet
the metabolic demands
The WOB at rest is low (<3% resting energy
expenditure); but it increases in proportion to the
inspiratory respiratory loads:
Elastic load (ARDS, pneumonia, pneumothorax)

Resistive load (epiglottitis, tracheal stenosis)
Inspiratory threshold load (intrinsic PEEP)
Inertial load (obesity)
WORK OF BREATHING
The Respiratory Muscles

Charis Roussos and Peter T. Macklem
(NEJM 1982;307:786-797)
WORK OF BREATHING
Respiratory Failure
Lung Failure
Pump Failure
Gas exchange failure

(Hypoxemia; dead
space ventilation)
Ventilatory failure
(Hypercapnia)
V/Q mismatch
Central
depression
Mechanical
defect
Demand for WOB

> energy supply
Respiratory muscle
fatigue
INSPIRATORY LOADS TO OVERCOME

Elastic Load: results from decreases in thoracic
cavity compliance increasing the pressure
required to reach a desired lung volume
ARDS
Pneumonia
Atelectasis
Pneumothorax
Pleural effusion
Kyphoscoliosis
Intra-abdominal
compartment
syndrome

Resistive Load: results from increases in
inspiratory airway resistance (upper and lower)
augmenting resistance to timely reach the
desired lung volume
Upper airway trauma

Vocal cord paralysis/spam
Epiglottitis (burn)
Laryngotracheobronchitis
Tube occlusion/kinks
OSA
Asthma/bronchiolitis
COPD
Thumb sign
Steeple sign

Threshold Load: results from air trapping
(intrinsic PEEP) making it necessary for the
inspiratory muscles to lower the alveolar
pressure from the intrinsic PEEP level to below
the pressure at the gas entry level before any
gas moves into the lungs
COPD
Asthma
Flow (LPM)
Ins
Exp
Increased compliance
(emphysema)
Decreased compliance
(fibrosis)
Inertial Load: results from increased force to

initiate expansion of the chest cavity and is
closely linked to elastic load.
Obesity
Ascites
WOB AND INSPIRATORY LOADS

Intrinsic muscle
capability
Elastic
Load
Inertial
Load
Resistive
Load
Threshold
Load
Drive
Mass
Strength
Length-force
Oxygen supply to
inspiratory muscles
Blood flow
Hemoglobin
Oxygenation
Critical Brain
Heart
Organ
Perfusion Inspiratory muscles
WOB AND INSPIRATORY LOADS

With increased respiratory load there is
proportional increase in WOB and, typically,
tachypnea and recruitment of accessory
respiratory muscles (both inspiratory and
expiratory)
Increased WOB risks respiratory muscle fatigue
and respiratory failure, which if not properly
recognized and treated leads to apnea and
cardiac arrest
Thus, recognition of increased WOB is important
to promptly institute treatment to prevent further
deterioration
RECOGNIZING INCREASED WOB

Increase respiratory rate
Recruitment of accessory inspiratory
muscles
SCM, scalene, trapezoid, internal
intercostal, nasal flaring
Recruitment of accessory expiratory
muscles
Abdominal muscles

Rapid Response System
Seizures Syncope Urine
1%
HR 4%
2%
4%
ResAcc
Muscles
10%
SO2
20%
ChestPain
13%
Mentation
13%
SystolicBP
18%
Respiratory
Rate
15%
WARNINGSIGNS(n=110)March2010 April2011

Recruitment of accessory inspiratory
muscles

Recruitment of accessory expiratory
muscles

Loss of diaphragmatic function
Unilateral: Typically well tolerated
Bilateral: Relegates the WOB to the accessory
muscles, both inspiratory and expiratory
Predisposes to respiratory muscle fatigue
It is often missed at the bedside
BILATERAL DIAPHRAGMATIC PARALYSIS
Neurologic causes Myopathic causes

Spinal cord transection
Limb-girdle dystrophy
Multiple sclerosis
Hyperthyroidism or hypothyroidism
Amyotrophic lateral sclerosis
Malnutrition
Cervical spondylosis
Acid maltase deficiency
Poliomyelitis
Connective tissue diseases
Systemic lupus erythematosus
Phrenic nerve dysfunction
Dermatomyositis
Compression by tumor
Mixed connective tissue disease
Cardiac surgery cold injury
Amyloidosis
Blunt trauma
Idiopathic myopathy
Idiopathic phrenic neuropathy

Postviral phrenic neuropathy
Radiation therapy
Cervical chiropractic manipulation
Clinical recognition
Dyspnea upon exercise that worsens in the supine
position (i.e., orthopnea, a symptom frequently
misinterpreted as caused heart failure)
Onset of orthopnea is dramatic, occurring within
minutes of recumbency, and associated with
tachypnea and rapid shallow breathing
Tachypnea and paradoxical abdominal wall
retraction (instead of normal protrusion) during
inspiration
Palpation under the costal margins fails to detect
descending of hemidiaphragms during inspiration

