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5-1-1938

Erythrocyte sedimentation test

Olfert W. Topp University of Nebraska Medical Center

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THE ERYTHROCYTE SEDIMENTATION TEST

by Olfert W.- Topp

Senior Thesis Presented to

The University of Nebraska, College of Medicine, Omaha, Nebraska, April 8, 1938.

480990 CONTENTS

Title ------i Illustrations ------iii Introduction ------iv History ------1 Technique ------6 Speculative explanations of the phenomenon ---- 15 Clinical applications of the sedimentation test 24 Norme.l res.dings -- .- 24 Tuberculosis ------27 Syphilis ------35 Pneumonia and compli.ca tions ------41 Arthritis ------42 Rheumatic fever ------49 .. Cardiac lesions ------55 Malignant disease ------61 Obstetrics, gynecology, medical and surgical considerations ---- 64 Anemia ------79 Diabetes mellitus and hyperthyroidism - - 85 Allergy and skin ------88 Neuropsycbia try - - - 89 Conclusion --- 93 Bibliography ------94 iii'

ILLUSTRATIONS

No. 1 Bilateral tuberculosis ------33 2 Tuberculosis: unilateral cavitation 34

3 Malarial therapy ---- 38 4 Syphilis ------40 5 Lobar pneumonia ------~ --- 43

6 Hypertrophic arthritis ------50 7 Rheumatic fever with endo card! tis and chorea 56 8 Pregnancy ------67 9 Acute gangrenous appendix ------71 10 Misc. readings ------76 11 Chronic cholecystitis ------80 iv

INTRODUCTION

The writer's interest in the sedimentation test was first aroused during the summer of 1937 while en­ gaged in laboratory work under Dr. s. Miles Bouton at the Hastings· state Hospital. Sedimentation tests were done on patients as part of the routine blood examina­ tion. Much of the time was devoted to personal obser­ vation and study of the relationship of sedimentation curves to various mental and organic diseases. The fundamental purpose of this paper is to explain and evaluate the use of the sedimentation test as a laboratory aid to diagnosis and prognosis. The d1scus­ sio-ns0will not be limited merely to one phase of the subject, but the history, technique, causative factors, and clinical applications will be considered. ------

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HISTORY

Many centuries ago, long before the advent of lab­ oratory methods, Hippocrates and Ga.lenus (Ostendorf, 1927) the founders of humoral pathology, called the whit- ish layer of fibrin, which appeared on top of venous blood after it had been exposed to the air for some time, "crusts. phlogistica. They observed that 1 t did not form in the blood of a healthy person, and the seriousness of the disease was judged from the size and consistency of this pseudo-membrane and they regarded it as the sub- stance of the disease which bad to be removed by fre­ quent venesections. This theory has come to us through the middle ages to the end of the last half of the nineteenth century. Musgrave in 1703 (Short, 1937) observed the accel- erated sedimentation rate of erythrocytes in rheumatism, and referred to this as the "buffy coat". Hewson in 1772 (Ostendorf) proved that the "buffy coat" was not the substance of the disease, but that the delayed coagulation of the plasma and the accelerated sedimentation of the erythrocytes was the cause of the dissociation. John H. Hunter (1796) observed that during an in­ flammatory process the erythrocytes settled more quickly in their own plasma. He was the first to demonstrate that the red cells of the normal blood when placed in r

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infected blood settled with greater rapidity. It was bis belief that the cause of this phenomenon was the fluctuation of the specific gravity of plasma and ery• throcytes in the inflamed and non-inflamed blood. Bellinger! in 1826 (Ostendorf) believed that the electricity of the blood was reduced in inflammatory conditions.

