Transcript Ketamine

Case Based
Presentations
Metabolic/Endocrine
Neil Mclean
October 2, 2008
Case #1
45 year male presents to the emergency
department with complaints of a persistent
headache and muscle weakness. He also
states he feels like his muscles are
cramping up on him. While at the triage
he develops palpitations.
His vitals are taken and are
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105 225/130 16 100% 37.2
He is moved into the ED and you are
called approx 1 hour later because of
“refractory hypertenstion” You see that
they have not been able to control his
blood pressure with the use of IV
Labetolol/hydralazine and SL captopril.
You send some blood work and his
sodium is 157 and his potassium is 2.1
You astutely consider Conn’s syndrome
in your differential and embark to prove
your case.
Functional Adrenal Anatomy
Functional Adrenal Anatomy
Conn Syndrome
Discovered by JW Conn in 1955
Primary Hyperaldosteronism
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Unilateral aldosterone producing adenoma
60%
aka Conn syndrome
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Idiopathic hyperaldosteronism
Bilateral adrenal hyperplasia
Epidemiology
Twice as common in women
~0.5-1.2% of pts with hypertension
Clinical Presentation
Hypertension
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Usually refractory
Hypokalemia
Hypernatremia
Metabolic Alkalosis
Conn Syndrome
Investigations
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The best screening is upright plasma
aldosterone to plasma renin activity ratio
stop meds for 2 weeks as most can affect the
levels of aldosterone or renin.
Alpha-blockers and sympatholytic agents can
be used to control BP
aldosterone–to–renin ratio
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renin activity ratio of >30 or plasma
aldosterone concentration of greater than 0.5
nmol/L (18ng/dL) is suggestive of primary
aldosteronism
sensitivity of 91%, positive predictive value of
69% and a negative predictive value of 98%
Test inaccurate if on ARB, ACEi
Investigations
Another test is oral sodium loading for 3 days
and 24-hour urine collections of
aldosterone
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urine sodium must be >200 meq to document
adequate sodium loading
urinary aldosterone of >14 μg is suggestive of
hyperaldosteronism
2 l of isotonic saline is infused over 4 h to
suppress aldosterone production and plasma
aldosterone level >10 ng/dl is diagnostic
Imaging
CT imaging should be performed to
assess for aldosterone-producing
adenoma
Radionuclide scanning with 131
iodocholesterol (NP-59 cholesterol)
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performed over 2 to 5 days and has 72%
accuracy
Investigations
Differential adrenal venous sampling is
quite useful in detecting unilateral disease
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Complications include adrenal infarction,
technical limitation, and failure to cannulate
the adrenal vein 25% of the time
Treatment
Andenomas
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A success rate for surgery is around 70-80%
and HTN may require treatment for 3 months
postop
Spironolactone used preop diminishes postop
hypoaldosteronism and hypokalemia
Most can be done by MIS
Treatment
All other conditions, treatment is
medical.
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Spironolactone at doses from 25 to 400 mg
per day have been used succesfully
BP may take about 2 months to normalize
Other antihypertensive agents may to be used
concomitantly
CASE #2
66 year old Female presents with 2 day
history of urinary symptoms. This am,
husband noticed that she was difficult to
rouse and called EHS. Pt arrived and is
obutunded.
Temp 39.4 BP 75/45 HR 123 RR 24
SAO2 99% on 10L mask
ICU called to assess and urine dip comes
back +++Leuks and Nitrites
PMHx: Hypothyroid, HTN
After a quick evaluation, this patient is
obviously septic and needs to be intubated
Medications for induction
Begin fluid bolus, phenylephrine on standby
Midazolam (fast-acting sedative), 2 mg in
this case
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Con: vasodilator, thus can worsen vasodilatory
shock
Pro: amnestic properties, see below
Ketamine 1-2 mg/kg
Fentanyl (analgesia, suppression of innate
respiratory drive)
Rocuronium for paralysis if needed (rapid
sequence)
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Fewer metabolic caveats (K) than sux, but
longer-acting if airway control proves impossible
Ketamine
Pro:
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Hemodynamically stable (may increase cardiac
output)
Fast-acting, short duration
? Bronchodilator
Con:
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Increased ICP in hypertensive patients, or those with
existing intracranial hypertension
Reemergence phenomenon
Hallucinations (K-hole)
Varying availability (such as in Surrey)
Etomidate
Also hemodynamically stable, fast-acting, short
duration of action
Main controversy is adrenal suppression
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In the adrenal gland, it inhibits C-11 Hydroxylase,
which metabolizes deoxycorticosterone to
corticosterone (which goes on to aldosterone), and
11-doxycortisol to cortisol.
First noted in the early 80s.
Does this translate into adverse clinical effects,
in setting of modern management of septic
shock?