Case
51 years old female admitted to ICU for emergency

airway management after seizure episode while
having a CT of head, neck, chest, and abdomen
Patient has been treated for undifferentiated

adenocarcinoma stage IV without know primary but
with metastasis to brain, neck, mediastinum, lungs,
liver, and one adrenal gland
Intubation was difficult but eventually successful

Chest-x-ray after extubation showed new bilateral
alveolar infiltrate in the upper lungs not present in
previous chest-x-ray

Case
Patient regained consciousness while on mechanical

ventilation. Review of imaging studies demonstrated
right frontal lobe metastasis with edema and midline
shift
Next morning patient stable and fully awake without

focal neurological deficits and chest-x-ray showed
upper lung infiltrates improving
Oxygenation was excellent on PEEP 5 cmH2O and FiO2

0.4
Patient was stable and comfortable during

spontaneous breathing trial but f/Vt was 100 attributed
to inability to increase tidal volume

Case
Because patients was fully awake, willing to be

extubated, and hemodynamically stable she was
extubated having BiPAP available
Extubated she had spontaneous breathing with

tachypnea 30 - 40 BPM while maintaining a pulse
oximetry of 100%
Given the extensive disease with cervical and

mediastinal involvement the possibility of bilateral
phrenic nerve paralysis was considered
Patient indicated she could not tolerate being flat for

months

Case
Examination showed inward

movement of abdomen
during inspiration and use
of abdominal muscles
during expiration
Given the likely possibility

of bilateral phrenic nerve
paralysis, the supine
position was avoided
Hypoxemia while laying flat

for the CT examination was
considered as the trigger
for the seizure episode

Case
Intra-abdominal pressure measured through Foley

catheter revealed decrease pressure during
inspiration confirming bilateral phrenic nerve
paralysis
FRC
Normal
Diaphragmatic
Paralysis

Utility of arterial blood gases
Oxygenation best assessed by O2
saturation (e.g., SpO2)
Respiratory muscle fatigue is late
and life-threatening event
The goal is to recognize and
manage increased WOB to avert
respiratory muscle fatigue
Hypercapnia is a late event
Decision needs to be made

based on clinical grounds
without (routinely) asking for
blood gas analysis and/or
waiting for the results
WOB SCALE
We propose a bedside WOB scale based on a
simple scoring system assigning points to the
respiratory rate and to the activation of specific
accessory respiratory muscles by examining the
nose, the sternocleidomastoid muscles, and the
abdominal muscles
Element
Respiratory Rate
Points
Method of Assessment
<20 = 1
21-25 = 2
26-30 = 3
>30 = 4
Count number of breaths in

20 seconds and multiply by 3
Nasal Flaring
Absent = 0
Present = 1
Observation
Use of Sternocleidomastoid Muscles
Absent = 0
Present = 1
Palpation
Use of Abdominal Expiratory

Muscles
Absent = 0
Present = 1
Palpation
WOB SCALE
Endocrine Emergencies 2
Lori B. Sweeney
VCU Health System
Case 1
46 y/o male with chronic pancreatitis previously admitted for
DKA admitted s/p seizure with blood sugar of 26 mg/dl per
EMS
Patient ran out of pain meds
What is going on?
By the way, the medicine team reported a sister on a
sulfonylurea and CT scan of the abdomen with fullness in
the head of the pancreas
Now what do you think is going on?
Case 1
Crazy high blood alcohol level
Very low prealbumin
Chronic diarrhea
Pt hasnt been eating
Begun on intensive insulin regimen during last admission
Case 1
Is glucagon likely to be effective?
How about octreotide 50 mcg q 6-8 hrs IV?
Blood sugars begin to normalize.....now what?
Insulinoma = hypoglycemia +plasma insulin level of 3
mcgU/ml or greater, c-peptide of 0.6 ng/ml or greater,
proinsulin of 5 pmol/L or greater, a beta-hydoxybutyrate of
2.7 nmol/L or less, and a rise in glucose of 25 mg/dl s/p
glucagon
Variations on a theme
What if the patient has breast cancer, on chemo?
What if the patient is s/p Roux en Y GBP?
Type 1 diabetic patient with A1C of 5.1%
Differential diagnosis
Impaired gluconeogenesis/glycogenolysis
Salicylates
Beta-blockers
Hepatic Failure
Renal Failure
Alcohol
Increased Insulin
Exogenous Insulin
Sulfonylurea
Quinine
Trimethoprim-sulfamthoxazole
Alcohol
Insulinoma
Other
Insulin receptor antibody, Insulin antibody
Dumping syndrome
Autonomic dysfunction
Adrenal insufficiency
Growth Hormone deficiency
Hypothyroidism
Case 2
64 y/o female with history of primary hyperparathyroidism,
parathyroid exploration with removal of two glands one week
ago
Precipitant symptoms: fatigue, weakness, abdominal pain,
numbness in hands, feet, and around the mouth, painful
muscle cramps in upper/lower extremities
Serum Calcium of 6
EKG: prolonged QT interval
What other labs do you want?
Hypocalcemia: Differential DX
Hypoparathyroidism
Surgical
Autoimmune
Magnesium deficiency
PTH resistance
Vitamin D deficiency
Vitamin D resistance
Other: renal failure, pancreatitis, tumor lysis
Hypocalcemia Work-up
Confirm low ionized calcium
History:
Neck surgery
Other autoimmune endocrine disorders
Causes of Mg deficiency
GI disorders (malabsorption)
Physical Exam Findings

