CORTICOSTEROIDS IN THE ICU:
D. P. Laporta MD
Pulmonary and Critical Care
the whole truth
June 1997
Sir MBD - Jewish General
Hospital, McGill University
Montreal, Quebec
PRO
REFERENCES- REVIEWS
Steroids and biologic agents in the ICU. RP Allen, Crit Care Clinics, July 1991:695-712
Adrenal crisis. R Chin, Critical Care Clinics January 1991:23-42
The utility of parenteral glucocorticoids in the emergency department. Hoang KD , Pollack CV
Jr, J Emerg Med 1994; 12:507-19
OBJECTIVE
To establish the evidence to justify the use of systemic corticosteroids (SCS) in specific clinical
situations in the ICU. Specific recommendations are made from a critical review of the literature.
METHODS
Clinical Experience
SMMBD-JGH ICU Database
ICU Textbooks (Shoemaker, Civetta, Rippe)
Evaluation of Published Literature1: Human, Clinical Trials, Reviews (Systematic, Narrative)
Not Used: Animal / Physiologic Studies
1
EVALUATION OF PUBLISHED STUDIES ON SCS IN THE ICU
1. Internal validity
Randomized, blinded. control group, similar at outset, treated similarly,
inclusion/exclusion criteria
2. Results:
treatment effect (how large, incl burden (side effects)), outcome measures,
followup, comorbid illness
3. Generalizability
(external validity)
4. Evaluation of literature (grading2)
5. Recommendations3
2
3
GRADING of clinical studies
I
II
III
IV
V
 1 RCT, low FP & FN
evidence from  1 RCT, high FP  FN
RECOMMENDATION
evidence from
GOOD evidence to support
non-randomized cohort comparisons
non-randomized historical cohort comparisons
case-series (no controls)
MODERATE evidence to support
POOR evidence to support


1
*specific clause if high-quality overview (systematic review)
2
SCS IN THE ICU: CLINICAL INDICATIONS
GRADE
Adrenal cortical insufficiency
Asthma
COPD
Sepsis/septic shock
Acute bacterial meningitis
Acute hepatitis viral
ETOH
Croup
Epiglottitis
Post-extubation stridor1
AIDS-PCP
Spinal cord injury
Head injury
ARDS pre (FES)
early
late
1
in high-risk, PEDS
3
RECOMMENDATION
V
I
II-III
I
II
I
II
I
III
I-II
I-II
II
I
II
I
V
POOR
GOOD
MOD-POOR
GOOD
MOD
USE




GOOD
MOD
GOOD
POOR
GOOD-MOD
GOOD-MOD
MOD
GOOD
MOD
GOOD
POOR





DONT

(adult)






NOT COVERED
Peds: Antenatal, Bronchopulmonary Dysplasia
Oncology: brain/spine mets
Collagen/vascular (SLE pneumonitis, cerebritis, renal failure; vasculitides)
Hemato: TTP, AIHA, AI-Tpenia,
Dermatologic
GI: inflammatory bowel disease
Infections: typhoid, tetanus, selected TB issues
Misc: Hypercalcemia, Myaesthania, Transplant, anaphylaxis, radioiodine contrast agents
INDICATIONS FOR SYSTEMIC GLUCOCORTICOIDS
Unfortunately, evidence comes in shades of gray
(the EBM Working Group JAMA 1993)
ADRENAL CORTICAL INSUFFICIENCY (ACI), or ADRENAL CRISIS


pathophysiology: adrenal hypoperfusion, cortical necrosis, thrombosis, hemorrhage
problem:
- making the diagnosis: difficult in the ICU pt : no gold
standard
- concept of relative, rather than absolute ACI

cortisol levels in the ICU (Drucker D CCM 85, Schein CCM 90, Bouachour IntCareMed95)
cg/dl
X 27.59
nmol/l (SI)
surgical stress
> 20
> 552
ACI: - no shock
< 10
< 276
- shock 1.
< 20
< 552
2.wACTH
<7 or value<20
<193 or value<552
prevalence (1+2): 0-37%
...ie RARE
* no predictive value (baseline or ACTH-stimulated)
* often higher in non-survivors, liver disease
how frequent is hypotension in steroid-treated patients who undergo acute stress without
SCS supplementation ?
The few studies available suggest that hypotension ...is
uncommon...adrenal steroids can and should be administered, but other contributory causes
for the hypotension should be sought Udelsman J Clin Endocrinol Metab 87
RISK FACTORS FOR ACI
- previous SCS1
- septicemia
Waterhouse-Friderichsen
Gm -ive (Pseudomonas)
- shock
- meds: anticoagulants
ketoconazole
dilantin, rifampin, phenobarb
- postoperative
- malnutrition
- chronic adrenal disease
autoimmune (Schmidts syndrome)
TB & other granulomatous
AIDS
metastatic disease
amyloidosis
- hypothal/pituitary disease
- coagulopathy
- thrombosis
1 In
the last year. >25mg/d X 5 days: blunted ACTH response, may last X months
4
SYMPTOMS/SIGNS OF ACI
- flank/abdominal pain (adrenal hemorrhage)
- nausea/vomiting
- SIRS
- BP (poor response to b agonists)
- encephalopathy
LABS
Hb (sudden) (adrenal hemorrhage)
K
Na
glucose
ASTHMA

