Continuous haemodiafiltration compared with intermittent haemodialysis in the treatment of methanol poisoning
George Kan1,
Ian Jenkins2,
Gopala Rangan1,3,
Andrew Woodroffe1,
Helen Rhodes1 and
David Joyce3
1Renal Department and 2Intensive Care Unit, Fremantle Hospital, Perth and 3School of Medicine and Pharmacology, University of Western Australia and Western Australian Centre for Pathology and Medical Research, Perth, Australia
Correspondence and offprint requests to: Dr George W. Kan, Renal Department, Fremantle Hospital, Alma Street, Perth, WA 6160, Australia. Email: georgekan{at}ausdoctors.net
Keywords: cerebellar hypoxia; cerebral hypoxia; continuous haemodiafiltration; haemodialysis; magnetic resonance imaging; methanol intoxication
 |
Introduction
|
---|
Methanol (MeOH) is a toxic alcohol present in many solvents and antifreeze solutions. Ingested MeOH undergoes enzymatic oxidation to toxic formic acid, resulting in acidosis, neurotoxicity and death in severe poisoning. Treatment relies on antidote administration (fomepizole or ethanol) to antagonize MeOH oxidation, folic acid to facilitate the catabolism of formic acid, correction of acidosis and dialysis to accelerate MeOH elimination [1]. Intermittent haemodialysis (HD) is used conventionally [1]. Continuous veno-venous haemodiafiltration (CVVHDF) has not been formally evaluated against this standard.
Here we compare the relative efficiencies of HD and CVVHDF in accelerating MeOH elimination and correcting metabolic abnormalities in three severely poisoned patients, seen simultaneously in two tertiary referral hospitals. At that time, only CVVHDF was available in the Intensive Care Department of the hospital that treated two patients. The third patient received HD. Toxicokinetics and clinical outcomes of CVVHDF and HD treated patients were compared.
 |
Cases
|
---|
Patients A, B and C were males aged 44, 25 and 43 years old, respectively. The poisonings occurred at sea,
1 day before presentation. The ingested solution was analysed to contain 54% MeOH and no ethanol. Both patients A and C had endotracheal tubes placed for airway protection. Patient A had earlier experienced central chest pain. Patient C had experienced epileptiform seizures. Table 1 summarizes the initial biochemical and clinical data and outcomes. Patients A and C were severely acidotic, obtunded and had Kussmauls respiration. All three patients were haemodynamically stable. Intravenous ethanol infusions (rate 10 g/h after bolus, doubled during dialysis) were commenced and serum ethanol levels were maintained above 100 mg/dl. Folic acid was administered.
View this table:
[in this window]
[in a new window]
|
Table 1. Biochemical and clinical data on presentation; MeOH toxicokinetics predialysis and during dialysis; and clinical outcomes
|
|
Veno-venous blood access was achieved with Vas-cath central venous catheters. CVVHDF was performed for 37 h on patient A using an Asahi APS-650 dialyser (1.3 m2) and the Kimal Hygieia Plus dialysis machine. CVVHDF was performed for 27 h on patient B using a Prisma M60 filter (0.6 m2) and the Prisma CFM dialysis machine. For both patients, the blood flow rates were maintained at 150 ml/min, dialysate flow rate at 16.7 ml/min and replacement fluid (bicarbonate based) flow rate at 33.3 ml/min (predilutional). Patient C initially received 4 h of HD using a Fresenius F8 dialyser (1.8 m2), after which blood MeOH concentration was 40 mg/dl. The blood flow rate on HD was 375 ml/min and the dialysate flow rate was set at 500 ml/min. Dialysis was then continued with 6 h of CVVHDF using a Prisma M100 filter.
Serum and dialysate MeOH concentrations were collected and measured by a gas chromatographic method. The serum half-life of MeOH (t1/2) for each stage in management was estimated by the relationship, t1/2 = 0.693/k(el), where k(el) is the elimination rate constant. The value of k(el) is derived by fitting the serum MeOH concentrations to an exponential decay function of the form C = C0ek(el)t, where C0 is the concentration at the beginning of the phase, C describes subsequent concentrations and t is the time between the first and subsequent measurements [2]. Total body clearances (ClTB) were estimated using the relationship, ClTB = k(el) x Vd, where Vd is the distribution volume for MeOH. Clearances due to CVVHDF (ClCVVHDF) were derived using the relationship, ClCVVHDF = D/AUC, where D (dose) is the measured amount of MeOH in dialysate (concentration x volume) and AUC is the area under the serum concentrationtime curve for MeOH, estimated by integrating the monoexponential function that describes the serum concentrations during CVVHDF for each patient [2]. Dialysate MeOH concentrations were not available for patient C.
Figure 1 displays the measured serum MeOH concentration over time from presentation. The elimination of MeOH closely followed first-order kinetics during CVVHDF. The serum MeOH declined slowly during post-HD CVVHDF in patient C, presumably reflecting redistribution of tissue MeOH into the circulation. We therefore do not have a valid estimate of ClCVVHDF for patient C.

