antidepressants represent the sixth leading substance category causing intoxication in the usa , with tricyclic antidepressants ( tcas ) being the most important category in that group . tca intoxications led to 69 fatalities in 2012 . with 6305 exposures in 2012 , amitriptyline was the single most important tca involved in intoxication . similar findings are reported all over the world : amitriptyline is the second most responsible drug for death in antidepressant poisoning in the uk , where antidepressant self - poisoning is used in 20% of all poisoning suicides . tcas were the most common suicide poison used in new zealand between 2001 and 2005 . in tehran , iran , amitriptyline is the most used tca in drug intoxication , where tcas are responsible for 16% of all admissions due to intoxication . in adult out - patients , amitriptyline is normally dosed between 75 and 150 mg / day , which provides therapeutic concentrations between 80 and 250 g / l . in cases of overdose , amitriptyline may cause an alteration of consciousness , hypernatraemia , convulsive seizure , arrhythmia and respiratory depression . first - line treatment focuses on general measures as well as correction of electrolyte disorders and arrhythmia . extracorporeal means of toxin removal consist of charcoal haemoperfusion   and plasma exchange , which decreased amitriptyline blood concentrations in a few cases . due to its high plasma protein binding and volume of distribution ( vod ) , amitriptyline the extracorporeal treatments in poisoning ( extrip ) workgroup therefore recommends not to use extracorporeal removal of tca , as this approach is not likely to offer a clinical benefit . we report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using a high cut - off ( hco ) dialyzer . essential information on both patients as recommended by the extrip workgroup   is summarized in table 1 . table 1.relevant case report characteristics recommended by the extrip workgroup case 1case 2general information  age ( years)5453  weight ( kg)5475  height ( cm)168157  gender  concurrent diseasesbreast cancer , chronic pain syndrome , depressionmgus , depression , chronic pain syndrome  source providing the history of the poisoningparamedicsparamedics  time from ingestion to hospital admission ( h)7.58.5  known co - medicationlorazepampantoprazole , citalopram , mirtazapine  other toxinstilidine , ethanolibuprofen , -blockers , alcohol  activated charcoal givennoyes  icu stay ( days)35  discharge from hospital ( days)320laboratory values  albumin ( g / l)34.842  creatinine at baseline ( mol / l)/egfr ckd - epi36/115.3643/6 ( akin iii )  serum amitriptyline peak concentration ( g / l)458412  serum nortipytilin peak concentrations ( g / l)283259  serum tilidine / nortilidin peak concentrations ( g / l)56/849na  urine excretion ( ml / days)3100anuria  urine amitriptyline concentration ( g / l)623na  haematocrit ( % ) 4036.5ectr characteristics  modality of ectrintermitted haemodialysisintermitted haemodialysis  indication for ectrdetoxificationaki , rhabdomyolysis , detoxification  ectr start after admission ( h)2.51.5  dialyser ( material / surface)hco dialyser ( polysulfone , 1.8 m)high - flux dialyser ( polysulfone , 1.3 m)hco dialyser ( polysulfone , 1.8 m )  dialysis time ( min)295 ( first treatment)220 ( second treatment)320 ( first treatment)775 ( second treatment)/350 ( hco )  blood flow ( ml / min)300 ( first treatment)110 ( second treatment)240 ( high - flux)240 ( high - flux )  dialysate flow ( ml / min)300 ( first treatment)55 ( second treatment)240 ( high - flux)240 ( high - flux )  ultrafiltration rate ( ml / h)5050 ( first treatment)/50 ( second treatment)/200 ( hco )  anticoagulationheparinheparin  amitriptyline reduction ratio ( % ) 2728 ( hco )  ectr amitriptyline clearance ( ml / min)587 ( high - flux)33 ( hco )  total amount of amitriptyline in the collected dialysate ( g)211920 ( high - flux)na ( hco)aki , acute kidney injury ; akin , acute kidney injury network ; ckd - epi , chronic kidney disease epidemiology collaboration ; egfr , estimated glomerular filtration rate ; hplc , high - performance liquid chromatography ; ms / ms , tandem mass spectrometry.amitriptyline and nortriptyline were quantified ( detection limit 5 g / l ) by hplc followed by electrospray ionization and mass spectrometric detection and quantification of selected ion fragments ( triple quadrupole ms / ms , api2000 , pe sciex ) after simple deproteinization with acetonitrile / methanol . g / l ) by hplc - ms ( waters micromass , quattro micro ) after fluid extraction with cyclohexane.additional membrane characteristics are reported elsewhere .calculations of reduction ratios were executed according to equation ( 1):(1)rr=(cpostcpre)/cpre100 
 dialyser clearance was measured according to equation ( 2 ) , using the patients hematocrit concentration ( hct ) at the time of clearance sampling:(2)kplasma = qb(1hct/100)((cartcven)/cart ) 
  relevant case report characteristics recommended by the extrip workgroup   aki , acute kidney injury ; akin , acute kidney injury network ; ckd - epi , chronic kidney disease epidemiology collaboration ; egfr , estimated glomerular filtration rate ; hplc , high - performance liquid chromatography ; ms / ms , tandem mass spectrometry . amitriptyline and nortriptyline were quantified ( detection limit 5 g / l ) by hplc followed by electrospray ionization and mass spectrometric detection and quantification of selected ion fragments ( triple quadrupole ms / ms , api2000 , pe sciex ) after simple deproteinization with acetonitrile / methanol . g / l ) by hplc - ms ( waters micromass , quattro micro ) after fluid extraction with cyclohexane . calculations of reduction ratios were executed according to equation ( 1):(1)rr=(cpostcpre)/cpre100 