Johannes M~ller in 1835 (Ostendorf) assumed an in­ crease of the fibrinogen, and in 1836 Nasse believed that a qualitative change of the fibrinogen content of the blood was the cause which accelerated the settling of the erythrocytes. John Ashhurst (1893) stated that the blood showed the following changes during inflammation: Due to the changes in the consitution of the blood in inflammation, its fashion of coagulation differs from normal blood. The clot forms more slowly than in health and is smaller and firmer in consistence. The slowness of coagulation and the increased cohesiveness of the erythrocytes per­ mits the separation of the fibrin and the leukocytes to take place before the process of clotting is completed, and this gives rise to the peculiar appearance which is known as the "buffy coat". Biernacki in 1897 (Morris, 1926) prevented coagu­ lation by the addition of powdered oxalate and made his - 3 -

determi~tions bJ' placing tbe blood in speciall7 con­ atrU.cted c7linders and measuring .the degree o.t' .t'all o.t' tbe er7tbrocytea at intervals o.t' thirty minutes and one hour. It was at this time tl:B t be reported a series o.t' sedimentation teats on seventy-five cases, including .t'our with pulmonary tuberculosis, and tabulated his compara­ tive results with defibrinated aDi oxalated blood. He concluded that the· test had clinical value; that tbe re- aults were not dependent on corpuscular volume; and that tbe sedimentatlon velocity was related to tbe content o.t' fibrinogen in tbe plasma and intimately related to con­ ditions of disordered oxidation. His work was confirmed bJ' his pupil, G. F. Muller" of Berlin, Germ:an7. Marcano, in 1901, described perhaps the first micro­ method of blood sed1mentat1on.(Korr1.s) Shortly after the time of Biernacki, under the in­ fluence of V1rcbow (Ostendorf) pathologic anatomy became more important than bematolog7 in bumoral patholog71 but this era was of short duration. Lattes (1925) found tba.t Biffi bad published a work in 1904 in Lo Sper1mentale. From a chapter beaded "Blood Sedimentation" be quotes as .follows: "Agglutination of erytbroc7tes cannot help having a.great at.feet on sedi­ mentation, changing the physical conditions under which • the latter is affected. Erythrocytes collected in groups - 4 -

sediment more rapidly and in shorter time than ones that are isolated or only collected in groups of few cells. The formation of the 'buffy coat' bas been attributed by pathologists to the retarded coagulation of the blood under certain conditions. This explanation is not suf­ ficient. It can be proved experimentally that a slight retardation in the coagulation of the blood is not suf- ficient to bring about the formation of a 'buffy coat•. But autoagglutination is a most important factor, and perhaps the principal one, in the formation of the ' buf ry coat ' • " Robin Fabraeus (1917) of Stockholm, while working in the Physiological Institute of the University of Kiel, rediscovered the phenomenon, and demonstrated that the formation of the "buffy coat" de~ends essential­ ly on the speed of sedimentation of erythrocytes, and that this acceleration is due to the nummular agglutina­ tion of the red cells in clumps or rouleaux which sink more rapidly, due to the reduction of the surface of contact. Hober, his teacher, had shown that the red cells were electrically negative, and he therefore as­ sumed that electrically positive substances in the pias­ ma, due to adsorption, approach the surface of the nega­ tive erythrocytes, neutralizing them and rendering them unstable. Fahraeus stated that the phenomenon might be employed in the form of a test for pregnancy, as - 5 -

there was a marked difference between the sedimentation of the red blood cells in parturient and non-pe.rturient women. He also noted that rapid settling of erythrocytes occurred in infectious diseases and malignant tumors. Linzenmeier, (Ostendorf) in 1920, another pupil of Hober, proved Fahraeua' theory experimentally. By add­ ing electronegative adsorbents to blood with an accel­ erated sedimentation rate, the reading became normal. He demonstrated tm t defibrinated blood caused a delayed sedimentation rate, and in blood with much fibrinogen the settling of the red cells was accelerated. From this he concluded that the fibrinogen of the blood is the principal factor controlling the velocity of the erythrocyte sedimentation. In the past twenty years there have been over three

thousand articles wr~tten, dealing with the sedimentation reaction. The work has been largely divided into two groups, •xperimental and clinical. The first attempts to discover a specific cause for the sedimentation reaction, by experimenting with various factors influ­ encing the velocity of the settling red blood cells. The second group has been trying to determine the val­ ue of the sedimentation test, as an aid in diagnosis and prognosis. - 6 -