CHVOSTEKS SIGN
Elicitation: Tapping on the face at a point just anterior to the ear
and just below
the zygomatic bone
Postitive response: Twitching of the ipsilateral facial muscles,
suggestive of
neuromuscular excitability caused by hypocalcemia
TROUSSEAUS SIGN
Elicitation: Inflating a sphygmomanometer cuff above systolic
blood pressure
for several minutes
Postitive response: Muscular contraction including flexion of the
wrist and
metacarpophalangeal joints, hyperextension of the fingers, and flexion
of the
thumb on the palm, suggestive of neuromuscular excitability caused by
hypocalcemia
FEATURES OF ACUTE vs
CHRONIC HYPOCALCEMIA
ACUTE
Arrhythmias
Tetany
Trousseaus, Chvosteks signs
Seizures (partial or generalized)
Shortness of breath/stridor
Acute confusion
Cardiac Failure
CHRONIC
cataracts, basal ganglia Ca
Dementia
Nail dystrophy
Papilledema
Dry Skin
Cataract
Hypocalcemia Treatment
Tetany, seizures, laryngospasm, cardiac dysfunction:
10-20 mL of 10% calcium gluconate in 50-100 mL 5% dextrose or NS given
over 10 min with ECG monitoring
Repeat until symptom free
Treat hypomagnesemia with IV magnesium sulfate
Start IV infusion of 100 mL of 10% calcium gluconate in 1 L NS or 5% dextrose
at a rate of 50-100 mL/hr
Adjust rate to normalize calcium
Start oral calcium and calcitriol
Case 3
18 y/o male with h/o aML, graft vs. host disease, admitted for
pancreatitis
Consulted to assist with transitiion off the insulin drip
24 hour insulin requirement greater than 300 units
Previous attempts to transition with long acting or intermediate
acting insulin analog plus prandial short acting insulin
unsuccessful
What might be going on?
Case 3
Graft vs. Host-scleroderma like skin change
Acquired lipodystrophy
IV insulin restarted
Clinical deterioration ensued
What are we missing
Case 4
Serum Triglycerides:
> 6000
Case 4
Chylomicronemia: most often Multifactorial Chylomicronemia
Syndrome
Predisposing genetics plus second hit
Second hit: obesity, DM, drugs: HCTZ, beta-blockers, oral
estrogens, retinoids, atypical antipsychotics, propofol, protease
inhibitors, alcohol
Therapies: fibrates, niacin, omega 3 FA, insulin (direct affects
on lipoprotein lipase), APO-C11 or LPL deficiency: FFP
Diet: FAT only 15% of diet10-15 grams fat per day
Case 4
What can we do next?
Plasma
Exchange
(some likely contribution of heparin induced
lipolysis)
Case 4
74 y/o female with Hodgkins lymphoma admitted for altered
mental status, ARF, anemia (hemorrhagic gastric erosion),
recently begun on HCTZ
Precipitant symptoms: polyuria, craving for ice chips,
progressive decline in sensorium over several days,
progressive abdominal pain
Serum Calcium of 14
What other labs do you want?
Hypercalcemia: Most common

etiologies
PTH mediated vs. non-PTH mediated
Hyperparathyroidism
primary
tertiary (underlying chronic renal insufficiency or malabsorption syndrome)
Multiple Endocrine Neoplasia syndrome
Malignancy (in rough order of frequency) squamous carcinoma of the lung
breast cancer
renal cell cancer
head and neck squamous cancer
multiple myeloma
hematogenous and lymphomatous malignancies
Granulomatous disease (in rough order of frequency) sarcoidosis
tuberculosis
leprosy
histoplasmosis/coccidiomycosis
disseminated candidiasis/cryptococcosis
berylliosis
Hypercalcemia: Most common

