Critically Appraised Topic

Christopher T. Oswald, MD

October 12, 2001

 

Clinical Question:  In a patient who presents with acetaminophen overdose is N-Acetylcysteine affective in improving outcome, even if given “late” > 10-36 hrs after ingestion.  In patients with acetaminophen overdose does N-acetylcysteine administered “late” increase mortality.

 

Search Strategy:  Various databases were explored, including Cochrane Reviews and DARE reviews as well as MDConsult and Up-to Date.  Search parameters included Acetaminophen (and syn), acetylcysteine (and syn) and acute hepatic failure.  Parameters were combined and limited to human studies, English language and then to randomized controlled trials.  The following articles were obtained via a MEDLINE search with the above listed parameters:

 

1.       Harrison PM, Keays R, Bray G, Alexander G, Williams R. Improved outcome in paracetamol-induced fulminant hepatic failure following late administration of N-acetylcysteine. Lancet 1990; 335:1572-3.

 

 

2.       Keays R et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective

        controlled trial. BMJ 1991; 303: 1026-9.

 

I will first review the earlier article using the Evidence Based Medicine Working Group (EBMWG) criteria for a therapy article, proceed to do the same on the second article, and then finish with a brief review of the first article using the EBMWG criteria for evaluating a prevention or harm article.

 

Harrison PM, Keays R, Bray G, Alexander G, Williams R. Improved outcome in paracetamol-induced fulminant hepatic failure following late administration of N-acetylcysteine. Lancet 1990; 335:1572-3.

 

Are the Results of the Study Valid?

No, the study is a retrospective case series evaluated 100 assumed consecutive cases of paracetamol induced liver failure that were referred to the King’s College Liver Failure Unit between October 1986 and April 1988.

  • Were all patients who entered the trial properly accounted for and attributed at its conclusion?

                 Yes, but again retrospective

  • Were patients, their clinicians, and study personnel 'blind' to treatment?

                 No
  • Were the groups similar at the start of the trial?

 

                Yes, demographic data is given on age, sex, quantity of APAP taken, median time between dose and presentation to hospital.

                 All had AST >1000 umol/l, met Trey and Davidson criteria for Fulminant hepatic failure and “were referred from other hospitals

                on the second or third day after a paracetamol overdose because of early encephalopathy or other features to indicate a poor

                prognosis (a rapidly rising PT, renal failure or early acidosis)”.  No mention of other co-morbidity, liver disease, co-ingestion,

                alcohol, etc. all were relatively young so one could assume other chronic co-morbid conditions did not exist.

 

 

 
  • Aside from the experimental intervention, were the groups treated equally?

               Difficult to tell, co-interventions not elaborated.  Once given N-acetylcysteine “administered by intravenous infusion

               according to a standard regimen”.

 

 

·         Overall, are the results of the study valid?

Due to retrospective non-randomized design of study there is an increased potential for bias.

 

 

What are the Results?

  • How large was the treatment effect?

                Two Groups:

                N-Ac > 10 hrs, (experimental group) n=41 and those that received no N-Ac (control) n=57

 

                For progression to grade III/IV Coma:

                CER 75% (43/57), EER 51% (21/41) ARR 24%+/-19% (5 to 43% 95CI) NNT 4

                For sub-group with one risk factor for increasing PT mortality rate: 

                CER 100% (17/17), EER 69% (11/16) ARR 31%+/-23% (8 to 54% 95CI) NNT 3

                For all mortality:

                CER 58%(33/57), EER 37%(15/41) ARR 21%+/-19% (2 to 40% 95CI) NNT 4

 

                Confidence intervals as above.

 

Will the Results Help Me in Caring for My Patients?

 

·         Can the results be applied to my patient care?

                Although the clinical scenario does not exactly reflect the case presented on Tuesday’s morning report, I do

               feel the patient population examined in the retrospective analysis typifies a large number of the patients

               referred to our institution in fulminant hepatic failure.

                Mortality is of obvious interest, although no long term follow-up of sequelae.  Prolongation

               PT not really reflective of prognosis.

  • Are the likely treatment benefits worth the potential harms and costs?

               No adverse side effects of N-ac were reported.  Given the low cost of the therapy and the low NNT

               (particularly in the context of ICU stay and when compared to the cost of liver transplant) it appears cost

               effective.

 

 

Keays R et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective

controlled trial. BMJ 1991; 303: 1026-9.

 

Are the Results of the Study Valid?

 

                Yes, study was prospective RCT.  Fifty consecutive patients were randomized to N-AC or placebo.

 

  • Were all patients who entered the trial properly accounted for and attributed at its conclusion?