TECHNIQUE

Many workers on the subject of red cell sedimenta­ tion have utilized much time in an attempt to standard­ ize a definite method whereby the rate of sedimenting erythrocytes could be numerically expressed. · Up to the present time there have been more than thirty methods devised, all of which are essentially the same and dif­ fer only in the amount of material used, the size of the tube, and the method of determining the reading and the collection of blood speciments. · Herein the writer gives the principal methods used. The Westergren (1926) method, a modification of the Fahraeus technique, is performed in a glass tube 300 mm. long and 2.5 mm. in bore, graduated downward from O to 200 mm. Blood is withdrawn from the anti­ cubi tal vein and mixed with a small amount of potassi­ um o.xalate (Bouton 1937) or sodium citrate about .4cc• The blood is then sucked up into the tube to the zero mark and the lower end closed by setting the tube into a rubbe~ stopper and the tube set perpendicular into a stand. The readings are tsken after an hour. A plasma column of 3-12 mm. in one hour is considered normal. The technique used by Linzenmeier (Waugh 1923) is described as follows: o.acc. of blood is drawn in­ to a special gradua tea. syringe containing 0.2 cc. of - 7 -

a 5 per cent sodium citrate solution. The blood is then transferred to a small sedimentation tube a bout 6 .5 cm. high and o.5 mm. in diameter, with oalibra ti ons marked at the l cc. mark. The sedimentation tube is filled exactly to the 1 cc. mark with the citrated blood, and the line of separation, uetween the blood corpuscles and the plasma is noted as it reaches the various mB.rks, tba t is 6, 12, 18 and 24 mm. below the 1 cc. mark. This is the sedimentation time. Cutler (1926 and 1929) uses a short stout tube with an internal diameter of 11.2 mm. This test re­ quires 0.5 cc. of 3 per cent sodium citrate and 4.5 cc. of blood. With this method, the readings are taken every five minutes for one hour and the observations are re­ corded on clllrt s designed for that purpose. Bouton has also designed a chart, to be used in recording the read­ ings obtained with the Westergren tube. This I feel is preferable to Cutler's chart, as there is a greater dis­ persal of indices in the Westergren tube, and thus a more readily measurable fluctuation of the readings, and the changes in the patient's condition can be more easily interpreted. The two charts will be illustrated in an­

other ~rt of the paper. Wintrobe and Landsberg, (1935) recommend the fol­ lowing method as satisfactory and accurate: - 8 -

1. Five cubic centimeters of venous blood is collect'94 by means of a dry syringe and needle and mixed in a small bottle containing 4 mg. solid potassium oxalate and 6 mg. solid ammonium oxalate. This concentration of oxalate does not alter as compared with that of blood collected in heparin. Less tmn l cc. ot blood is needed tor the sedimentation test. The remainder can be used far other blood examinations. Other workers ( Greia­ heimer, 1935) state potassium oxalate hastens the rate. Heparin increases the speed of sedimentation unless the amount of solvent is greater than the control amount. 2. Blood should be used within four . hours after collect! on. 3. The hematocrit is filled to the 10 cm. mark with blood. The upper level of sedimenting corpuscles may be read at frequent intervals up to an hour. Dunn and Sharpe (1936) have devised a set of nomagraphic alignment charts to correct the volume of pa eked erythrocytes for the - 9 -