etiologies
Hyperparathyroidism
primary
tertiary (underlying chronic renal insufficiency or malabsorption syndrome)
Multiple Endocrine Neoplasia syndrome
Malignancy (in rough order of frequency) squamous carcinoma of the lung
breast cancer
renal cell cancer
head and neck squamous cancer
multiple myeloma
hematogenous and lymphomatous malignancies
Granulomatous disease (in rough order of frequency) sarcoidosis
tuberculosis
leprosy
histoplasmosis/coccidiomycosis
disseminated candidiasis/cryptococcosis
berylliosis
Key components to PE
Blood pressure
HR (heart block, bradyarrhytmia)
Neck exam: lymphadenopathy, neck mass (adenomas are
almost never palpable)
Dont forget: the breast exam, rectal exam, mental status
exam (endocrinopathy, paraneoplastic syndrome)
Treatment
Emergent therapy: calcium greater than 14 mg/dl or > 12.5
mg/dl with symptoms
Fluid resuscitation is the cornerstone of therapy (most
patients will require 2-4 L in the first 24 hrs)
In general, fluids + furosemide + bisphosphonate
Calcitonin is reserved for severe hypercalcemia (due to time
course of bisphosphonate therapy)
Therapy cont.
Goals of correction: IVFs should decrease the serum
calcium by 1.5-3 mg/dl in 24-48 hours
Do not use furosemide until adequate volume expansion
Dosing of Lasix: lower dose in nave patients, young
patients, higher dose often needed in patients with CV
dysfunction
Monitor electrolytes especially if diuresis is brisk
The Issue with Furosemide RX

Natriuretic effect >> calciuretic effect
So without adequate volume resuscitation, the volume status
will worsen
It has largely reserved for patients with heart failure in whom
the volume resuscitation is likely to be problematic
When to use glucocorticoids

Hematologic malignancy (lymphoma or myeloma)
Granulomatous disease (sarcoidosis, Vitamin D intoxication)
- given IV in a dose of 200 - 300mg/day of hydrocortisone (or
its equivalent) for 3 - 5 days
Effects are often delayed for a couple of days
Bisphosphonates cont.
Pamidronate: older preferred agent
In general: 60 mg over > 4 hours for a serum calcium < 14
mg/dl (< 3.5 mmol/L), 90 mg infused over 90 minutes to 6
hours > 14 mg/dl
Zolendroic Acid IV, 4 mg in 100 mL 0.9% saline over 15-30
minutes
Ibandronate IV, 6 mg in 100 mL 0.9% saline over 15 minutes
Therapy
Calcitonin:
Good option in renal failure
Low potency
Mechanism of action: decreases bone resorption and promotes urinary
clearance of calcium
Also has anlagesic properties
Used routinely if calcium is >16 mg/dl, tachyphylaxis occurs within a
few daysbut will bridge to bisphosphonates
Glucocorticoids potentiate the effects of calcitionin and decreases the
escape phenonmenon
Salmom-calcitonin: 4 units/kg sc/IV every 12 hours (1 unit skin test)
Synthetic human calcitonin: 0.5 mg sc daily
Time course: an effect will be seen within a few hrs, nadir at 12-24 hrs
Hypercalcemia in renal failure

Dialysis with zero calcium bath
Etiology may be the vitamin D supplementation
Case 5
Called to see 50 y/o female with T1DM on insulin pump
therapy admitted for psychosis
No suicidal ideation
Last blood sugar 140 mg/dl
What would you do?
Contraindications for pump therapy

Altered state of consciousness
Patient at risk for suicide
Critical illness
Inability of patient or family member for management of CSII
DKA or hyperglycemic hyperosmolar state at admission
Case 5
One to one nurse
Pt would not allow me to access the pump
Reported she last filled reservoir two days ago
Called risk management
Judicial order
required to
remove pump
Case 5
Clarify with your institution, before it happens
Tubing can but cut
One-on-one, to see if the patient manipulates the pump
In a type 1 patient, the continuous infusion rate should keep
the patient out of DKA, but sometimes is set too high for a
non-fasting state, so low blood sugars may occur if patient is
NPO
Questions?
Elderly Trauma:
Pitfalls and Lessons Learned
Kaysie L. Banton, MD
UMMC Trauma Medical Director
Fairview System Trauma Medical Director
Case Scenario
A 76-year-old male is brought to the ED after he

fell from a ladder while cleaning his gutters.
Prior to falling, felt dizzy. On Coumadin for
recent MVR. Lethargic, MAE, garbled speech.
Initial vital signs: RR 32, Pulse 86, BP 146/86,

GCS score 12
Objectives
Understand physiology differences
Review injury patterns
Special considerations
Aged Definitions
Trauma Old = 35 years
Elderly = Over age 65 years
Young old = 65-80 years
Old old = Over age 80 years
The Problem of Trauma

7th leading cause of death >65yo
Currently 13% of population
32% injury related hospitalizations
33% injury related deaths
Grey Tsunami coming 2030

1/5 of population will be >65yo
14 million >85yo
Unique Trauma
Falls
Leading
Causes
of Injury
Motor vehicle
crash
Alcohol
Burns
Pedestrian vs.
vehicle
Geriatric Trauma
Falls are the most common mechanism
40% of elderly trauma
3.8% have a significant fall each year
55% mortality
Most occur at home from ground level