Etomidate
This effect has been shown to be both dosedependent and duration-dependent, with a
single dose inhibiting adrenal function for up to
24 hours.
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A crucial period for resuscitation in septic shock.
No good RCT data
Does etomidate have a bad rap?
Etomdiate
Systematic review by Jackson, et al.
Chest 2005 Mar; 127 (3):1031-8
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Given known side effects, caution should
be used in septic shock patients (?
Concomittant steroids)
1 small RCT (10 etomidate @ 0.3
mg/kg, 8 midazolam 0.05-0.1 mg/kg),
with outcome cosyntropin stim test
result.
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Acad Emerg Med. 2001 Jan;8(1):1-7.
Etomidate
Statistically significantly different at 4
hours (normal in all controls and 30% of
intervention group), but all still within lab
reference range of normal. No difference
at 12 or 24 hrs.
No clinical outcomes measured
Consecutive patients, not necessarily septic shock
Observational data
Ray, McKeown. Critical Care 2007,
11:R56 (doi:10.1186/cc5916
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159 pts in a single ICU (Scotland); found that
patients who were induced with etomidate
(septic shock) required less vasopressor
support, and had no increased requirement
for steroids, nor was clinical outcome
affected.
Etomidate + steroids had higher mortality (p=0.12)
Retrospective Corticus
Etomidate treated patients had lower basal
cortisol levels
Etomidate use was associated with
increased mortality, especially in non
steriod group
What about just giving
steroids…?
This is a complex issue, as Dr. Mountain
will elucidate…
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CIRCI vs primary adrenal insufficiency as a
direct result of etomidate.
Should prophylactic steroids be given to any
patient induced with etomidate?
Data suggest not (Ray study), but there is no large
RCT data either way.
The patient is successfully intubated
and brought to the unit. She is initially
volume resuscitated with 5 L of
crystalloid and requires 45 mcg/kg/min
of Levophed to keep her MAP barely
above 60. She is started on
appropriate antibiotics. On exam she is
cold peripherally and has minimal urine
output. Your rock star medical student,
says that “she appears to be in
refractory shock do you think her
adrenal function is impaired?”
What is the incidence of relative adrenal
insufficiency in sepsis?
Depends on your definition of relative adrenal
insufficiency – no real consensus exists.
Currently accepted definition is based on a study
by Annane et al. (2006, Am J Respir Crit Care
Med).
In two cohorts of septic patients, (N=61 and
N=40), the incidence of relative adrenal
insufficiency was 60%, as defined by the single
dose metapyrone stimulation test.
Metapyrone stim test works by blocking
the last step of cortisol synthesis, so the
immediate precursor (11-B-deoxycortisol)
accumulates in serum. Accepted
reference standard for relative adrenal
insufficiency is an increment of < 7 mcg/dL
after overnight test.
In the patients that were adrenally insufficient via
the metapyrone stim test, base-line cortisol (< 10
mcg/dl), delta cortisol (< 9 mcg/dl), and free
cortisol (< 2 mcg/dl) had a positive likelihood
ratio equal to infinity, 8.46 (95% confidence
interval, 1.19–60.25), and 9.50 (95% confidence
interval, 1.05–9.54), respectively.
The best predictors of normal adrenal response
were cosyntropin-stimulated cortisol of 44 mcg/dl
or greater and delta cortisol of 16.8 mcg/dl or
greater.
Why does it occur? (Discuss WF
syndrome as part of your answer).
Normal stress response
Increase in cortisol production by a factor
of up to 6 (proportional to degree of
stress).
Loss of diurnal variation.
Increase in production of CRH and ACTH,
and loss of negative feedback from
cortisol.
HPA axis is stimulated by circulating
cytokines.
Normal stress response (cont’d)
Levels of corticosteroid binding globulin
decrease, leading to increase in free
fraction.
Also, binding globulin cleaved by enzymes
at sites of inflammation.
Inflammatory cytokines also increase
affinity of glucocorticoid receptors for
cortisol.
Impaired stress response
CRH and ACTH response can be impaired by
head injury, central nervous sytem depression,
or pituitary infarct, exogenous steroids.
Adrenal cortical synthesis can be impaired by
multiple mechanisms (eg):
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Etomidate
Antifungals.
Steroids, progesterone (decreased production)
Rifampin, phenytoin (incr. Hepatic metabolism)
Impaired stress response
Inflammatory cytokines during sepsis can
induce systemic or tissue-specific steroid
resistance.
“Relative” insufficiency can simply indicate
elevated cortisol levels that are
nevertheless insufficient to control the
inflammatory response.
Adrenal hemorrhage
Acute adrenal insufficiency may occur as a result of
bilateral adrenal infarction caused by hemorrhage or
adrenal vein thrombosis.