amount of shrinkage that results from the use of an anticogulant. However, tbey state t:t:Bt if the ammonium and potassium o:xala te mixture is used as recommended by Wintrobe then there is no shrinkage, and this correction chart is not necessary. 4. Since sedimentation rate increases with rising temperature, the sedimentation test should be carried out at a temperature not less than 22 degrees centigrade nor greater than 27 degrees centigrade. Within tb1s range variations resulting from dif­ ferences in temperature are small. Gordon and Cohen (1928) observed that varying tem­ peratures caused fluctuations in tbe velocity of the settling erythrocytes, heat acceler­ ating and cold slowing. Rourke and Plasa, (1929) while experimenting with blood, took two specimens of the same blood and kept one tube in an incubator at 37 degrees centigrade and the other tube was kept at room tempera­ ture (19 to 23 degrees centigrade). They concluded tbs. t the rate of sedimentation was accelerated at the higher temperature. Walton (1933) and Yardumian (1937) substantiated - 10 -

the above findings. 5. The hematocrit should be kept in an exact vertical position during the sed.1- . mentation ot the blood corpuscles, tor when the instrument stands at an angle ot even 3 degrees trom the vertical, significant ac­ celeration ot sedimentation takes place. Ponder (1925) demonstrated that 11' a 200 mm. tube deviated as little as 7.5 degrees, the sedimentation rate would almost double· 1n a vert1 cal tube. 6. After sedimentation rate bas been de­ termined, the hematocrit containing the blood should be centritugalized and volume of packed red cells determined. The sedi­ mentation rate may then be corrected for al­ terations due to anemia. These corrections will be discussed in this paper under the heading "Anemia" • Zwecker and Goodall (1925) collect 8 cc. of blood in a graduated centrifuge tube containing 2 ce. or 3 cc. ot 3 per cent sodium citrate solution and allowed to stand for an hour and the cell column is then meas­ ured. Beaumont and Maycock (1935) mod11'1ed this method; their sedimentation tube bas a bore of o.75 cm. and 1 ts - 11 -

length is marked in ten di visions, each of 1 cm. Sodi­ um citrate ( 3.$%) is pl.aced in the tube up to the 2 mark. About 5 cc. of blood is drawn from a vein and placed in the tube containing sodium. citrate to the 10 mark. The rate of sedimentation is read in cm. at the end of an hour by placing a millimeter rule along side of the tube. The column of supernatant fluid is not recorded. This method can be compared to others by subtracting result from 10 and then multiplying by ten, thus giving the supernatant fluid per cent. The normal is about 9.7 cm. of corpuscles. Landau (1933) describes the micrometbod of Lin­ zenmeier-Raunot. The tube used is a capillary pipette of thick glass about 6 inches long, with a bore of 1.13 mm.. and graduated fran above downward in mm. from l-100. The patients .finger is pricked, after warming it in bot water, and eight drops of blood are sucked into a specially tested pipette; the blood is then mixed in a small test tube with two drops o.f' 3.8 per cent solution of sodium. citrate. The citrated blood is then sucked into the capillary pipette to the. l mark, and the tube set in a water•batb at a temperature of 37 degrees centigrade. The reading o.f' supernatant .fluid is taken at the end of half an hour by some ob­ servers, and at the end of one hour by ot,bers. The - 12 -

final reading is expressed as so many mm. of supernatant f'luid per cent. Normal readings are between 0.5 and 4.0 per cent for men, and between 1.0 and 8.0 per cent for women after half an hour. Harvey and Hamilton (1936) g1ve details of a cap­ illary tube technique which they maintain is easy to perform and repeat, and is a dependable measurement of the rate of sedimentation and blood volume. They use capillary vaccine l,mph tubes of standard and uniform bore, graduated with India ink to 7 em. With a tested pipette, one drop of citrate solution is placed in a watch-glass; this pipette is emptied am used to draw up blood, four drops of which are mixed with the citrate drop. The mixture is then quickly taken up into the

capillary tube to the im rk, and then the column of blood is given a tilt to bring it higher up the tube. Both ends of the tube are sealed with plasticine, and the tube is set in a vertical position. The time is record­ ed. The process is repeated with the operator's blood, and the time again recorded. This "simultaneous con­ trol" becomes unnecessary .when standards have been es­ tablished. The amount of. settling in the tubes is read with a millimeter rule at the end of one hour; a settling of 7 mm. in a 7 cm. blood column would represent 10 per cent. The capillary tubes are' next placed in a centr1- - 13 -

