consequences of ethylene glycol poisoning: report of four cases and review of the literature

Consequences of Ethylene Glycol Poisoning*

Report of Four Cases and Review of the Literature

ELI A . FRIEDMAN, M.D ., JONATHAN B. GREENBERG, M.D ., JOHN P. MERRILL,and GUSTAVE J . DAMMIN, M.D .

Boston, Massachusetts

LTHOUGH several chemical refinements haveprolonged the useful life of commercial

antifreeze solutions, aqueous ethylene glycolremains the active ingredient . The increasingavailability of this compound has been asso-ciated with an augmented incidence of humanintoxication due to ingestion by error andingestion by those seeking an ethanol substitute .A conservative estimate ascribes forty to sixtydeaths annually in the United States as aconsequence of ethylene glycol intoxication,primarily as a result of renal failure [21] . Despitethe lack of immediate efficacious therapy,salvage of patients with severe poisoning can beeffected by employment of a regimen to managethe anuric phase, and appropriate supportivecare for the survivors of the first day followingingestion [18] . An experience in the care ofseveral teenage students exposed to ethyleneglycol prompted this addition to the limitedliterature concerning the clinical course andpathologic correlates of ethylene glycolpoisoning .

During a winter recess party in December1958, sixteen high school students inadvertentlyconsumed small quantities of antifreeze whichhad been placed for storage in a liquor bottleone month earlier. Approximately 20 ounces of"Marvel" brand antifreeze mixed with wateror ginger ale were consumed in amounts varyingfrom a sip to about 4 ounces. Analysis by theState Police Laboratory of the cork and bottlefragments confirmed that the stored liquid,according to boiling point, density and emissionspectra determinations consisted of about 94 percent ethylene glycol .

M.D .

CASE REPORTS

CASE I . This seventeen year old white girl (C . C .,P.B.B.H. 9M996) ingested 3 to 4 ounces of ethyleneglycol in mixed drinks, with no immediate adverseeffects . At 4 A .M., and again at 10 A.M . on the morningfollowing the party, the patient awoke to urinate andwas noted to be rational although her speech seemedunusually loud and giddy . Near normal behavior atnoon yielded to somnolence and deepening confusionby early afternoon . Later that afternoon the patientsuffered several convulsions and lapsed into a semi-comatose state while in transit to a communityhospital . Oxygen, given nasally, and dextrose, givenparenterally, failed to initiate improvement duringthe night and the now constantly convulsing patientwas transferred to another Boston hospital for moreintensive care. Two bouts of vomiting and a nocturnaloutput of 120 ml . of blood-tinged urine had beenrecorded prior to transfer, approximately thirty-sixhours after ingestion of the antifreeze . Because ofprofound acidosis characterized by a blood pH of6.8, and a serum carbon dioxide content of 6 mEq .per L . associated with an elevated serum potassiumof 6.8 mEq. per L ., and precordial T wave peakingon the electrocardiogram consistent with earlypotassium intoxication, she was transferred to theCardio-Renal Service at the Peter Bent BrighamHospital .

Physical examination disclosed a well developed,slightly obese girl who was cyanotic and unresponsiveto painful stimuli. The blood pressure was 60/0 mm .Hg and the pulse 105 . The respirations were 35 perminute and Kussmaul in type . There was no edemaor icterus . Frequent myoclonic jerks of the shouldersand arms contrasted with the absence of spontaneousor responsive movement elsewhere . There was noevidence of trauma to the head, and the neck wassupple. The pupils were dilated and unreactive tolight although corneal reflexes were present bilater-

* From the Departments of Medicine and Pathology of the Harvard Medical School, and the Peter Bent BrighamHospital, Boston, Massachusetts . This work was performed during Dr . Friedman's tenure as an American HeartAssociation Research Fellow . It was supported in part by National Heart Institute Grant HTS-5274 . Manuscriptreceived July 19, 1961 .VOL . 32, JUNE 1962

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892

FIG . 1 . Case I, kidney. The striking finding is the presenceof numerous calcium oxalate crystals in the tubules, twoof which are indicated by arrows . Cells of the convolutedtubules are swollen, and some are disrupted and lacknuclei. Interstitial edema is slight. Hematoxylin andeosin stain .

ally . Marked papilledema without retinal hemorrhagesor exudates was seen bilaterally. The chest was clearto percussion and exhibited coarse diffuse rhonchi .Examination of the heart and abdomen was withinnormal limits . The deep tendon reflexes were hypo-active and no pathologic reflexes were detected .

No urine was obtainable from the bladder bycatheterization. Gastric aspiration was productive of200 cc. of black material containing clotted blood .On lumbar puncture a pressure equivalent to 200mm. of water was noted . The fluid obtained was clearand negative to a Pandy protein test . It contained200 lymphocytes and no bacteria. The hematocritwas 48 per cent, the white blood count 14,000 percu. mm. with 86 per cent polymorphonuclear cellsand 14 per cent lymphocytes . The serum sodium was140 mEq. per L ., potassium 6 .0 mEq, per L ., carbondioxide content (after sodium bicarbonate adminis-tration) 25 mM per L ., and blood pH 6.58 .Hemodialysis was undertaken to correct the

acidosis and to remove any dialyzable metabolitespossibly still present. The constant administration ofvasopressor agents was required to maintain adequatearterial perfusion of the Kolff twin coil artificialkidney. During the second hour of hemodialysis,striking lividity was observed, associated with a met-hemoglobin concentration of 21 per cent. Shortlythereafter, while receiving ascorbic acid and methyleneblue infusions, the patient died, forty-seven hoursfollowing the ingestion of ethylene glycol .The lungs showed interstitial pneumonitis and

pulmonary edema. The kidneys showed dilatation ofthe proximal tubules with marked cloudy swellingof the lining epithelial cells and loss of many of thenuclei. (Fig. 1 .) Most prominent were large, bril-liantly birefringent crystals in the lumens and cyto-

Ethylene Glycol Poisoning-Friedman et al.