Even isolated hip fractures are significant
32% die within 12 months of fall
25% of falls due to underlying medical

problem
Unique Characteristics
What are the unique characteristics of
geriatric trauma?
Aging Differences
Effects of age:
Anatomy
Physiologic functions
Comorbidities
Medications
Unique Characteristics
Brain mass
Diminished hearing
Eye disease
Sense of smell and taste

Saliva production
Esophageal activity
Cardiac stroke volume and rate
Depth of perception
Discrimination of colors
Pupillary response
Renal function
2- to 3-inch loss in height

Impaired blood flow to leg(s)
Degeneration of the joints
Total body water depletion

Nerve damage (peripheral
neuropathy)
Stroke
Heart disease and high blood

pressure
Kidney disease
Gastric secretions
Number of body cells
Elasticity of skin, thinning of
epidermis
15 30% body fat
ATLS - Primary Survey

Airway
with c-spine protection
Breathing
Oxygenation and ventilation
Circulation
And hemorrhage control and vascular access
Disability:
Neurological deficits
Exposure / Environment
Elements at scene (chemicals, temperature), removal of
clothing and hypothermia prevention
Airway/Breathing changes with

aging
Airway Pitfalls
Factors affecting airway management
Dentition (including dentures)
Nasopharyngeal mucosal fragility
Cervical arthritis
Arthritic joints including Mandibular joints
Decreased cardiopulmonary reserve may require

early intubation
Pulmonary changes with aging
Chest changes with aging

Decreased:
Airway clearance/ cough

Laryngeal reflexes
Mucociliary clearance
Number of Alveoli
Reduced elastic recoil

of lungs/chest wall
Reduced chest muscle
strength
Increased V/Q
mismatch
Increased risk:
Increased aspiration risk
Infection
Decreased response to
hypercapnea
Arterial hypoxemia
Ave PaO2 78-92 mmHg
Unique Breathing Changes

Respiratory
Lung less compliant
VC, FEV1, PaO2 decrease with age
Muscles of respiration weaker in the elderly
Airway management may be affected by changes

with aging
Difficult intubation secondary to neck/jaw mobility
Chest wall more rigid and brittle
More prone to traumatic injuries
Breathing Pitfalls
Diminished respiratory reserve
Use of supplemental oxygen
Comorbidities:
COPD/Asthma,OSA
Chest injuries poorly tolerated
Minor chest injuries have major effects
Rib Fractures in the elderly

Often have associated head injury
Common cause of readmission to ICU
10% mortality
1:1 relationship to complication
Aggressive pulmonary toilet

Pain
Blocks (indwelling vs injection)
Non-narcotic
Epidural
Consider rib fixation
Unique Circulatory Problems

Decreased cardiovascular function and reserve
Preexisting CHF
Cautious fluid administration
Anticoagulants and other medications
Pharmacologic effects
Catecholamine effects and dysrhythmias
Unique Cardiovascular Issues

Inadequate cardiovascular response to
trauma
Occult shock
Less cardiovascular reserve
Respond to hypovolemia with increased SVR vs.
increased CO
Unable to tolerate and respond to fluctuations in
blood volume
Become hypothermic easier/faster

Blunted baroreflex and altered b-adrenergic
responsiveness
decreased dependence on chronotropy
increased reliance on stroke volume in response
to stress
Atrial Fibrillation
Common Chronic comorbidity
Common acutely as reaction to stress
No superior treatment
Resume BB if previously taking
Circulatory Pitfalls
Elderly trauma patients are at higher risk
Less compliant vessels
Preexisting CAD
With increased HR, less diastolic filling of
coronary vessels
Increased turbulent flow = decreased coronary
perfusion
Circulatory Monitoring
NIBP
Skin at risk
CVP
Limitations
Pulse wave (FloTrac)

Limited in peripheral arterial disease
Use compilation of measures
Circulatory Support
Colloid not better than crystalloid
Small volumes
Hemorrhagic shock transfuse early
Optimization of fluid status may fail to correct

hypoperfusion
Dobutamine can cause tachycardia increase in
myocardial oxygen demand precipitating AF
Milrinone (nonadrenergic MOA), but less
effective
NE/Vasopressin common
Unique Neurologic Characteristics

Central nervous system
Dura adherent to inside of skull
Brain atrophies
More tendency to move inside skull during
trauma
More likely to develop CNS bleeds
Spinal stenosis / DJD complicates

evaluation
Unique Neurologic Characteristics

Acute and chronic subdural
hematomas
Altered sensorium
secondary to cerebral
atrophy, hypoperfusion, and
medications
Spinal osteoarthritis, leading
to frequent spinal column
and cord injuries
Neuropathy
Neurologic Pitfalls
Baseline dementia
Comorbid neuropathy/deficits
Narcotic use
Unique Exposure Characteristics