.fuge tube with a plug o:f wool at the bottom and :filled with water, and are then centrifuged to constant volume. The authors found that this was attained with two cen­ trifugings at about 3,000 revolutions per minµte. They also noted that preservation o:f the citrated blood seemed to slow the sedimentation rate, but add that this is of no significance i:f a "simultaneous control" has been performed with the operator's blood. Others (Morris and Rubin, 1926) have felt the need of a mi cromethod. Although venous puncture is canpara­ ti vely easy, there are e. few cases in which successful venous punctl.ll'e is very difficult, owing to veins which are deeply embedded in subcutaneous adipose tissue, or those veins which collapse spontaneously on puncture. Still another reason for developing the micromethod is for use on children and infants. For this reason the workers on sedimentation felt it would be feasible to

devise a method whereby small po~tions of blood could be used, and could be obtained in the same manner as the blood used in blood counts. Greisheimer, Treloar and Ryan (1934) studied the Cutler, Linzenmeier, and Westergren methods, which are to-day the three most comm.only used methods. They com­

pared the curves produced by each in 99 men and 102 women. Cutler and Westergren record the sedimentation - 14 -

index as the length of clear plasma at the end of one hour, while Linzenmeier records the time for the blood cells to settle 18 mm. Through these experiments they found that the average sedimentation index for normals was reasonable concordant for all three methods, and tmt the measure of sedimentation is in part specific for the technique employed. - 15 -

SPECULATIVE EXPLANATIONS OF THE PHENOMENON

Herein a brief review of the literature will be presented, dealing with the theoretical aspects of the phenomenon. Biffi 1n 1904, (Lattes 1925) concluded that auto­ agglutination was the most important factor, and per­ haps the principal one, in the formation of the "buffy coat". Fa.hraeus, (1929) also believed that the sedim­ entation reaction was due to the autoagglutination of the red cells in clumps or rouleaux. Gram in (1921) concluded that both fibrinogen and cell volume were the important factors in the sedimen­ tation reaction. Starlinger in 1922 (Ostendorf) ex­ tended the electrophysical theory by a colloid-chemi­ cal one, assuming an increase of coarsely dispersed, readily flocculating globulins as the cause of a rapid sedimentation. Gram, however did not investigate the electrical factors but did determine the cell volume percentage and the temperature are directly proportion­ al to the decreased sedimentation time in the normal. Hober in 1922, (Ostendorf) summarizes these theo­ ries: The processes which accelerate the sedimentation reaction, change the globulin fraction of the blood quantitatively and qualitatively. The adsorption of r

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these changed globulins changes; (1) the electro­ physical nature of the erythrocytes, because the iso­ electric point at which the red cells precipitate is. reached; (2) the degree Of dispersion of the plasm.a, upon which the dissociation of the red cells fran the plasm.a depends, and (3) the viscosity of the plasma, which controls the adhesiveness of the surface of the

blood cells,; and the single protei~ particles. Waugh (1923) stated, that the viscosity of pro- . teid ·solutions is indirectly· proportional to their electrical burdens; globulins having a very high, al­

bumins a relatively low, viscosity. Th~refore, be believed that if the globulin of the blood plasma is increased and the albumin is diminished, two changes take place which unite in aiding agglutination of the red cells, hence, the sedimentation ·of the red blood cells is aecelera ted. In the first change, the vis­ cosity is raised and the more viscid protein particles cling more readily to the corpuscles, and the red cells to each other; and, in the second place, the electri­ cal burden is diminished, the isoelectric point is approached and the corpus cl es tend t.o aggregate. Friedlander ( 1924) supports. the experiments of Gram and .found in all cases after he had defi brin- a ted blood that it took from four to six times longer, - 17 -