FIG. 2 . Case I, kidney. Section containing brilliantbirefringent crystals demonstrable with crossed polaroidfilters.

plasm of the proximal tubules, and, to a lesser degree,in the distal and collecting tubules . (Fig. 2 .) Inter-stitial edema was slight, and there was no inflamma-tory infiltrate . The glomerular tufts were increasedin density, primarily due to a focal thickening of thebasement membrane . The vessels appeared normal .

Moderately severe fatty metamorphosis of centro-lobular hepatic cells was present and scattered smallbirefringent crystals, presumably calcium oxalate,were found in the parenchyma and interstitial tissueof the liver . The cellularity of the sinusoids wasincreased. In the skeletal muscle, the sarcoplasmappeared normal but the number of sarcolemmalcells was excessive. In the adrenal cortex there weresmall foci of hyperplasia and pseudoacinar trans-formation. Interstitial myocarditis, manifested bycellularity and edema of the interstitial tissues, waspresent .

Minute crystals were noted in most other organsincluding the meninges and choroid plexus . Dr. BettyBanker, neuropathologist at the Children's MedicalCenter, Boston, reviewed sections of the brain andnoted a diffuse increase in astrocytes in the cerebralcortex, nuclei of the thalamus and globus pallidusand in the reticular substance and griseum pontis ofthe brain stem as well as focal loss of cerebellarPurkinje cells . (Fig . 3 .) In some areas, there wasperivascular cuffing .

CASE II . This seventeen year old white male highschool athlete (R. K., P.B .B.H. 9M998) was ad-mitted forty-eight hours after the ingestion of about4 ounces of antifreeze, because of confusion, ocularpalsy and anuria . He also had experienced no illeffects for the first few hours after drinking the poison .Upon arising the morning after the party the patientcomplained of fatigue, headache and blurred vision .That afternoon, nausea appeared, with intermittent

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Ethylene Glycol Poisoning-Friedman et al .

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FIG . 3 . Case t, cerebellum . There is focal loss and pyknosis of the Purkinje cells .Hematoxylin and eosin stain .

retching, and marked malaise . His physician, awareof the grave consequences of antifreeze intoxicationin Case i, arranged the patient's transfer to PeterBent Brigham Hospital on the second day followingingestion, after detecting progressive worsening andbilateral ophthalmoplegia .

The patient, a disoriented, wiry boy, lay flat in bedappearing acutely ill . There was no edema, cyanosis,icterus or hemorrhage . The temperature was 99 ° F .,the blood pressure 140/60 mm . Hg, the pulse 72 andthe respirations 20 . There was medial strabismus ofthe left eye and bilateral disc blurring ; no hemor-rhages or exudates were seen through the mioticpupils . There was no nuchal rigidity . The chest wasclear to auscultation and percussion . No abdominalorgans or masses could be palpated but exquisite backand flank tenderness precluded satisfactory examina-tion . Neurologic findings were limited to the stuporand ophthalmoplegia .The hematocrit was 40 per cent, the white blood

cell count 12,480 per cu . mm. with 84 per centneutrophils, 6 per cent band forms, 7 per cent lympho-cytes and 3 per cent monocytes . The platelet countwas 206,000 per cu. nim. The blood urea nitrogenwas 14.7 mg. per cent, serum total protein 6 .6 gm .per cent, albumin 4.3 gm . per cent, globulin 2 .3 gm .per cent, plasma glucose 139 mg . per cent, sodium139 mEq . per L ., potassium 5 .0 mEq. per L., carbondioxide 20 .3 mM per L ., chloride 108 mEq. per L .,alkaline phosphatasc 5 .1 Bodansky units (normal2-5), total bilirubin 0 .44 mg. per cent, serum mag-nesium 2.45 mEq. per L ., lactic acid dehydrogenase130 Wacker units (normal), methemoglobin 4 percent, and stool benzidine reaction for occult bloodnegative. An electrocardiogram was interpreted assatisfying the voltage criteria for left ventricularhypertrophy. X-ray studies of the chest showedchanges consistent with bronchopneumonia, coupledVOL . 32, JUNE 1962

with a prominent heart, particularly in the area ofthe left ventricle . Repeated films of the abdomen,obtained with the patient recumbent, failed to definethe kidney margins and were consistent with perirenaledema. A lumbar puncture performed shortly afteradmission yielded clear fluid under an opening pres-sure equivalent to 140 mm . of water with a proteinconcentration of 98 mg. per cent and 42 lympho-cytes per cu. mm. An electroencephalogram wasnormal .

This patient survived the acute phase of ethyleneglycol poisoning but went on to present the subacutephase problem of renal failure, as described bySmith [12] . Fluids were restricted, and potassiumcontrol with ion exchange resin and sorbitol wasinstituted [48] . The anuria proved unremitting andthe uremia worsened . On the sixth hospital day anopen renal biopsy and decapsulation of the leftkidney was performed by Dr . J . Hartwell Harrison .The biopsy (Fig. 4) showed focal hydropic degenera-tion of the proximal tubules with complete oblitera-tion of many of the lumens . In other areas there wasmarked interstitial edema with scanty inflammatoryinfiltrate and widely dilated tubules, many of whichshowed degenerate epithelium . Numerous birefrin-gent calcium oxalate crystals and some eosinophilicamorphous casts were present in the tubular lumens .Calcium oxalate crystals were noted in the cytoplasmof some of the tubular epithelial cells . Most of theglomeruli were increased in density and cellularity,with thickening of the basement membrane anddeposition of protein in Bowman's space . Hemo-dialysis was accomplished on the tenth hospital day,using the Kolff twin coil artificial kidney . There wasconsiderable clinical improvement and a fall in theblood urea nitrogen from 305 to 198 mg . per cent.Urinary suppression continued to be virtually com-plete, and the difficult problems of hyperkalemia and

894

FIG. 4. Case u, kidney biopsy, day 6 . Numerous calciumoxalate crystals are demonstrable in the tubules throughuse of partially crossed polaroid filters . Some of thetubules contain casts. The glomerulus has increaseddensity and cellularity . Hematoxylin and eosin stain.

lung and wound sepsis necessitated a second dialysison the fifteenth hospital day, this time with the Kolff-Brigham rotating drum dialyzer . There was noclinical change although the blood urea nitrogen waslowered from 465 to 235 mg. per cent . The patientdied quietly on the seventeenth hospital day .