  dialyser clearance was measured according to equation ( 2 ) , using the patients hematocrit concentration ( hct ) at the time of clearance sampling:(2)kplasma = qb(1hct/100)((cartcven)/cart ) 
  a 54-year - old caucasian woman , who ingested an unknown amount of amitriptyline and tilidine in a suicide attempt , was admitted to our hospital deeply unconscious with a glasgow coma scale score of 5 . electrocardiography showed a broad qrs complex ( 134 ms ) and prolonged qtc ( 517 ms ) , representing increased risk for ventricular arrhythmias . based on the clinical condition , we started a 5 h dialysis using an hco emic2 dialyser ( polysulfone ; 1.8 m ) with a dialysate and blood flow of 300 ml / min to eliminate tilidine and other potentially ingested drugs . the treatment was well tolerated , and immediately afterwards a dialysis with low dialysate and blood flow was started with the aim of performing an extended dialysis . due to clotting of the extracorporeal circuit , this dialysis prematurely ended after 220 min . plasma concentrations of both substances were drawn at different time points ( figure 1a ) . plasma dialyser clearances for amitriptyline and tilidine were 58 and 67 ml / min , respectively , at the beginning and decreased towards the end of the first dialysis session ( supplementary table s1 ) . for comparison , dialyser clearances for creatinine and urea were 115 and 132 ml / min , respectively . dialyser reduction ratios , dialyser clearance and total loss into the collected spent dialysate are listed in supplementary table s1 . open triangles denote myoglobin values at the upper laboratory detection range . * amitriptyline concentration measured in different laboratories . amitriptyline concentration measured in different laboratories . into the sixth hour of treatment , the patient regained consciousness and was transferred to psychiatric care after 3 days in the intensive care unit ( icu ) . a 53-year - old caucasian female who ingested 1750 mg of amitriptyline and 12 g of ibuprofen in a suicide attempt was admitted to our hospital . serum creatinine was 634 mol / l , sodium 137 mmol / l and creatine kinase 27 308 u / l . amitriptyline serum concentration was 412 g / l . the unconscious patient was transferred to our icu , intubated and mechanically ventilated . gastroscopy revealed unabsorbed pills in the stomach , and activated charcoal was administered after they were removed . haemodialysis was started 2 h after admission due to anuric acute kidney injury caused by rhabdomyolysis . dialysis using an fx60s polysulfone dialyser ( fresenius medical care ; 1.3 m ) was performed with a blood and dialysate flow of 240 ml / min . g / l at the start of the second dialysis treatment , amitriptyline concentrations did not show any remarkable decline in the following hours of treatment ( figure 1b ) . to enhance extracorporeal removal , we employed the hco emic2 dialyser ( fresenius medical care , polysulfone ; 1.8 m ) with a dialysate and blood flow of 240 ml / min , decreasing amitriptyline to 163 g / l . the increased removal was also confirmed by a plasma dialyser clearance of 33 ml / min for amitriptyline and 124 ml / min for myoglobin . myoglobin serum concentrations decreased from > 60 000 g / l ( upper detection limit ) to 11 642 five days after admission , the patient was transferred to the nephrology ward , and renal replacement therapy was stopped after 14 days of intermittent haemodialysis . on renal biopsy , twenty days after initial admission , the patient was transferred to a psychiatric hospital . of note , therapy with proton pump inhibitors , a therapy the patient had been prescribed for years , can cause both rhabdomyolysis and interstitial nephritis . a 54-year - old caucasian woman , who ingested an unknown amount of amitriptyline and tilidine in a suicide attempt , was admitted to our hospital deeply unconscious with a glasgow coma scale score of 5 . electrocardiography showed a broad qrs complex ( 134 ms ) and prolonged qtc ( 517 ms ) , representing increased risk for ventricular arrhythmias . based on the clinical condition , we started a 5 h dialysis using an hco emic2 dialyser ( polysulfone ; 1.8 m ) with a dialysate and blood flow of 300 ml / min to eliminate tilidine and other potentially ingested drugs . the treatment was well tolerated , and immediately afterwards a dialysis with low dialysate and blood flow was started with the aim of performing an extended dialysis . due to clotting of the extracorporeal circuit , this dialysis prematurely ended after 220 min . plasma concentrations of both substances were drawn at different time points ( figure 1a ) . plasma dialyser clearances for amitriptyline and tilidine were 58 and 67 ml / min , respectively , at the beginning and decreased towards the end of the first dialysis session ( supplementary table s1 ) . for comparison , dialyser clearances for creatinine and urea were 115 and 132 ml / min , respectively . dialyser reduction ratios , dialyser clearance and total loss into the collected