View larger version (12K):
[in this window]
[in a new window]
|
Fig. 1. Serum MeOH concentrations for patients A, B and C over time from presentation (0 h). The time points of commencement (HD or CVVHDF) and cessation (OFF) of dialysis, and commencement of ethanol infusion (arrows) are indicated.
|
|
Table 1 displays the toxicokinetic results. Aggregating the data, the T1/2M were 1930 h predialysis, 1012 h on CVVHDF and 2 h on HD. The MeOH clearances on CVVHDF with patients A and B were 45 (83% of ClTB) and 48 ml/min (96% of ClTB), respectively. For patient A, CVVHDF increased the ClTB 3-fold compared to without dialysis. Comparing the dialysis clearances between patients and dialysis modalities (patient C on HD vs patients A and B on CVVHDF), the ClHD was
5-fold greater than ClCVVHDF. For patient C, HD increased the ClTB 10-fold compared to no dialysis. The duration of dialysis required for the bicarbonate concentration to normalize was 24 h for patients A and B, and within 12 h for patient C.
Patient A died from severe neurological toxicity and the MRI demonstrated extensive subcortical and putaminal necrosis associated with haemorrhages. No clinically detectable neurological deficits occurred with patient B who was treated with CVVHDF. Patient C sustained intellectual deficits resulting in impulsiveness and memory loss associated with decreased visual acuity. The MRI demonstrated severe ischaemic hypoxic injury involving the water-shed distributions of the cerebral and cerebellar arteries and these were most pronounced in the peripheral putamen and external capsules.
 |
Discussion
|
---|
These three patients presented with severe MeOH poisoning, as evidenced by clinical and metabolic abnormalities and by persisting or lethal, neurological damage in two. Toxicokinetic analyses confirm the superiority of HD over CVVHDF in clearing MeOH, reaching target serum MeOH concentrations and correcting metabolic derangement. Similar HD clearances of MeOH have been reported previously [3,4].
MeOH clearance during HD in patient C was 5-fold higher than during CVVHDF in the other two patients. Nonetheless, CVVHDF still increased ClTB 3-fold above the pre-dialysis clearance and, judging from the 3-fold reduction in MeOH t1/2, would have substantially reduced the time to safe serum MeOH concentration and to correction of metabolic derangement. The pre-dialysis estimates themselves probably exceed endogenous clearance during dialysis, because endogenous clearance would have been nearly completely blocked by ethanol during dialysis. This accords with our observation that nearly all the cleared MeOH could be accounted for in dialysate during CVVHDF.
We did not examine the effects of HD or CVVHDF on formic acid toxicokinetics in these patients. Serum formic acid levels and the degree of acidosis on presentation strongly influence outcome in MeOH poisoning [3,57]. Formic acid levels correlate with serum pH [8] and there is a latent period of 1224 h from MeOH ingestion before symptoms of toxicity occur [1]. HD clears formic acid [9,10] but this may not be clinically important because formic acid has a high endogenous clearance. Its half life is
3.4 h [10].
In summary, we conclude that CVVHDF accelerates MeOH elimination usefully, shortens the time to target serum MeOH concentrations and likely shortens the period of metabolic derangement and blockade of neural tissue energy metabolism. However, it is materially slower than HD in reaching important treatment endpoints and is not a substitute for HD. It may have limited application in less severely poisoned cases if HD is unavailable or not feasible, for example, because of haemodynamic instability. It remains important to characterize the efficiency of CVVHDF in removing formic acid.
 |
Acknowledgments
|
---|
The authors wish to thank the Sir Charles Gairdner MRI unit for providing the MRI images, ICU nursing staff at Fremantle Hospital and Sir Charles Gairdner Hospital for providing information on the CVVHDF methodology, and the attending physicians.
Conflict of interest statement. None declared.
 |
References
|
---|
- Barceloux B, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice guidelines for the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002; 40: 415446[CrossRef][ISI][Medline]
- Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edn. Williams and Wilkins, Baltimore, MD, 1995
- Jacobsen D, Jansen H, Wiik-Larsen E, Bredesen JE, Halvorsen S. Studies on methanol poisoning. Acta Med Scand 1982; 212: 510[ISI][Medline]
- Gonda A, Gault H, Churchill D, Holomby D. Hemodialysis for methanol intoxication. Am J Med 1978; 64: 749758[ISI][Medline]
- Osterloh JD, Pond SM, Grady S, Becker CE. Serum formate concentrations in methanol intoxication as a criteria for hemodialysis. Ann Intern Med 1986; 104: 200203[ISI][Medline]
- McMartin K, Ambre J, Telphly T. Methanol poisoning in human subjects. Role of formic acid accumulation in the metabolic acidosis. Am J Med 1980; 414418
- Liu JJ, Daya MR, Carrasquillo O, Kales SN. Prognostic factors in patients with methanol poisoning. J Toxicol Clin Toxicol 1998; 36: 175181[ISI][Medline]
- Brent JB, Mcmartin K, Phillips S, Aaron C, Klug K. Fomepizole for the treatment of methanol toxicity. N Engl J Med 2001; 344: 424429[Abstract/Free Full Text]
- Jacobsen D, Ovredo S, Sejerted OM. Toxicokinetics of formate during hemodialysis. Acta Med Scand 1983; 214: 409412[ISI][Medline]
- Kerns W II, Tomaszewski C, McMartin K, Ford M, Brent J. Formate kinetics in methanol poisoning. J Toxicol 2002; 40: 137143[CrossRef][ISI]
Received for publication: 2.12.02
Accepted in revised form: 6. 7.03