1956 BMRC: SCS are efficacious.

1992 Meta-analysis (Howe BH Am J Emerg Med )
* NB: po = iv
30 RCTs
( Odds Ratio for Admission .47, for Relapse .15)

1993 Systematic review
(McFadden ER Jr, ARRD) ? lowest
effective dose...
Effect
Conclusion
nil
too low
good
sufficient
no different
no better
mg/kg/day hydrocortisone-equivalent
4
10-15 (ie 40 mg MP q6h)
250
...does not support the concept that very large doses of [SCS] are more
efficacious than smaller ones ER McFadden, Jr

1995 Corbridge TC and Hall JBFurther studies are needed to establish the best dose
and dosing frequency of [SCS] in status asthmaticus.
SYSTEMIC CORTICOSTEROIDS IN ASTHMA - EFFECT OF WEIGHT
mg Q6H MP mg/day MP
mg/day OHmg/kg/d OH CORTISONE CORTISONE
WT (kg)
40
60
125
160
240
500
900
1200
2500
40
22
30
62
50
18
24
50
60
15
20
42
70
13
17
36
80
11
15
31
Note the greater than 5-fold variation in dose over usually-suggested dosages !
COPD: The scripture according to Albert

1978 Review (Sahn SA, Chest 78)
Conflicting results, burden of evidence disfavors SCS (of the 6 positive studies,
1controlled, none double-blind; of 11 negative studies, 8 controlled, 1 double-blind)

2 RCTs
* Albert RK, (AIM 80)
MP .5mg/kg q6h
more rapid improvement in FEV1, FVC after 12 hrs, continues to 72hrs
Chest 87 91:289-90: letter to editor re critique of study
5
(stats, no clinically relevant outcome measures)
* In Emergency Dept (Emerman CL Chest 89) no difference at 5 hours
COPD (Continued)

Physiologic intervention (Rubini AJRCCM 94) measurement at 90 minutes

Civetta: We routinely use similar doses...but...for more than 3 days.
After...improvement,...switch to a tapering course of prednisone over several weeks.
SEPSIS/SEPTIC SHOCK

2 Meta-Analyses (10 RCTs, >1000 pts)
Lefering (CCM 95)
No effect on gi bleed, 2ndary infections, hyperglycemia)
Cronin (CCM 95)
Trend to increase in 2ndary infections

Current RCT (Annane D): An unexplored side
SCS attenuates NOS at physiologic (replacement) doses in severe sepsis.
ACUTE BACTERIAL MENINGITIS (ABM):


Animal studies: decrease mortality
PEDS:
Meta-analysis Havens PL (Am J Dis Child 1989)
RCTs : DEX .6 mg/kg/d D1-4 given early with Abx, age 2yrs
no change in mortality, improvement in hearing loss
not recommended routinely
May be useful (H Flu, S Pneumoniae) for hearing
ADULTS:
4 Narrative reviews (Townsend, Harvey, Lauritsen , Berkowitz)
Systematic review (Prasad J Neur, Neurosurg & Psych 95)
7 RCTs: DEX in ABM
problematic methodology
:
Use is unjustified
ALCOHOLIC HEPATITIS (AH)
5 Meta-analyses (89 - 91) outcome: hospital mortality
- Imperiale (Ann Int Med 90) 10 RCTs
results: protective efficacy of SCS 37% overall, provided active gi bleed excluded, and PSE present
- Christensen E (Gut 95) 12 RCTs, adjusted for confounding variables
conclusion:
previous meta-analyses not valid (major flaws in RCTs)
6
no effect (even PSE). Interaction with gender
NB: ACUTE VIRAL HEPATITIS (FHF): 5 RTCs: contraindicated
CROUP
commonest cause of acute upper airway obstructionn in children.