spent dialysate are listed in supplementary table s1 . open triangles denote myoglobin values at the upper laboratory detection range . * amitriptyline concentration measured in different laboratories . * amitriptyline concentration measured in different laboratories . into the sixth hour of treatment , the patient regained consciousness and was transferred to psychiatric care after 3 days in the intensive care unit ( icu ) . a 53-year - old caucasian female who ingested 1750 mg of amitriptyline and 12 g of ibuprofen in a suicide attempt was admitted to our hospital . serum creatinine was 634 mol / l , sodium 137 mmol / l and creatine kinase 27 308 u / l . amitriptyline serum concentration was 412 gastroscopy revealed unabsorbed pills in the stomach , and activated charcoal was administered after they were removed . haemodialysis was started 2 h after admission due to anuric acute kidney injury caused by rhabdomyolysis . dialysis using an fx60s polysulfone dialyser ( fresenius medical care ; 1.3 m ) was performed with a blood and dialysate flow of 240 ml / min . after a quick decrease of amitriptyline to 205 g / l at the start of the second dialysis treatment , amitriptyline concentrations did not show any remarkable decline in the following hours of treatment ( figure 1b ) . to enhance extracorporeal removal , we employed the hco emic2 dialyser ( fresenius medical care , polysulfone ; 1.8 m ) with a dialysate and blood flow of 240 ml / min , decreasing amitriptyline to 163 g / l . the increased removal was also confirmed by a plasma dialyser clearance of 33 ml / min for amitriptyline and 124 ml / min for myoglobin . five days after admission , the patient was transferred to the nephrology ward , and renal replacement therapy was stopped after 14 days of intermittent haemodialysis . on renal biopsy , twenty days after initial admission , the patient was transferred to a psychiatric hospital . of note , therapy with proton pump inhibitors , a therapy the patient had been prescribed for years , can cause both rhabdomyolysis and interstitial nephritis . very recently , the extirp workgroup recommended not performing any extracorporeal treatments ( ectrs ) for intoxication with tcas . this recommendation is based on the fact that conventional haemodialysis is ineffective due to the high protein binding ( > 90% ) and large vod ( 1417 l / kg ) and the lipophilic properties of tca . however , most of the haemodialysis data the workgroup based the recommendation on are from the 1960s and 1970s . hence , data about the performance of modern membranes in tca intoxication are limited . the potential benefit of modern means of renal replacement therapy was suggested in a report on haemodiafiltration after acute amitriptyline intoxication in which the patient showed an improved vigilance during treatment . as no amitriptyline blood concentrations recently , extended dialysis using an hco dialyser has been introduced to remove large quantities of free light chains in patients with multiple myeloma . these dialysers are characterized by a larger pore size , which allows enhanced middle molecule removal without substantial elimination of albumin . myoglobin , accumulated in rhabdomyolysis as in one of our cases , is also dialysed by highly permeable membranes . so far , there are only anecdotal reports on the use of hco dialysers for the removal of toxins . we could show that even with an increase of the amitriptyline dialyser clearance using hco instead of high - flux dialysis , the estimated total eliminated amount of amitriptyline by hco dialysis remains low ( < 0.1% of the ingested dose ) and therefore may not exceed 3% of the ingested dose per hco dialysis session , which is considered to be the lower threshold for dialysability according to extrip criteria . an additional factor influencing amitryptilin concentrations is concomitantly ingested drugs , especially those that are metabolized mainly via cyp2d6 . although these drugs , especially pantoprazole in our cases , might have an effect on metabolization notwithstanding , the inherent limitation of only two reported patients , is an important shortcoming of this article . in summary , even the elevated amitriptyline clearance by hco membranes in the context of extended dialysis is unlikely to confer a clinical benefit , supporting a recent recommendation of extrip to refrain from any ectr in intoxication with tcas . as a finding unrelated to the topic of extracorporeal toxin removal , we could show that hco extended dialysis is very effective in lowering elevated myoglobin in rhabdomyolysis .
antidepressants , especially amitriptyline , are among the most frequent drug classes involved in intoxications . despite its small molecular weight , 
 amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution . 
 new high cut - off dialysers have so far not been used for removal of amitriptyline . 
 we report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut - off ( hco ) dialysis . despite dialyser clearances of 33 and 58 ml / min , resulting in the reduction of initial serum concentrations by 30% , 
 only 211 and 920 g of amitryptilin , respectively , ( < 3% of the ingested amount ) could be recovered in the total collected dialysate . 
 hence , due to the high volume of distribution of amitriptyline , even hco dialysis does not contribute substantially to the extracorporeal removal of amitryptilin .