                Yes, all fifty were accounted for in final analysis.  In fact, two patients in the treatment group who went on to OLT were 

                counted as having died.

 
  • Were patients, their clinicians, and study personnel 'blind' to treatment?

                Theoretically, but the authors stated that because of the smell of the therapy nobody was truly blinded to it.

 

 
  • Were the groups similar at the start of the trial?

 

               Table 1 on p 1027 lists the baseline characteristics of the study groups.  Demographic as well laboratory and

              Exam (coma) criteria were also compared.  Criteria for “poor prognosis” were also similar between the two

              groups.

 

 

 

  • Aside from the experimental intervention, were the groups treated equally?

                 Unlike the previous study, other co-interventions were well described.  These included floatation of PA

                 catheter, PCWP measurements, colloid infusion, presence of oliguria and treatment with of dopamine

                 “renal dose”, MAP and administration of epinephrine or norepinephrine, mechanical ventilation with use of

                 paralytics and therapy with mannitol, hyperventilation and thiopentone if clinical signs of ICP were

                 present.

 

·         Overall, are the results of the study valid?

Yes, the study was well designed, prospective with allocation concealment.  Patients were properly

 accounted for and co-interventions were minimal.

 

What are the Results?

  • How large was the treatment effect?

                Two groups:  those that received N-ac (experimental) n=25 and those that did not (control) n=25.

 

                For patients needing inotropic support:

                    CER 80% (20/25), EER 48% (12/25) ARR 32%+-25%(7 to 57% 95CI) NNT 3

                For cerebral edema (clinical):

                    CER 68% (17/25), EER 40% (11/25) ARR 28%+/-27%(1 to 55% 95 CI) NNT 4

                For mortality in subgroup with one criteria for “poor prognosis”:

                    CER 29% (5/17), EER 6% (1/18) ARR 23%+/-26% (-3 to 49% 95 CI) NNT 4

                For all mortality:

                   CER 48% (12/25), EER 24% (5/25) ARR 24%+/-26% (-2 to 50% 95 CI) NNT 4

 

                Confidence intervals as above.

 

Will the Results Help Me in Caring for My Patients?

As discussed in the previous article we can apply these findings to our patients.  Because of the prospective randomized nature of this study we can place even more confidence in the therapeutic effect of N-acetylcystiene in fulminant liver failure.  The first article alludes to the fact that a prospective trial needed to be done to answer the question of whether N-ac actually improved mortality, these findings confirm that it does.

 

Now back to the earlier article with an analysis with respect to causation of harm.  Namely, does late exposure of N-ac increase mortality (harm) in paracetamol-induced fulminant hepatic failure?

 

Harrison PM, Keays R, Bray G, Alexander G, Williams R. Improved outcome in paracetamol-induced fulminant hepatic failure following late administration of N-acetylcysteine. Lancet 1990; 335:1572-3.

 

Are the Results of the Study Valid?

  • Were there clearly identified comparison groups that were similar with respect to important determinants of outcome, other than the one of interest?

                Again, retrospective case control.  Demographics comparable as well as time from ingestion and presentation to 

                hospital.  Other co-morbidities not known.  Three groups:  N-ac <10 n=2, N-ac>10 hr n=41 and no N-ac n=57.

 
  • Were the outcomes and exposures measured in the same way in the groups being compared?

                Endpoint of death most important.  Exposure in terms of Dose the same, time to dose the main variable.

 
  • Was follow-up sufficiently long and complete?

                All 100 accounted for assumed follow-up to death or hospital discharge.

 

 
  • Is the temporal relationship correct?

               All were exposed to N-ac before outcomes were measured.

 

 
  • Is there a dose-response gradient?

                No dose variation, but may be time to first dose vs. response gradient.

 

 

 

                As answered above in previous analysis.

What are the Results?

  • How strong is the association between exposure and outcome?

                Exposed Group (N-ac > 10 hrs) mortality 15/41

                Control (no N-Ac) mortality 33/57

 

               Therefore Odds Ratio OR = 0.42

 

 

Outcome Positive

(Death)

Outcome Negative

 

 

Exposure (N-ac)

A (15)

B (26)

 

 

 No Exposure (no N-AC)

C (33)

D (24)

 

Odds Ratio
  • Case-control studies

OR=

(a/c)/(b/d)=ad/bc

 
  • How precise is the estimate of risk?

                No idea

 

 

Will the Results Help Me in caring for My Patients?

  • Are the results applicable to my practice?

                Yes, as above.

 

 
  • What is the magnitude of the risk?

                 OR as above, <1

 

 

  • Should I attempt to stop the exposure?

                Exposure leads to OR <1 therefore exposure less likely to cause death (harm).  In fact it improves mortality.