Abnormal thermoregulatory
mechanism
Increased sensitivity to hypothermia
Increased risk of infection
Lack of tetanus protection
Geriatric skin and soft tissue

Thinning, loss of dermal appendages
increase the risk of injury and impair wound
healing
Minor trauma results in large hematomas,
skin tears and sloughing
More prone to pressure ulcers after short
time on back boards
30 mmHg/30min (may be much shorter for
malnourished thin elderly patient)
Elderly and Burns

Higher risk
Lower rates of healing
Fewer hair follicles
Hypertrophic scarring
Burn healing is running a marathon

LD50 at 80y is 8%
Unique Musculoskeletal
Characteristics
Structually
Osteoporosis
More prone to fractures
Decreased mobility of joints
Spinal column problematic
Less circulating catecholamines

Poorer balance
Vision problems
Musculoskeletal Pitfalls
Most frequent cause of morbidity
Susceptible to certain fractures
Hip fx - 1%/year in men and 2%/year in
women over 85 years of age
Osteoporosis
Preexisting deformities complicate evaluation
Immobility will lead to complications
Unique Renal Characteristics

Reduced renal blood flow
10% per decade after age 40
Reduced glomeruli (replaced with fibrosis)

loss of 30-50% by age 70
Medullary hypotonicity and increased water loss
Hyponatremia
Tubular frailty
Sensitive to nephrotoxic/hypoxic insult
Aging kidneys and AKI

Higher risk of contrast induced nephropathy
No benefit of pre-exposure bicarb or Mucomyst
No particular treatment better

If requires acute RTT
Same indications
Same options
Same outcomes for renal recovery
14.29% likelihood of initiating RRT within 2 years
Recommendations
MAP >60 to promote renal perfusion
Mortality rates higher if
Hospital 15-40%
2 year mortality 28.2% 57.7%
14.29% likelihood of initiating RRT within 2 years
Injury Patterns think fragility

Pedestrian vs MVC
Ribs, head, long bone
High speed MVC

Head, Ribs/sternum, Aortic dissection, long
bone
Fall from height

Rarely landing on feet: head, chest, pelvis,
ribs
Fall from standing

Head, hip, ribs
Mortality
After controlling for Injury Severity Score,
Revised Trauma Score, preexisting disease,
and complications, the elderly were 4.6 times
as likely to die.
directly related to trauma (40.9%)
likely related to trauma (31.8%)
unrelated to trauma (27.3%)
Admitted to ICU? Higher mortality at 1 year
Early predictors of death

elderly trauma patients >55y
ABG <1 hour of patient admission
Predictor of ICU length of stay and mortality
Base deficits mild ( 3-5), moderate ( 6-9), and
severe (10)
Severe BD had 80% mortality

Moderate BD had 60% mortality
Even a normal base deficit carried a
mortality of 24%
Early predictors of Death

Base deficit < 6 is particularly ominous in
elderly trauma patients
SBP <90 mmHg is associated with an 82%
mortality rate
Geriatric Physiology
Older adults respond to trauma differently
than their younger counterparts
More occult hypoperfusion
Comorbid conditions
Polypharmacy
Beta-blockers, calcium channel blockers,
diuretics, narcotics
Occult Shock
Inability to maintain organ perfusion
Use base deficit, lactate as resuscitation
measure
Early use of invasive monitoring
Judicious use of vasopressors to augment
CO
Triad of Death
Approach to the Geriatric Trauma

Patient
BP
May be deceivingly normal
Many patients with underlying hypertension
Increasing SVR in response to hypovolemia
Pulse
May be falsely normal
Medication effects, blunted catecholamine
response
Approach to the Geriatric Trauma

Patient
Laboratory
Serial hematocrit or hemoglobin
Consider resuscitating to LA or base deficit levels
(Q6h)
Low threshold to transfuse
PT / PTT
Serum electrolytes
Rapid glucose
Medication levels
EKG
Trauma Physiology
Immediate disruption in thermoregulation
Keep the patient WARM
Cardiac contusion uncommon

If initial EKG normal, no additional work up needed
SOB can mean many things

Pulmonary contusion, hemorrhage, sepsis, COPD,
airway compromise, CHF
Hypotension should still be presumed to be

hemorrhage
The Geriatric Trauma Patient

>80yo TBI requiring craniectomy
Sim 30d mortality, outcomes, more resources
>65yo, nl GCS >2% risk of requiring neurosurgery,

>5% if anticoagulated
PCC reversal = shorter ICU time
Older patients (>65-70) probably better outcomes

at Trauma Centers regardless of injuries
Can manage non-op spleens just like younger patients
Dedicated geriatric trauma unit has better outcomes
Older with severe TBI (GCS <8) who dont improve at
72h should move to comfort cares
Aging and Trauma