At autopsy, the right and left lungs weighed 910and 775 gm., respectively, and showed severe hemor-rhagic bronchopneumonia with a few partiallyorganized pulmonary emboli in smaller arteries . Theright and left kidneys weighed 310 and 290 gm .,respectively, and were pale and swollen . Micro-scopically, there was severe hydropic degenerationof the proximal tubules with pyknosis or completeloss of most of the nuclei . (Fig . 5 .) Large, brilliantlybirefringent crystals were present in the lumens ofthe proximal tubules and a few of the distal andcollecting tubules . Intracytoplasmic crystals werealso present. Many of the distal tubuli were dilated,with loss or pyknosis of nuclei of the lining epithelialcells . There was slight to moderate interstitial edemawith focal accumulations of neutrophils, plasma cellsand lymphocytes . Eosinophilic granular casts andcellular debris were present in many of the distal andcollecting tubules . The glomeruli were undulyprominent because of increased cellularity andthickening of the basement membrane . Although theepithelial cells appeared swollen, no crystals werenoted in either the autopsy or biopsy specimens .

The degree of tubular damage in autopsy sectionswas far more severe than in the antemortem renalbiopsy, consistent with progression of a toxic tubularnecrosis with hydropic degeneration of the proximaltubules and calcium oxalate crystal deposition .

Centrolobular fatty metamorphosis, with scatteredmicroscopic foci of central parenchymal necrosis, was


FIG. 5. Case n, kidney, autopsy specimen . Hydropicdegeneration of the cells of the tubules is marked .Birefringent crystals, demonstrable with partiallycrossed polaroid filters, are abundant. Interstitial cellsand edema are prominent . Hematoxylin and eosin stain .

present in the pale swollen liver which weighed2,370 gm . (Fig. 6 .) The degree of cardiac involvementwas more severe than in Case I. There was margina-tion of leukocytes and an excessive numbers of cellsin the interstitial tissue . In the skeletal muscle, therewas a profound degree of interstitial and paren-chymatous myositis. (Fig . 7 .) No crystals were foundin the myocardium or skeletal muscle .

The brain weighed 1,445 gm . Microscopic sections,reviewed with Dr . Betty Banker, demonstrated adiffuse increase in protoplasmic astrocytes and inmicroglia in the cerebral cortex and nuclei of thebasal ganglia and thalamus . As in Case I, the moststriking changes were in the cerebellum in whichthere was focal loss of Purkinje cells and increase ofBergmann's astrocytes . (Fig. 8.) Meningeal andparenchymal vessel congestion was present. Smallbirefringent crystals were deposited in the choroidplexus.

CASE In . This sixteen year old white male student(T. B., P.B.B.H. 3N5) drank about 1 ounce of anti-freeze, noting a taste "like cough medicine ." Heremained well until early in the morning followingthe party, then complained of dizziness, poor co-ordination, confusion and dysuria . By mid-day,nausea, abdominal pain and repeated emesis led tohis collapse and admission to a community hospital .Because of scanty urine output, continued abdominalpain and confusion throughout the first hospital day,he was transferred to the Brigham Cardio-RenalService about forty hours after ingestion of ethyleneglycol .On admission, he appeared well developed, well

nourished, alert, cooperative and in no obviousdiscomfort . The temperature was 98 .7°F ., pulse 66,


FIG . 6 . Case ii, liver . There are scattered foci of necrosis .Fatty mctamorphosis is diffuse . Hematoxylin and eosinstain .

respirations 16, and blood pressure 130/75 mm . Hg.Physical examination was within normal limitsexcept for tenderness in upper right quadrant of theabdomen elicited by deep palpation .

Laboratory data included a white blood cell countof 11,900 per cu . mm. with 70 per cent neutrophils,3 per cent band forms, 24 per cent lymphocytes and3 per cent monocytes, hematocrit 43 per cent . Theurine had a specific gravity of 1 .009, protein 2 plus,glucose 0, sediment 2 to 4 erythrocytes and 4 to 8leukocytes. Numerous calcium oxalate crystals andfrequent granular casts were present . The blood ureanitrogen was 53 mg. per cent, the serum sodium was134 mEq . per L., potassium 4 .2 mEq. per L ., carbondioxide 17 .5 mM per L., and chloride 101 mEq . perL. The serum cholesterol was 75 mg . per cent, totalprotein 6 .5 gm. per cent, albumin 4 .3 gm . per cent,plasma glucose 104 mg . per cent and lactic aciddehydrogenasc 90 units (normal) . An electrocardio-gram, an electroencephalogram, chest and abdominalroentgenograms were within normal limits . Duringthe next three days the patient had a mild tempera-ture elevation of 100 .2 °F ., although he looked welland remained asymptomatic . Considerable impair-ment of renal function was indicated by repeatedlyelevated blood urea nitrogen determinations, rangingfrom 67 to 88 mg. per cent, associated with an(endogenous) creatinine clearance of 11 .9 cc. perminute on the sixth hospital day . On the seventhhospital day the patient was still azotemic (bloodurea nitrogen 88 mg . per cent), acidotic (carbondioxide 15 .3 mM per L .) and anemic (hematocrit34 per cent) . Despite these findings, the patient con-tinued to be clinically well, with a twenty-four hoururine output rising from 370 cc . on the first day to2,400 cc. on the seventh day . Liver function testsshowed slight derangement, with serum bilirubin1 .2 mg. per cent, prothrombin time 56 .5 per cent ;VOL . 32, JUNE 1962

Ethylene Glycol Poisoning-Friedman et al . 895

FIG . 7 . Case n, skeletal muscle . The number of sarcolem-mal nuclei is increased, as is the cellularity of the inter-stitial tissue. Hematoxylin and eosin stain .

bromsulfalein retention was only 4 per cent at forty-five minutes . Because of the approaching Christmasholiday, the rising urine volume and the absence ofsymptoms, the patient was allowed to return homeon the seventh hospital day under the care of hisprivate physician . His later convalescence wasuneventful .