Adrenal hemorrhage has been associated with
meningococcemia (Waterhouse-Friderichsen syndrome)
, but Pseudomonas aeruginosa was the most common
pathogen in one report of 51 children dying of sepsis and
bilateral adrenal hemorrhage.
Waterhouse-Friderichsen syndrome has also been
reported with sepsis from Streptococcus pneumoniae,
Neisseria gonorrhoeae, Escherichia coli, Haemophilus
influenzae, and Staphylococcus aureus.
Adrenal hemorrhage
Symptoms and Signs
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hypotension or shock (>90 percent of patients);
abdominal, back, flank, or lower chest pain (86
percent); fever (66 percent); anorexia, nausea, or
vomiting (47 percent); confusion or disorientation (42
percent); and abdominal rigidity or rebound (22
percent)
Risk factors
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anticoagulant drug or heparin therapy or
coagulopathy, thromboembolic disease,
hypercoagulable states such as antiphospholipid
syndrome, physical trauma, the postoperative state,
sepsis, and any cause of severe stress
Adrenal hemorrhage
Pathogenesis
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Unclear.
Increased adrenal blood flow stimulated by ACTH secreted in
response to stress may play a contributory role
Anticoagulation therapy is implicated in about one-third of
patients, but adrenal hemorrhage occurs very rarely in patients
who are anticoagulated; when it does, it is usually within the first
2 to 12 days of therapy.
A case-control study (23 patients with bilateral massive adrenal
hemorrhage and 92 control patients) reported that
thrombocytopenia, heparin use, and sepsis were the variables
that were most strongly and independently associated with
adrenal hemorrhage risk
How can you assess adrenal dysfunction
in sepsis, and is it a useful test?
High dose ACTH stim test:
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baseline serum cortisol drawn and then 250
mcg of synthetic ACTH (cosyntropin)
administered intravenously. Serum cortisol
levels drawn 30 and 60 minutes later.
In a prospective inception cohort study, a
high-dose ACTH stimulation test was
performed on 189 patients with septic shock
and the results correlated with 28-day
mortality
Outcomes of septic shock associated with baseline cortisol level and adrenal
responsiveness to 250 mcg injection of cosyntropin
Data from: Annane, D, Sebille, V, Troche, G, et al. A 3-level prognostic classification in septic shock based on
cortisol levels and cortisol response to corticotropin. JAMA 2000; 283:1038.
Corticus - 477 patients with severe sepsis or septic
shock underwent high-dose ACTH testing .
Nonsurvivors had a higher baseline cortisol level (30
versus 24 mcg/dL) and a smaller cortisol increase (6
versus 11 mcg/dL) than survivors.
Patients with either a baseline cortisol level <15 mcg/dL
or a cortisol increase ≤9 mcg/dL had a higher mortality,
longer duration of shock, or shorter survival time.
High-dose (ACTH) stimulation appears to separate
patients with septic shock into different prognostic
groups.
However, while identification of poor response to
ACTH stim test can split groups prognostically, it
is controversial whether it predicts response to
steroid therapy.
Annane study suggests that among patients with
inadequate adrenal reserve, hydrocortisone
administration decreased 28-day mortality (53
versus 63 percent), ICU mortality (58 versus 70
percent), and hospital mortality (61 versus 72
percent), as well as more vasopressor
withdrawal (57 versus 40 percent)
However, Corticus found no change in mortality
in steroid vs. non-steroid group, regardless of
response to stim test, and shorter duration of
shock in steroid group regardless of response to
stim testing.
Opinion based recommendation: ‘Classification
of adrenal reserve as adequate or inadequate
fails to identify patients who are more likely to
benefit from glucocorticoid therapy’.
You evaluate her adrenal function and feel
it is a good idea to give her some steroids
Question: Evidence for
steroids
Annane study (JAMA 2002)
300 pts, placebo vs 200mg /d hydrocort +
fludrocort
229 nonresponders to corticotropin:
benefit for steroids clear on 28d mortality
(NNT7)
Faster wean from pressors
Not more complications
CORTICUS NEJM 2008
500/800 pts recruited (underpowered)
Corticotropin responsive: best prognosis
Steroid supplement did not change survival (primary
endpoint)
Steroid reverse shock earlier
Steroid assoc more infection and sepsis recurrence
Etomidate associated with 60% depression of
adrenal axis x 24h
In patients with severe nonresponsive septic shock,
benefit might be greater
Trend for increased mortality if non hypotensive and
steroids added
Doses of steroids in sepsis
and Duration
Have we answered these ?
Do we use etomidate as induction agent in
sepsis?
Is there any value in ACTH stim test?
Who, if anyone do you give steriods to in
sepsis?
CCM 2007 Marik
T60-T0
T30-T0
T60-T0
more
sensitive
Δ max