>45yo: increased fatality, end organ failure,
coagulopathies
45-65 increased infections
fewer infections >65
Anticoagulation is more likely to cause SDH with any

trauma
not associated with recurrence rates, but recurrence onset
Specific Therapeutic Approaches

Intranasal insulin helps with cognitive impairment
recovery
Geriatric protocols improve outcomes
ATLS - Primary Survey

Airway
Remove dentures, careful with mouth opening, c spine
Breathing
100% Oxygen, sats of 91% may be patients baseline
Circulation
Poor circulation, vascular disease, CAD, BB, CCB
Disability:
Neurological deficits vs neurological baseline,
neuropathy
Exposure / Environment
Hypothermic, move off of hard surfaces immediately
Recommendations
All trauma patients over age 55 should be
considered for evaluation in a trauma center
lower threshold for trauma activation should be
used for injured patients aged 65
Physiologic age more important than

chronologic age in approaching patients
Frailty score
Special Issues
What are the special issues to
consider in treating geriatric trauma
patients?
Medications
Elder maltreatment
End-of-life decisions
Drugs That Affect Resuscitation

Beta blockers
Corticosteroids
Antihypertensives
Diuretics
NSAIDS
Hypoglycemics
Anticoagulants
Psychotropics
Alcohol
Recognizing Elder Maltreatment

High index of suspicion
Patterns of injury
Multiple types
Physical maltreatment
Sexual maltreatment
Neglect
Psychological maltreatment
Financial and material exploitation
Violation of rights
Strategy For Elder Maltreatment

Dont query in presence of possible
abuser.
If maltreatment is suspected, remove
patient from abusive environment.
End-of-Life Decisions
When is enough, enough?
Advance directives?
Right to self-determination is paramount
Treatment only in patients best interest
Benefits of treatment outweigh adverse
consequences
Case Scenario
A 76-year-old male is brought to the ED after he

fell from a ladder while cleaning his gutters.
Prior to falling, felt dizzy. On Coumadin for
recent MVR. Lethargic, MAE, garbled speech.
Initial vital signs: RR 22, Pulse 86, BP 146/86,

GCS score 12
What should you consider
in management of this patient?
Summary
Trauma in the elderly is increasing
Treatment priorities are the same
Remember anatomic and physiologic changes
Comorbid conditions and medications
Consider elder maltreatment
Early conversations about goals of care
Questions?
4/13/2015
The ProCESS,
ARISE and Promises Trials
Optimization Trials
A Closer Look
Late
Early
Mortality
(Boyd, New Horiz, 1996)
(Kern, Crit Care Med, 2002)
4/13/2015
POST-RESUSCITATION
INTENSIVE CARE PROTOCOL
Fluids:
PCWP:
Hgb:
MAP:
Renal:
Inotropes:
Preload:
Afterload:
Pressors:
D02:
V02:
Vent.:
crystalloids and colloid

above 18 mm Hg
10 g/dl
greater than 70 mm Hg
dopamine 2 ug/kg/min
dobutamine
nitroglycerin
sodium nitroprusside
norepinephrine (4 mg/250 ml NS)
600 ml/min.m2
120 ml/min.m2
Controlled Mechanical Ventilation
Am J Cardiol, 1998
4/13/2015
Am J Emerg Med 1996
The Evolution of Early Sepsis Care
NEJM, 2014
NEJM, 2014
Whats is Early Sepsis Care in 2015?
4/13/2015
Who and what do you believe?

Whats the best thing to do for my next
patient?
4/13/2015
Curative and Palliative Approaches to Care throughout a Critical Illness.
SIRS and Lactate
Antibiotics
Sudden CP Collapse
Delayed EGDT
EGDTProCESS Enrollment
Admission
to ER
Admission
to ICU with 2 hours
Cook D, Rocker G. N Engl J Med 2014;370:2506-2514.
Enrollment and Center Description
4/13/2015
Antimicrobials had to be commenced

prior to randomization.
Crit Care Med, 2014
8.5% Increase in Mortality
The lactate screening and risk

stratification:
Its impact on mortality
4/13/2015
Outcome Impact of
Lactate Measurements
51.4 to 29% (11.4%) - No Hypotension

58.6 to 44.5% (12.1%) - Hypotension
Prevention of
Sudden Cardiovascular Complications
Outcome - EGDT
Rivers et al.
Rivers E, Nguyen HB, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock.
N Engl J Med 2001;345:1368-77.
4/13/2015
12.1% of All
Cardiac Arrests
Hemodynamic Phenotyping of Sepsis
4/13/2015
Inflammatory Mediators Produce Cardiovascular Insufficiency
Increased Metabolic Demands:

Fever, Tachypnea
Hypovolemia,Vasodilation &
Myocardial Depression
Microvascular Alterations:
Impaired Tissue Oxygen
Utilization
Cytopathic Tissue Hypoxia