CASE iv. This seventeen year old white malestudent (G . T., P.B .B.H. 3N6) ingested about 2ounces of ethylene glycol and showed no ill effectuntil the following mid-morning when he wasobserved to be disoriented, unable to ambulate andincontinent of urine. He was admitted to a localhospital where the principal findings were limitedto the signs of central nervous system intoxication .

FIG . 8 . Case n, cerebellum. There is a marked reductionin the number of Purkinje cells . Hematoxylin and eosinstain .

896


Within twenty-four hours he became well oriented COMMENTSand alert with no abnormal physical signs . His urineoutput during the first hospital day was only 7 ounces,and he was transferred to the Brigham Cardio-RenalService .

The vital signs and physical examination werenormal with the exception of a slightly hazy sen-sorium. The urine had a specific gravity of 1 .005,protein 1 plus, sugar 0, sediment 0 to 2 erythrocytes,5 to 20 leukocytes. Numerous calcium oxalate crystalswere seen in the sediment. The hematocrit was 40per cent, the white blood cell count 13,550 per cu .mm., with a normal differential, the blood ureanitrogen was 80 mg . per cent, the serum total protein6.7 gm. per cent, albumin 5 .3 gm. per cent, plasmasugar 102 mg. per cent, serum sodium 123 mEq .per L., potassium 4 .6 mEq. per L., carbon dioxide17.9 mM per L ., chloride 92 mEq. per L., alkalinephosphatase 3.7 Bodansky units, bilirubin 1 .05 mg .per cent, lactic acid dehydrogenase 116 units (nor-mal), calcium 4.7 mEq. per L . and phosphorus 2 .0mM per L. Initial chest and abdominal x-ray studieswere non-contributory save for the suggestion ofslight renal enlargement . An electrocardiogramshowed precordial peaking of the T wave consistentwith early potassium intoxication. An electro-encephalogram was considered abnormal because ofexcessive diffuse slow wave activity of moderatelyincreased amplitude without focal or lateralizingsigns .

The urine volume continued at a high level, andreplacement of electrolytes was determined by urineconcentration. His blood urea nitrogen rose to 116mg. per cent on the third hospital day, then graduallyfell to 44 mg. per cent by the eighth day . At this timea percutaneous renal biopsy specimen was obtained .Histologic examination disclosed a small core of renaltissue with normal architecture, slight interstitialedema and scanty focal interstitial infiltrate consistingmainly of neutrophils. Numerous large, brilliantlybirefringent crystals with the characteristic sheaf-shape of calcium oxalate were present within thetubules . The tubules were dilated but no degenerationof the lining epithelium was evident, although nucleardebris was seen in some of the tubular lumens . Theglomeruli showed only moderate prominence of theepithelial cells, thus differing from the picture seenin the other cases .

On the ninth hospital day, Christmas Eve, thepatient was allowed to return home . At this time hissensorium was clear, and abnormal findings werelimited to his improving although still impaired renalfunction. The blood urea nitrogen was 44 mg. percent, and the endogenous creatinine clearance was68 cc. per minute . On restudy ten days later, theblood urea nitrogen was 5 mg. per cent, the endoge-nous creatinine clearance was 119 cc . per minute, andthe phenosulphonephthalein excretion was 35 per centin fifteen minutes and 70 per cent in 120 minutes.

H Hi

Ethylene glycol H-C-C-H,I

I

•

O•

H

•

H H H14

I

I

its dimer, diethylene glycol H-C-C-O-C-C-HI

I

I

I

•

O O O•

H H H

•

H HI

I

I

and propylene glycol (glycerin) H-C-C-C-HI

I

I

•

O O•

H H

are aliphatic straight chained saturated poly al-cohols used industrially as solvents and freezingpoint depressants. Unlike the three-carbon pro-pylene glycol, which may be metabolized to py-ruvate, the two-carbon ethylene glycol and thefour-carbon diethylene glycol have proved con-sistently toxic to both animals and man, withsome two hundred fatalities reported [1-25] .

Ethylene glycol was synthesized about onehundred years ago and was at first considered oflittle commercial value until the World War ishortage of glycerin led to a widespread searchfor a practical non-toxic substitute . Its mostfamiliar use as radiator antifreeze is due to itshigh boiling point (197 .5°c .) . It is this highboiling point and low vapor pressure thateliminates the danger of poisoning by inhalation .Direct skin contact has not resulted in sufficientabsorption to induce intoxication, althoughsevere conjunctivitis and chemosis has beenreported after eye contamination [40] .

To promote their contention that ethyleneglycol was non-toxic, Bachem [28] in 1917 andPage [30] in 1927 courageously drank, respec-tively, 45 and 15 cc . of this compound, withoutill effect. Based primarily on their misleadingexperiments, Hanzlik et al . [31] wrote in 1931that ethylene glycol was "comparatively in-nocuous as a solvent for medicinals" eventhough their own data had established anintravenous minimal fatal dose for white ratsof 2.2 gm. per kg. In the same year Hunt [32]extrapolated from animal experiments that thehuman lethal dose would be approximately 100cc., an estimate which was borne out by subse-quent reports of human fatalities [15,16,19,21] .


The specific predilection for nephrotoxicitywas described by Brekke [1] in 1930 in hisreport of two patients who recovered fromethylene glycol-induced uremia treated byunilateral renal decapsulation. The first Ameri-can cognizance of the potential hazard ofethylene glycol ingestion appeared in the"Queries and Minor Notes" section of theJournal of the American Medical Association with areport of the death of two young men twelvehours after drinking "Prestone" antifreeze,which is almost pure ethylene glycol . Thesepatients exhibited rapid respiration, cold skin,stupor, cyanosis and prostration .

