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• Response to Dr Kruger
  Tim M Reynolds
  Published on: 18 April 2016
• Statin precipitated lactic acidosis: A very big question mark
  Peter S Kruger
  Published on: 18 April 2016

• Published on: 18 April 2016

  Response to Dr Kruger

  • Tim M Reynolds, Consultant Chemical Pathologist
  • Other Contributors:
    • Neale R, Saweirs W

  Dear Editor

  In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.

  • As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones tha...

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  Dear Editor

  In response to Dr Kruger, we provide extra minor details that had been omitted for reasons of word count.

  • As described, dyspnoea had been present and worsening for 6 weeks. The blood gas results cited were from 5 days after the date of hospital admission but were not significantly different from gases taken on 2 earlier occasions during the admission. The results cited were the ones that lead to consideration of the possibility that the statin was the culprit. We regarded the mixed acid-base disturbance as a metabolic acidosis compensated by respiratory alkalosis.
  • We would agree that there were other unmeasured components in the acidosis but can exclude the suggested salicylate and paracetamol on the basis of the six weeks preceding medical history and the five days known medication intake, by virtue of the in-patient stay. Beta-hydroxy-butyrate assay was not available but we agree this may have contributed. CK on admission was 99 U/L (ref range 0-160 U/L).
  • The patient was receiving nebulised salbutamol 5mg qds. This was continued after discontinuation of the statin, at which time the acidosis resolved. Salbutamol may of course have been a third element contributing to the acidosis.
  • Immediate is a relative term. Symptomatic relief began on the day after the first missed dose. However, Atorvastatin has a long half life and a blood gas taken 6 days after statin cessation was pH 7.44, pCO₂ 3.9kPa, pO₂ 10.8 kPa, HCO₃ 22.3 mmol/L, base excess –3.9 mmol/L; indicating near complete normalisation of results.
  • The blood gas analyser output for the sample indicates that HCO₃(s) was 13.8 mmol/L as correctly stated in the report; tCO₂ however was 5.7 mmol/L, which is consistent with Dr Kruger's estimate.
  • The inspired pO₂ recorded for the blood gas sample reported is 21%. However, this is also the default in the event of a non-entry so we concur that supplemental oxygen was probably in use at the time of sampling.

  Finally, we would like to point out that we did not specifically suggest that we were adding to the body of evidence linking statins to lactic acidosis; we suggested that the combination of statin with thiamine deficiency may be important; i.e. the proximate cause of the acidosis was the thiamine deficiency but the symptomatic presentation was precipitated by the statin. On this point, it is significant that after some months of thiamine therapy (and after publication of the report), the patient was restarted on Atorvastatin because of new ischaemic vascular symptoms with no recurrence of acidosis. We therefore conclude that the combination of the two factors was critical.

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  Conflict of Interest:
  None declared.

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• Published on: 18 April 2016

  Statin precipitated lactic acidosis: A very big question mark

  • Peter S Kruger, Intensive Care Specialist
  • Other Contributors:
    • Bala Venkatesh and Thomas J Morgan

  Dear Editor

  We read with interest the report on postulated atorvastatin induced lactic acidosis [1]. In our view, the arguments outlined by its authors do not support this hypothesis at all, for the reasons outlined below:

  a) The patient clearly had a mixed acid-base disturbance (combined respiratory alkalosis and metabolic acidosis, as evidenced by the normal pH of 7.39 coupled with severe hypocapnia)....

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  Dear Editor

  We read with interest the report on postulated atorvastatin induced lactic acidosis [1]. In our view, the arguments outlined by its authors do not support this hypothesis at all, for the reasons outlined below:

  a) The patient clearly had a mixed acid-base disturbance (combined respiratory alkalosis and metabolic acidosis, as evidenced by the normal pH of 7.39 coupled with severe hypocapnia).

  b) Both the delta anion gap (24.2 –16= 8 mEq/L) and the decrease in standard base excess (which we use in preference to whole blood base excess and calculate to be -17.9 mEq/L) are much larger than the delta lactate, which is only approximately 1.5 mmol/L. This clearly indicates that the metabolic acidosis is multifactorial, and that another pathological process rather than hyperlactaemia is the major contributor to the raised anion gap. This should lead to a search for other causes of a raised anion gap. For example, one would need to measure serum salicylates, the osmolar gap and plasma beta-hydroxybutyrate. With concerns of statin myopathy, a serum CK would be useful. With a history of paracetamol ingestion, pyroglutamic acidosis is a likely possibility and could be diagnosed using a urinary organic acid screen [2].

  c) The authors’ discussion of potential causes of an elevated plasma lactate concentration is incomplete. For example, they have failed to discuss the possible contribution of salbutamol to the hyperlactaemia. Furthermore, covert tissue hypoxia is a possibility despite normal arterial oxygenation, which can lead to hyperlactaemia.

  d) If it were to be a mitochondrial paralysis from statin therapy, it is hard to imagine an immediate clinical improvement upon cessation of the medication.

  Other significant and fundamental errors in the report detract from its validity. They include the following:

  a) The [HCO3-] is said to be 13.8 mmol/L, whereas at the quoted pH (7.39) and PCO2 (1.2 kPa) it would be much lower at 5.3 mmol/L.

  b) The quoted PO2 of 19.3 kPa on room air implies a negative A-a gradient of nearly 1 kPa. This is clearly impossible in any patient, let alone an 82 year old woman. Presumably supplemental oxygen was being administered.

  c) The mention of unmeasured cations instead of anions in the abstract when discussing a raised anion gap is a cause for confusion.

  We recognise that simvastatin has been reported to induce lactic acidosis through mitochondrial failure [3]. However, this report describes a mixed acid-base disorder not primarily due to lactate. Hence, the authors cannot claim that it adds to the body of evidence supporting the link between statin therapy and lactic acidosis.

  References

  (1) Neale R, Reynolds TM, Saweirs W. Statin precipitated lactic acidosis? J Clin Pathol 2004;57(9):989-90.

  (2) Dempsey GA, Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis. Crit Care Med 2000;28(6):1803-7.

  (3) Goli AK, Goli SA, Byrd RP, Jr., Roy TM. Simvastatin-induced lactic acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72(4):461-4.

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  Conflict of Interest:
  None declared.

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