1989 Suggested but unproven

1 Meta-analysis (Yates Drug Safety 97)
Mild- mod
2mg budesonide neb = DEX .6mg/kg IM
Severe
1mg/kg prednisolone q12 h*
* varicella occurence
EPIGLOTTITIS




no RCT.
1 Grade III: 50% LOS with observation + SCS (irrespective of whether intubated)
5 Narrative reviews. Used extensively empirically.
Widely recommended (may decrease inflammatory edema & contribute to recovery,
and avert trach if angioneurotic edema)
POST-EXTUBATION CROUP/STRIDOR



5 RCTs
animals:
efficacious
case series:
Id
PEDS: Louser RJ (J Peds 92), Tellez DW (J Peds 91),Anene O (CCM 96)
ADULTS: Darmon JY (Anesth 93), Ho LI (Int Care Med 96)
CONCLUSIONS (ADULT & PEDS):
- Unwarranted in routinely ventilated pts
- Effective in selected (high-risk) patients
Female
tracheal trauma
reintubation
prolonged intubation
hemodynamic instability
young age (in PICU population)
AIDS-PCP
3 RCT (Montaner JS AIM 90, Gagnon S NEJM 90, Bozzette SA NEJM 90)
...Moderate-severe ( Pao2 (RA) >75, Pao2/Fio2 <350)
Outcome: respiratory failure (AOR=5.87), hospital mortality
effective


NIH Consensus (NEJM 90) and letter (NIAID 90):
...in mod-severe PCP, give steroids
Day 1-5
80mg/d (Severe PCP 320mg/d)
Day 6-10
40mg/d
Day 11-21
20mg/d
NB: give early, taper slowly ie 1month (flareup)
Textbooks (Rippe, Civetta): as per NIH consensus
7
Authors unpublished observations:Less septra rash, but more long-term
secondary opportunistic infections (CMV, MAI, aspergillus, mucor)
SPINAL CORD INJURY (SCI)hrs

preclinical studies: positive

Narrative reviews (Ducker Spine 94, Nguyen Adv Surg 96)
NASCIS I
low-dose MP (100mg/d X 11) vs high-dose MP (1000mg/d X 11) NS

F/U:
Result:
Critique:
NASCIS II
3 groups:
1) MP 30mg/kg  5
mg/kg/hr X23
2) Narcan
3) Placebo
6wks, 6 mo, 1 yr
effective
different outcome of the 2 placebo groups
Recommendation: despite controversy and unresolved issues, advocate...
initiation of steroids ASAP after acute SCI, but not beyond the first 8 hours.
There is too much data available to arrive at any other conclusion
HEAD INJURY

2 RCTs in J Neurosurg (1979 Cooper PR, 1985 Brackman R)
DEX 16mg/kg/d, or 96mg/d or Placebo X 6 days
F/U 1, 6 months
DEX 100 mg/d (within 6hrs) 


Results: No effect
Despite this...

2 Surveys of ICU practice in ICU/Trauma centers: SCS in head injury
UK (Jeevaratnam BMJ 96) SCS used in 19/39 ICUs
USA (Ghajar CCM 95)
SCS used in >50% of the time in 64% centers
NB: SCS in head injury: increased infection rate (De Maria Ann Surg 85)
ARDS
Pre ARDS (Outcome: the occurrence of ARDS)

2 uncontrolled trials (Weigelt Arch Surg 85, Sprung NEJM 84)
Ineffective

2 RCT in pts at risk for Fatty Embolism Syndrome
(Schonfeld AIM 83, Lindeque BGP JBBJSS 87)
8
Effective
9
Early ARDS
2 RCTs (Bernard NEJM 87, Bone Chest 87) 30mg/kg MP q6 X 24h
saw natural course of disease
only large enough group: sepsis
...Ineffective
Late (fibroproliferative) ARDS

Grade V evidence (5 studies, 55 pts)

NS
Physiological evidence
(mediators/outcome) ... positive, ?
promising
NOT DISCUSSED:
MYAESTHENIA GRAVIS
Grade V (case series -no control) (Arsura E Arch Neurol '85)
Plasmapheresis may offset initial steroid-related deterioration, enabling more rapid institution of therapy 
Rippe
...pulse ...[medrol]...may also benefit...appears to produce ledd inital worsening, and more rapid
immprovement than conventional doses of prednisone. Further studies...should be awaited before widespread
use is adopted in myasthenic crises Civetta
ANTENATAL
SEVERE HYPERCALCEMIA
- NIH Consensus JUSTIFIED in fetuses 24-34 wks X 24-48 hrs
- 2 Meta-analyses (Crowley PA and Sinclair JC Am J OBGYN 95, )
Decrease risk of RDS, IVH, NEC. No strong evidence of increased infection
- Narrative review (CCClinics Jan 91: Endocrine crises)
useful if: 1) vitamin D intoxication/sarcoidosis, or 2) lymphoproliferative disease
not useful if solid tumors, hyper-PTH
- Text: useful if life-threatening, paraneoplastic (lymphoproliferative, breast)
CONCLUSION: CORTICOSTEROIDS IN THE ICU:
Documentation of rational therapeutic regimens does not exist for most disease states, due
to lack of evidence... this has given rise to a variety of approaches that define timing,
duration, quantity, tapering schedule
Allen RP, CCC 91
Corticosteroids are powerful tools, their potential benefits and risks are known, but their
precise indications and contraindications are not clear
1)
2)
3)
4)
give the lowest effective dose
for the shortest effective time.
treat the underlying disease vigorously
think physiologically
The ART of medicine: practicing with much evidence but few thresholds
10