It was the 1937 "Massengill Disaster" whichforced recognition of the toxicity of the glycols .Precise and rapid detective work by Geiling andCannon [23] established that the cause of deathin at least seventy-six persons treated with"Elixir of Sulfanilamide-Massengill" was theunlabeled solvent, 72 per cent diethylene glycol,and not, as originally suspected, the then newdrug, sulfanilamide . They delineated the clinicalpicture of diethylene glycol intoxication as oneof heartburn, nausea and abdominal crampsimmediately after ingestion, followed by pro-teinuria, oliguria and anuria . Important nec-ropsy findings were hydropic degeneration ofrenal tubular epithelium with some instancesof symmetrical cortical necrosis and centralhydropic hepatic degeneration . The "Massen-gill Disaster," in addition to illuminating thetoxicology of diethylene glycol, was a majorcontributing factor to modification of thisnation's legislation regarding the labeling andanimal testing of new drugs .

Popular knowledge of the danger of anti-freeze ingestion still is wanting . Thus, duringand after World War ii, reports of deaths amongmilitary personnel and prisoners of war werefrequent [3-10] but probably represent only asmall proportion of those afflicted with poisoningsubsequent to the ingestion of antifreeze as analcohol substitute . The largest series, reportedby Pons and Custer [6], lists eighteen deathsin soldiers who drank antifreeze . All but onedied twenty-two to forty-four hours afteringestion. Sequential neurologic deficits, con-vulsions, hyporeflexia and coma were associatedwith a trace to 4 plus albuminuria and calciumoxalaturia . At autopsy, the kidneys all con-tained calcium oxalate crystals, but only theone patient who survived five days had definitedegeneration of tubular epithelium and markedVOL. 32, JUNE 1962


897

fatty infiltration of the liver. Early acuteencephalitis was found in four cases, three withassociated meningitis .

Hagemann and Chiffelle [10] in 1948 reportedthree cases of acute ethylene glycol poisoningand summarized the clinical events as coma,acidosis, hypertension, convulsions, leukocytosis,albuminuria, microhematuria, azotemia andincreased protein in the cerebrospinal fluid .Reports in the last ten years [11-22] have largelysubstantiated the clinical and pathologic find-ings of earlier investigators . Particularly note-worthy are the detailed autopsy findings ofSmith [12], and the toxicologic-pathologicstudies of Hjelt et al . [19] . Wordley [24] andOliver [25] added three more fatal cases ofdi-ethylene glycol intoxication .

Berman, Schreiner and Feys [18] substan-tiated the efficacy of hemodialysis in the therapyof acute tubular necrosis due to ethylene glycolpoisoning, and first employed percutaneousneedle biopsy of the kidney to establish thediagnosis via the detection of calcium oxalatecrystal deposition. They divided the clinicalcourse of ethylene glycol poisoning into threestages, which with modification correspond tothe course in our cases .

The first stage is that of central nervoussystem involvement with symptoms manifestthirty minutes to twelve hours after ingestion .Smaller doses produce a picture of pseudo-ethanol intoxication while larger amounts areassociated with rapid development of stupor,coma, convulsions and death (Case i) . Nausea,hematemesis and vomiting may occur . Theurine usually contains albumin and oxalatecrystals, the specific gravity is low . If deathsupervenes during the first twenty-four hours,the principal microscopic findings at autopsyare calcium oxalate crystals in the kidneys,without destruction of tubular epithelium .There is cerebral edema, congestion, focalhemorrhages and chromatolysis of Betz andPurkinje cells .

An indistinct second stage is that of cardio-pulmonary symptoms with rapidly progressivetachypnea, cyanosis, pulmonary edema anddeath between the first and third day . Autopsyfindings include pulmonary edema, broncho-pneumonia, cardiac dilatation and rarely cal-cium oxalate crystals in the kidneys . In none ofour four patients was this stage seen .

Should the patient survive the first two stages,the renal phase predominates, with flank pain,

898


costovertebral angle tenderness and renal im-pairment ranging from proteinuria to anuria .Since even long-term anuria may remit [18],careful fluid restriction and hemodialysis [48],when available, should be employed whileawaiting return of renal function . Case ivpresented little problem but in Case ii thepatient showed progression of renal damageduring a period of careful control . Perhapsearlier and more frequent use of the artificialkidney would have altered the outcome in Caseii, although the autopsy sections showed adegree of damage which offered little evidenceof reversibility had the patient survived for alonger period .

PATHOPHYSIOLOGY

Ethylene glycol toxicity is intimately relatedto its metabolism . Pohl [26] in 1896 first showedoxalic acid to be the metabolic end product ofethylene glycol . Almost pathognomonic ofethylene glycol or oxalic acid poisoning are the

renal pallor and swelling to increase in epithelialbulk and interstitial edema, with resultingcompression of renal vessels causing a decreasedfiltration rate .

Levy [22] speculates that "oxalate is secretedby proximal convoluted tubular cells andchelates intracellular essential divalent metals,calcium or magnesium, leading to necrosis ofthe cell ." This is the rationale for therapy aimedat neutralizing or metabolizing oxalic acid byeither excess calcium administration or mobiliza-tion of endogenous calcium with parathyroidextract [18,22] . The actual amount of ethyleneglycol converted to oxalic acid is only 3 to 10per cent [18,36,37,44] . Lehmann and Flury [37]concluded that ethylene glycol is more toxicthan propylene glycol because the latter isoxidized to pyruvic or lactic acid, normalmetabolites, while the former is oxidized to theforeign substance, oxalic acid . According torecent work by Voigt [43], the intermediarysteps in the oxidation of ethylene glycol are :

H O

O O11

11

11

H-C-C-OH

H-C-C-OH

•

H 0H

H-C-C-H

Glycolic acid>Glyoxylic acid

•

O•

HEthylene glycol

11

11

11

11

HC-C-H~

HO-C-C-OH>Oxalic acidGlyoxal

large birefringent calcium oxalate crystals inthe renal tubules, first described by Mayer [27]in rabbits given 13 to 15 gm . of ethylene glycol .In a remarkable paper published in 1924, Dunn,Haworth and Jones [29] anticipated the classicstudies of Oliver and co-workers on acutetubular necrosis . These early workers observedspecific necrosis of the epithelial cells lining theproximal convoluted tubules, with incompleterepair at forty-eight hours, in rabbits givensoluble intravenous oxalates . It was theirhypothesis that the deposition of calciumoxalate crystals played no important role inproducing the lesion and they attributed the

Central nervous system symptoms are not aprominent feature of acute oxalate poisoning[38], and the acidosis seen in ethylene glycolpoisoning, which does not occur in di-ethyleneglycol intoxication [23], may be due to acidicintermediates . Sollman [36], in studies whichfound ethylene glycol twice as toxic as propyleneglycol and half as toxic as diethylene glycol,was not convinced that oxidation to oxalic acidcould fully explain the toxicity of ethyleneglycol. On a molal basis, presuming 10 per centconversion of ethylene glycol to oxalic acid,insufficient acid is produced to account for theprofound acidosis seen in Case I .


