Corticosteroids in the Icu

CORTICOSTEROIDS IN THE ICU:D. P. Laporta MD

the whole truth Pulmonary and Critical Care

June 1997 Sir MBD - Jewish General Hospital, McGill University

PROMontreal, Quebec

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 validityRandomized, 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 GRADING of clinical studies3 RECOMMENDATION

Ievidence from  1 RCT, low FP & FN GOOD evidence to support

IIevidence from 1 RCT, high FP  FN MODERATE evidence to support

IIInon-randomized cohort comparisons POOR evidence to support

IVnon-randomized historical cohort comparisons 

Vcase-series (no controls) 

*specific clause if high-quality overview (systematic review)

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SCS IN THE ICU: CLINICAL INDICATIONS

GRADERECOMMENDATIONUSEDONT

Adrenal cortical insufficiencyVPOOR 

Asthma I GOOD 

COPD II-III MOD-POOR 

Sepsis/septic shockI GOOD 

Acute bacterial meningitis II MOD  (adult)

Acute hepatitisviral I GOOD 

ETOHII MOD 

Croup I GOOD 

EpiglottitisIII POOR 

Post-extubation stridor1I-IIGOOD-MOD 

AIDS-PCPI-II GOOD-MOD 

Spinal cord injuryIIMOD 

Head injury I GOOD 

ARDSpre (FES) II MOD 

early I GOOD 

late V POOR 

1in high-risk, PEDS

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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

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- previous SCS1

- septicemia

Waterhouse-Friderichsen

Gm -ive (Pseudomonas)

- shock

- meds:anticoagulants

ketoconazole

dilantin, rifampin, phenobarb

- coagulopathy

- thrombosis

- postoperative

- malnutrition

- chronic adrenal disease

autoimmune (Schmidts syndrome)

TB & other granulomatous

AIDS

metastatic disease

amyloidosis

- hypothal/pituitary disease

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1 In the last year. >25mg/d X 5 days: blunted ACTH response, may last X months

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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

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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...

mg/kg/day hydrocortisone-equivalent EffectConclusion

4niltoo low

10-15(ie 40 mg MP q6h)goodsufficient

250no differentno better

...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

Note the greater than 5-fold variation in dose over usually-suggested dosages !

COPD: The scripture according to Albert

 1978Review (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

(stats, no clinically relevant outcome measures)

* In Emergency Dept (Emerman CL Chest 89) no difference at 5 hours

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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 ABMproblematic 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)

no effect (even PSE). Interaction with gender

NB: ACUTE VIRAL HEPATITIS (FHF): 5 RTCs: contraindicated

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CROUP

commonest cause of acute upper airway obstructionn in children.

 1989 Suggested but unproven

 1 Meta-analysis (Yates Drug Safety 97)

Mild- mod2mg budesonide neb = DEX .6mg/kg IM

Severe1mg/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

 animals: efficacious

 case series: Id

 5 RCTsPEDS: 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 1-580mg/d (Severe PCP 320mg/d)

Day 6-1040mg/d

Day 11-2120mg/dNB: give early, taper slowly ie 1month (flareup)

 Textbooks (Rippe, Civetta): as per NIH consensus

Authors unpublished observations:Less septra rash, butmore long-term

secondary opportunistic infections (CMV, MAI, aspergillus, mucor)

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SPINAL CORD INJURY (SCI)hrs

 preclinical studies: positive

 Narrative reviews (Ducker Spine 94, Nguyen Adv Surg 96)

NASCIS Ilow-dose MP (100mg/d X 11) vs high-dose MP (1000mg/d X 11)NS

 NASCIS II 3 groups: 1) MP 30mg/kg  5 mg/kg/hr X23

2) Narcan

3) Placebo

F/U: 6wks, 6 mo, 1 yr

Result: effective

Critique: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 daysF/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)

Effective

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Early ARDS

2 RCTs (Bernard NEJM 87, Bone Chest 87) 30mg/kg MP q6 X 24hNS

saw natural course of disease

only large enough group: sepsis ...Ineffective

Late (fibroproliferative) ARDS

 Grade V evidence (5 studies, 55 pts)

 Physiological evidence (mediators/outcome) ... positive, ? promising

NOT DISCUSSED:

MYAESTHENIA GRAVISGrade 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- NIH ConsensusJUSTIFIED 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

SEVERE HYPERCALCEMIA - 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) give the lowest effective dose

2)for the shortest effective time.

3) treat the underlying disease vigorously

4) think physiologically

The ART of medicine: practicing with much evidence but few thresholds

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