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Three Part Question

In [patients presenting to the ED with an acute porphyric attack] does [IV heme therapy as compared to conservative therapy] result in [better pain control, more rapid resolution of symptoms and biochemical improvement ]?

Clinical Scenario

A 33 year old female presents to the ED with an acute porphyric attack. The medical student shadowing you tells you that he has done a special study module on porphyria and suggests IV heme therapy. You wonder if this would be better than conservative therapy.

Search Strategy

Medline 1966 to 06/06, Embase 1980 to 06/06 and Cinahl 1982-06/06 via the Ovid interface
Medline:[exp hemin/ or hemin.mp. or hematin.mp. or heme arginate.mp. or haem arginate.mp. or exp panhematin/ or panhematin.mp. or normosol.mp.] AND [exp porphyrias/ or porphyrias.mp. or porphyria.mp. or AIP.mp. ] LIMIT humans and english language
Embase and Cinahl:[exp hemin/ or hemin.mp. or hematin.mp. or heme arginate.mp. or haem arginate.mp. or exp panhematin/ or panhematin.mp. or normosol.mp.] AND [exp porphyria/ or porphyrias.mp. or porphyria.mp. or AIP.mp. ] LIMIT humans and english language

Search Outcome

Medline: 129 results- 2 relevant
Embase: 169 results- 0 additional relevant
Cinahl: 2 results-0 relevant
Cochrane:32 results-0 additional relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Herrick AL, MC Coll KE, Moore MR, Cook A, Goldberg A 1989 UK	12 patients with acute intermittent porphyria. 2 days after admission for the attack patients recieved either IV haem arginate 3mg/kg/day for 4 days or placebo. 9 patients were readmitted with a further attack and given the alternative treatment. Exclusion criteria were preganancy and previous reaction to haem. Diagnosis of the acute attack was made on both clinical and biochemical grounds.	Double blinded randomised controlled trial. Level 2+ evidence.	Median total analgestic requirement	8150 mg placebo vs 6425 haem arginate (p=0.1)	Small study group and no sample size estimate therefore possible type 2 error. Patients only recieved heme arginate on day 3 of admission.
			Median pain score	59 placebo vs 52 haem arginate (P=0.25)
			Median hospital stay	11 days placebo vs 8 days haem arginate (P=0.4)
			Lowest median urinary ALA	160umol/24hr placebo vs 18umol/24 hr haem arginate. (p<0.01)
			Lowest median urinary PBG excretion	235 umol/24hr placebo vs 40umol/24hr haem arginate. (p<0.01)
			Side effects	Phlebitis. 2 patients in the placebo group and 5 in haem arginate group.
Dover SB, Moore M, Fitzsimmons, Graham A, McColl KE. 1993 UK	8 patients with acute intermittent porphyria. 34 attacks were studies and the effects of placebo (9 patients) and haem arginate (10 patients) were studied. The effect of tin protoporphyin was also studied. Treatment given on day 3 of admission	Randomised controlled trial. Level 2+	Median urinary PBG excretion on final day of treatment	227 umol/24h placebo vs 54 umol/24 h haem arginate. (P<0.005 Mann Whitney)	No pain scores recorded Small study group Treatment only started on day 3 od admission No sample size estimate Study not double blinded as the patients recognised haem arginate infusion due to its stinging quality.
			Median urinary ALA excretion on final day of treatment.	146 umol/24 h placebo vs 18umol/24h haem arginate (P<0.005 Mann Whitey)
			Time to clinical resolution of symptoms	No difference

Comment(s)

The study by Dover et al again showed a significant decrease in porpyrin precursors with haem arginate vs placebo but no difference in the time to resolution of symptoms. The study by Herrick AL et al showed that haem arginate treatment in comparison to placebo resulted in a statistically significantly fall in the porphyrin prescursors. The decrease in pain score, analgesic requirement and duration of hospital stay was not statistically significant but as no sample size estimate was made and the study group was small this is likely to be due to a type 2 error. More research, in the form of much larger, randomnised control trials needs to be undertaken before the value of haem arginate can be definitively determined.

Clinical Bottom Line

The evidence suggests that haem therapy results in a decrease in pain and more rapid resolution of symptoms when compared to convervative therapy alone. The decrease in urinary porphyrins is strikingly marked. However, as there is only a small amount of evidence further research is needed.

References

1. Herrick AL, MC Coll KE, Moore MR, Cook A, Goldberg A Controlled trial of haem arginate in acute hepatic porphyria Lancet. 1989;1(8650):1295-1297
2. Dover SB, Moore M, Fitzsimmons E, Graham A, McColl KE. Tin Protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria Gastroenterology 1993;105:500-506.