VOL . 32, JUNE 1962

PATHOLOGY

The pathologic changes seen in ethyleneglycol intoxication are so striking as to be almostpathognomonic. Oxalic acid will produce thelarge, brilliantly birefringent calcium oxalatecrystals in the renal tubules noted in Cases t, iiand iv. These crystals are light yellow andarranged as sheaves, rhomboids or prisms ; theyare much larger than those found in othertissues, presumably as a result of tubular con-centration of oxalic acid . The importance of thisspecific histologic picture as an aid to diagnosisof unexplained acidotic coma, particularly in aknown alcoholic, is illustrated in Berman'scases [18] and in our Cases ii and iv, in whichthe diagnosis was confirmed and the degree ofrenal damage accurately assessed by percu-taneous renal biopsy . At autopsy, the crystalsare easily demonstrable, especially with the aidof polarizing filters. They can be identified ascalcium oxalate by histochemical [43] andmicroincineration technics [42] . Should thepatient die within the first forty-eight hours,little more than calcium oxalate crystals maybe detected in the kidneys on routine section,which explains Allen's statement [39] that "theepithelium of the proximal tubules may besomewhat flattened but shows no significantdegenerative or regenerative changes ."Later studies by Oliver and co-workers

[25,41], in diverse types of renal poisoningincluding two cases of fatal di-ethylene glycolintoxication, have proved that two types oftubular injury are present : a nephrotoxicnecrosis limited to that part of the nephronwhich is functionally involved in handling thepoison-the proximal tubule; and disruptionof the renal tubule (tubulorrhexis) which occursat random with reference to both the nephronpopulation and the individual nephron, and isdue to focal cortical ischemia . The microscopicfindings in our cases are in complete accordwith Oliver's concept of nephrotoxic andischemuric injury gained with the aid of micro-dissection studies . Little mention has been madein other reports of alteration in the glomeruli .Proteinuria occurs at an early stage when themajor finding in the kidney may be only thecrystalline deposits . These may be present inthe glomeruli, but most are noted in the tubularcomponent of the nephron . The increasedcellularity of the glomerular tuft, the prominenceof the epithelial cells, the thickening of the base-

Ethylene Glycol Poisoning -Friedman et al .

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ment membrane and the granular deposits inthe Bowman's space are acceptable correlatesof proteinuria. It should be mentioned that thebasement membrane seen with light microscopymakes up most of the glomerular capillary wall .Although different from that identified by elec-tron microscopy, its thickening correlates wellwith the presence of proteinuria .

Central hydropic degeneration or fatty meta-morphosis of the liver with focal necrosisis a common finding in ethylene glycol poison-ing but is more marked in diethylene glycolpoisoning [23-25,39] . These ancillary liverfindings do not appear to be of great clinicalsignificance in view of the predominance ofcentral nervous system, cardiopulmonary andrenal symptomatology.

Microscopic findings in the brain in our twofatal cases and in others [6,10,12,16,19] aremeager when contrasted with the severe centralnervous system derangement and the frequentgross finding of cerebral edema. Except for thesmall calcium oxalate crystals noted in themeninges and choroid plexus, the anatomicalterations, although profound, are not specificand may be observed in such metabolic dis-turbances as anoxia, uremia and hypoglycemia .These alterations include petechiae, focal chro-matolysis of Betz and Purkinje cells and satel-litosis of neurons . The mild meningoencephalitisreported by some workers [3,6,10,16,19] isprobably due to a direct irritant action ofethylene glycol or its metabolite, oxalic acid .

Some of the clinical manifestations of cardiacand pulmonary involvement may be explicableon the basis of a direct effect of the chemical,since these changes are usually seen early,namely, between the first and third days .Cardiac enlargement and pulmonary edemadevelop rapidly in persons previously well, andthe myocarditis noted in our cases, and de-scribed in some of the other reports, may be themost significant lesion at this stage of thepatient's course .

In both cases in which skeletal muscle couldbe obtained for study (Cases i and n) there wasevidence of a possible direct effect of ethyleneglycol or possibly its intermediate and/or endproducts . Since evidence of parenchymatousand interstitial myositis was present as early asforty-seven hours after ingestion (Case i), andonly a small percentage of the ethylene glycolis converted to oxalic acid, such a postulationappears valid. In the cases of acute poisoning

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described by Smith [12], there was an inter-stitial inflammatory reaction in the diaphragm .Few other reports mention skeletal musclelesions, although it is suggested by some of theearly clinical manifestations that they may beexplicable on the basis of a myositis .

THERAPY

Early identification of the toxin in containerresidue or gastric contents by chemical reactions,boiling point determination, ultra red spectros-copy and paper chromatography [19,46], coupledwith the presence of calcium oxalate crystals inthe urine sediment and quantitative determina-tion of oxalates in the urine, strongly indicatethe diagnosis. Emergency therapy is largelysymptomatic and consists of prompt inductionof emesis followed by lavage with 1 :5,000potassium permanganate . The profound earlyacidosis may respond to parenteral bicarbonateor molar lactate infusions . The newer organicbuffers, such as trihydroxy amino methane,which are of value in other causes of metabolicacidosis deserve judicious trial . Should thesemeasures fail, either peritoneal dialysis orhemodialysis by the artificial kidney offersfurther hope of salvage .