Fink, Crit Care Clin, 2002
MAP
Cardiac Index
CVP
ScvO2
Was there equipoise:

Were the centers practicing
standard care?
4/13/2015
In summary, our results suggest that usual resuscitation may have

evolved over the fifteen years since the Rivers study and that NHS
hospitals now achieve similar levels of in-hospital survival to those
achieved with EGDT in the Rivers study for patients with early
septic shock if they are identified early and receive intravenous
antibiotics and adequate fluid resuscitation.
Comparing the screen and risk

stratification between ProCESS and EGDT
10
4/13/2015
Can this be adequately

recommended based on the study?
Central line placement
The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. NEJM 2014; March 18 Epub
11
4/13/2015
Late
Early
999,949
203,481
12
4/13/2015
Early
Late
Age-adjusted
hospital mortality
declined from 40.4%
in 1998 to 31.4% in
2009
13
4/13/2015
Does delayed care influence

outcomes
14
4/13/2015
2011
Does protocolized care

decrease mortality?
15
4/13/2015
The Changing Landscape of

Sepsis Mortality:
Are we getting better at
sepsis management?
EGDT after More Than a Decade at HFH
Mortality %
NEJM, 2001
51%
46%
30%
15%
November 8, 2001
Pre-EGDT
EGDT(2001)
Cumulative Studies
ProCESS
Control
EGDT
2015
Before or Control
After
130
46.5%
133
30.5%
12,456
46.8 (26)%
14.567
29.1 (12) %
18-20%
16
4/13/2015
Baseline Hemodynamics:
What do they tell you?
Stage
Hemodynamic Picture
SBP
Hypovolemia
B
Myocardial Suppression
Resuscitated, compensated and

vasodilatory
Supranormal DO 2 dependency
Impairment of tissue O 2 utilization
CVP
Treatment and Comments
Variable
Variable
to normal
Volume
Correct anemia, Inotropic
Therapy
Vasopressors, low dose
corticosteroids
Increased VO2 after
augmentation of DO 2
Variable
Decreased VO2
r-APC
Resuscitated
Heterogeneity in Hemodynamic
Optimization
17
4/13/2015
18

Sepsis

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Sepsis

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4/11/2015

The First 6 Hours of Sepsis

The First 6 Hours of Sepsis Diagnosis and

Starting a Sepsis Program: Practice, Politics and

The First 6 Hours of Sepsis Diagnosis and

Resuscitating Sepsis: After ProCESS, ARISE and

Steroid Use in Critical Illness - Update 2015

Sepsis: A Complex and Dynamic Landscape

Cases per year Mortality (%)

Acute Myocardial Infarction

A Need to Change the

Time Sensitive Diseases

2004, 2008, 2012

The Evolution of Early Sepsis Care

Whats is Early Sepsis Care in 2015?

The Fundamental Evidence

The Origin of SIRS

SIRS in the Emergency Department

The Timing of Antibiotics

Dogs with septic shock induced by an

Crit Care Med,

Crit Care Med,

8.5% Increase in Mortality

Importance of Blood Cultures and

Crit Care Med, 2004

Patients who had surgical source control delayed for

Risk Stratification for

Stephen Hales - 1733

A Subtle and Deadly Disease Transition

Global Tissue Hypoxia:

Seminal Lactate Studies

56 patients with clinical signs of shock:

Screening for Severe Illness in the ED

SIRS SIRS + LA SIRS + LA

Aduen, JAMA, 1994; Grzybowski, Chest, 1999

Crit Care Med, 2014

51.4 to 29% (11.4%) - No Hypotension

What patients are at high risk for

Importance of the Fluid Challenge

2.5 3.5 Liters for 70 kg

Is Fluid Administration Within Six Hours Early Enough for

Earlier fluid resuscitation (within the first 3 hours) reduces

Initial Lactate minus Later Lactate

Quartiles of Lactate Clearance

Care of the Hospitalized

I have no conflict of interest to disclose

Vitals: T 99.6, BP 87/45, HR 98, RR 20, O2 sats 91% on RA

CXR- Right pleural effusion, no other acute cardiopulmonary pathology

Abdominal U/S- large ascites with thickened and distended gallbladder,

Adapted from Hepatitis C Education Society: http://hepcbc.ca/stages-of-liver-disease/

Natural History and Prognosis

Baveno IV International Consensus Workshop Staging

DAmico G et al. J Hepatol. 2006;44:217-231.

Classification of Cirrhosis Severity

Patients in Class A are considered

Adapted from Garcia-Tsao G et al. Am J Gastroenterol. 2009;104:1802-1829.

Classification of Cirrhosis Severity

Most Common Causes of Death

3) Right pleural effusion

4) Acute kidney injury

Overt Hepatic Encephalopathy

82 (74%) died during follow-up period

Bustamante J et al. J Hepatol. 1999;30(5):890-895.