An unconfirmed report by De Lucia [30b] in1929 is of great interest . He administered smallamounts of insulin to dogs given parenteralinjections of oxalic acid and reduced the urinerecovery rate of oxalic acid from a control valueof 15 to 3 per cent. If his thesis that in vivooxalate metabolism may be hastened by insulinproves correct, it would be rational to includethis hormone in the therapeutic regimen .

Late stage survival presents the managementproblems inherent in acute reversible renalfailure [48] . Because of increasing reports ofrecovery following prolonged anuria, repeateddialysis and meticulous attention to fluidrestriction are indicated .

Perhaps the most important point falls in theprovince of preventive medicine . Measuresrequiring prominent "poison" labeling of allcommercial antifreeze and other glycol-con-taining solutions, and education of the medicalprofession and public as to the hazards of thisall too easily available poison are clearly inorder. The practice of frugal motorists whodrain and save antifreeze in miscellaneoussecondary containers must be discouraged .Such non-original containers are commonly leftin cellars and garages where they represent a

constant danger to small children, intrepidteen-agers and impecunious alcoholics .

SUMMARY

Four cases are described which illustrate themajor clinical and pathologic manifestations ofethylene glycol poisoning. The high toxicity ofethylene glycol for even the healthy young adultis illustrated by these cases .

The findings on microscopic examination ofthe kidney, when viewed in relationship to theclinical observations, are pathognomonic . Alter-ations in the glomerular tuft, not cited hereto-fore, may be the basis for the findings in theurine in the initial phase of the clinical pictureof ethylene glycol poisoning . In addition, myo-cardial lesions, observed in these cases, mayexplain the prominence of cardiopulmonarysymptoms noted also during an early phase .Tenderness of the muscles may occur on thebasis of a myositis, as noted in the two fatalcases described . The symptoms related to thecentral nervous system, which are invariablythe first to appear, have anatomic correlateswhich are specific only in that calcium oxalatecrystals are demonstrable in the tissue .The toxicity of ethylene glycol is probably

related to the intermediary metabolites as wellas to the end product, oxalic acid . Early therapyconsists of correction of the acidosis ; later treat-ment is concerned with the careful managementof renal failure .

The importance of proper labeling of anti-freeze containers, and of education of the publicto the potential hazard of ethylene glycol inges-tion, is stressed .

Acknowledgment : Acknowledgment is made ofthe assistance given by the Office of the MedicalExaminer, Dr . Michael Luongo, Director of theSouth District, Suffolk County . Also to M. Glass,Suffolk County Medical Examiner's Officethrough whose courtesy Figures 1, 2, 3, 5 and 8are published .

REFERENCES

Reported Cases of Ethylene Glycol Intoxication(Chronologically Arranged)

1 . BREKKE, A. Two cases of poisoning by ethyleneglycol : acute uremia cured by unilateral decapsu-lation of kidney . Norsk. mag . laegevidensk., 91 : 381,1930 .

2. Possible death from drinking ethylene glycol(Prestone), queries and minor notes . J. A. M. A.,94 : 1940, 1930 .


3 . BOEMKE, F. Beitrag zur Toxikologie and Pathologicdes Aethylenglykols (Glysantin) . Arch . path . Anat .,310 : 106, 1943 .

4. DOERR, W. Ueber Frostschutzmittelvergiftung.Arch. path. Anat ., 313 : 137, 1944 .

5. WIDMER, C . A few cases of ethylene glycol intoxica-tion . Acta med. scandinav ., 126 : 295, 1944 .

6 . PONS, C. A. and CUSTER, R . P. Acute ethylene glycolpoisoning : a clinico-pathologic report of eighteenfatal cases . Am. J. M. Sc ., 211 : 544, 1946 .

7 . MILLES, G . Ethylene glycol poisoning; with sug-gestions for its treatment as oxalate poisoning .Arch . path ., 41 : 631, 1946 .

8. WIDMAN, C. Nagra Fall av etylenglykol-forgiftning .Nord. med ., 31 : 1921, 1946 .

9. MCDONALD, S. F. Poisoning from drinking glycolethylene . M. J. Austral ., 1 : 204, 1947 .

10. HAGEMANN, P. O. and CHIFFELLE, T. R. Ethyleneglycol poisoning, a clinical and pathologic studyof three cases . J. Lab. & Clin. Med., 33 : 573, 1948 .

11 . KAHN, H. S. and BROTCHNER, R. J . A recoveryfrom ethylene glycol (antifreeze) intoxication :case of survival and two fatalities from ethyleneglycol, including autopsy findings . Ann . Int. Med.,32 : 284, 1950 .

12. (a) SMITH, D. E. Morphologic lesions due to acuteand subacute poisoning with antifreeze (ethyleneglycol) . Arch . Path ., 51 : 423, 1951 .

(b) GRANT, A . P. Acute ethylene glycol poisoningtreated with calcium salts. Lancet, 2 : 1252, 1952 .

13. WELLS, A. H. and COLL, J . J. Clinicopathologicconference. Am. J. Clin . Path., 23 : 263, 1953.

14. NADEAU, G., COTE, R. and DELANEY, F. J. Twocases of ethylene glycol poisoning . Canad. M . A . J .,70 : 69, 1954 .

15. MORINI, I . Su alcuni casi di avvelenamento daglicol etilenico commerciale. Minerva med., 45 : 72,1954 .

16 . Ross, I . P. Ethylene glycol poisoning with meningo-encephalitis and anuria . Brit. M . J., 1 : 1340,1956 .

17. BENESTAD, A . M . Etylenglykolforgiftning medhypokalcemi . Nord. med., 57 : 255, 1957.

18. BERMAN, L. B., SCHREINER, G. E. and FEYS, J. Thenephrotoxic lesion of ethylene glycol . Ann. Int.Med., 46 : 611, 1957 .

19. HJELT, E ., TAMMINEN, V., FORTELIUS, P., RAEKALLIO,J. and ALHA, A. Zwei todliche Aethylenglykol-vergiftungen ; chemische and pathologische Unter-suchung . Deutsche Ztschr. ges . gerichtl. Med., 46 :730, 1958 .

20. SIMON, W . H. and PFUNDT, T . R. Ethylene glycolantifreeze poisoning. J. Oklahoma M. A., 51 : 57,1958 .

21 . HAGGERTY, R . J . Toxic hazards : deaths from perma-nent antifreeze ingestion . New England J. Med.,261 : 1296, 1959.

22. LEVY, R . I. Renal failure secondary to ethylene

VOL . 32, JUNE 1962

Ethylene Glycol Poisoning--Friedman et al .

90124. WORDLEY, E. Diethylene glycol poisoning : report

on two cases . J. Clin. Path., 1 : 44, 1947 .25. OLIVER, J., MACDOWELL, M. and TRACY, A. The

pathogenesis of acute renal failure associated withtraumatic and toxic injury. Renal ischemia,nephrotoxic damage and the ischemuric episode .J. Clin. Invest ., 30: 1307, 1951 .

Reports on Pharmacology, Toxicology and Pathology of

Glycol Poisoning (Chronologically Arranged)

26. POHL, J . Ueber den oxydativen Abbau der Fett-ktirper im thierischen Organismus. Arch. exper.Path. u. Pharmacol ., 37 : 413, 1896 .

27. MAYER, P. Experimentelle Beitrage zur Frage desintermediaren Stoffwechsels des Kohlhydrate . I.Uber Aethylenglykol and Glykolaldehyd . Ztschr.physiol. Chemie, 38 : 135, 1903 .

28. BACHEM, C. Pharmakologische Untersuchungenfiber Glykol and seine Verwendung in derPharmazie and Medizin . Med. klin., 1 : 7, 1917 .

29. DUNN, J. S., HAWORTH, A. and JONES, N . A. Thepathology of oxalate nephritis . J. Path. & Bact .,27 : 299, 1924 .

30. (a) PAGE, I . H. Ethylene glycol : pharmacologicalstudy . J. Pharmacol. & Exper . Therap ., 30 : 313,1927 .

(b) DE LUCIA, P. Richerche sul metabolismodell'acido ossalico. v. Influenza della insulinasulla ossidazione dell'acido ossalico iniettatonell'organismo. Boll . Soc. ital . biol. sper ., 4 : 756,1929 .

31. HANZLIK, P . J., SEIDENFELD, M. A. and JOHNSON,C. C . General properties, irritant and toxic actionsof ethylene glycol . J. Pharmacol., 41 : 387, 1931 .

32. HUNT, R . Toxicity of ethylene and propylene glycol .Indust. & Eng. Chem., 24 : 361, 1932 .

33. KESTEN, H. D., MULINOS, M. D. and POMERANTZ, L .Pathologic effects of certain glycols and relatedcompounds. Arch . Path., 27 : 447, 1939 .

34. LAUG, E. P., CALVERY, H. 0., MORRIS, H . J. andWOODWARD, G . Toxicology of some glycols andderivatives . J. Indust. Hyg. & Toxicol., 21 : 173,1939 .

35. SMYTH, H . F ., JR ., SEATON, J. and FISCHER, L. Thesingle dose toxicity of some glycols and derivatives ..1. Indust . Hyg . & Toxicol., 23 : 259, 1941 .

36. SOLLMANN, T. A Manual of Pharmacology, 6th ed .,p . 941 . Philadelphia, 1942 . W. B. Saunders Co.

37. LEHMAN, K. B. and FLURY, F. Toxicology andHygiene of Industrial Solvents, p. 254 . Baltimore,1943 . Williams & Wilkins Co .

38. JEGHERS, H . and MURPHY, R. Practical aspects ofoxalate metabolism. New England J. Med., 233 :208 ; 238, 1945 .

39. ALLEN, A. C. The Kidney : Medical and SurgicalDiseases, p. 226. New York, 1951. Grune &Stratton .

SYKOwsKI, P. Ethylene glycol toxicity . Am . J.Ophth., 34 : 1599, 1951 .

OLIVER, J. Correlations of structure and function andmechanisms of recovery in acute tubular necrosis .Am. J. Med., 15 : 535, 1953 .

JOHNSON, F. B. A method for demonstrating calciumoxalate in tissue sections . J. Histochem . & Cytochem .,4 : 404, 1956 .

glycol intoxication . J. A. M. A ., 173 : 1210, 1960 .40 .

Cases of DI-Ethylene Glycol Poisoning41 .

(Chronologically Arranged)

23. GEILING, E . M. K. and CANNON, R. R . Pathologiceffects of elixir sulfanilamide (diethylene glycol) 42 .poisoning; clinical and experimental correlation :final report . J. A. M. A., 111 : 919, 1938 .

90243 . VOIGT, G . C. Der histochemische Nachweis des

Calciums im Calciumoxalat bei der Aethylen-glykolvergiftung. Acta p ath . e t microbiol. scandinav.,41 : 89, 1957 .

44. GESSNER, P . K., PARKE, D. V. and WILLIAMS, R. T.Studies in detoxication . The metabolism of theglycols . Biochem. J., 74 : 1, 1960 .

Therapy

45. BORNMANN, G. Grundwirkungen der Glykole andihre Bedeutung fur die Toxizitat . In. Die Be-


deutung der Grundwirkungen fur die spezifischeToxizitat einzelner Glykole . Arzneimitt . Forsch.,5 : 38, 1955 .

46. KAYE, S. Poisoning due to anti-freeze . Virginia M.Monthly, 85: 670, 1958 .

47. VON OETTINGEN, W. F. Poisoning: A Guide toClinical Diagnosis and Treatment, 2nd ed .Philadelphia, 1958 . W. B. Saunders Co.

48. MERRILL, J. P. The Treatment of Renal Failure :Therapeutic Principles in the Management ofAcute and Chronic Uremia. New York, 1955 .Grune & Stratton .


consequences of ethylene glycol poisoning: report of four cases and review of the literature

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