for tbe red cells to settle and from this be drew the following conclusions~ That neither the red cells nor the viscosity of the plasma was changed by the process. Fischl {1924) held that the erythrocyte sedimen­ tation was due to the' alteration of the albumin-globu­ lin ratio, with an increase in globulin. Meeker (1925) stated that the most acceptable theory is the hypothesis that a decrease in sedimenta­ tion time depends on a protein phenomenon, a disturb­ ance of the normal album.in-globulin, fibrin ratio in the blood. Schmitz (1926) also believed in the albumin­ globulin theory. Ostendorf {1927) observed tbs t the change of the globulin fraction with all its attending phenomena, depends upon the products of the protein metabolism affected in the organism, by the disintegration of tissue, bacteria and toxins, which activates defensive ferments. The ferments again produce products of decom­ position and their increase in the blood influences the plasma and the figured elements which enter into the sedimentation reaction. Newham (1926) and Fahraeus in 1929, while doing separate investigation on the sedimentation reaction of blood, took into consideration the well-established law - 18 -

of physicists known as ttstokes Law". "stokes Law" (Fahraeus 1929): The sedimentation velocity of the corpuscle in a $Uspension of globular elements in fluid is proportionate to the square of their radius. Newham gives a detailed description of the law, according to which the speed of sedimentation, V, is directly proportionate to F, the force of gravity and inversely proportional to N, the viscosity of the dis• persion medium, as well as to R, the radius of the particle in accordance with the formula V:P/6 "!P NR. He.further states that one or more of these factors may be much altered in different disease conditions. Thus, in anaemia of the Addison type it is obvious that R, the radius of the sedimenting particle.or red cell, is very considerably altered, and consequently F also will be affected, but in anaemias of the chlo­ rotic type where the hemoglobin is much reduced and the plasma is increased, it is reasonable to expect the viscosity of that medium will be considerably altered, as also will the force of gravity, F, of the cells. Again, it is reasonable to suppose that the factors F, N, and R may in certain disease conditions, be alter­ ed in such proportions as to merely affect V very little. r

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Rosenthal (1928) noted a definitely rapid sedimen- tation rate in cases of tuberculosis, when the choles­ terol was over 300 mg. He concluded that the sedimen­ tation of the blood might be due to a shift in the cho- lesterol metabolism. Westergren (1928) supports some of the above au­ thorities by stating the chief cause of accelerated sedimentation rate is a rise in the globulin and fibrin- ogen content of the plasma proteins. Reyner {1929) attempted to prove that a difference in surface tension of the blood' plasma is responsible for the phenomenon. He increased the surface tension by adding formaldehyde to the blood specimen and main­ tained that a decrease in tpe rapidity of the red cell

sedimentation occurred in dir~ct proportion to the amount of formaldehyde added. Greisheimer, Johnson and Ryan (1929) examined the blood of 200 women and 213 men, whose ages ranged. from 7 to 94 years, and found that the sedimentation rate was accelerated along with an increased fibrin content in the blood. They also noted tbit the fibrin content was higher in women than in men, and maintained that this explained the reason for the increased velocity of blood sedimentation in women. Cutler (1934) after an extensive study of the - 20 -

subject, stated that the phenomenon depends upon the amount of cellular destruction in the body. As the blood circulates from part to part it carries away prod­ ucts of tissue destruction wbicb alters its stability. In healthy persons as a result of wear and tear of every day life, a certain amount of tissue destruction always takes place, although this varies from day to day it re­ mains within normal limits. Even tbis small amount of destruction is registered by sedimentation of red cells. Kunz (1934) points out that the factors controlling the sedimentation reaction must be looked for in the plasma rather than in the blood cells. Hunt,(1929) Fahraeus and many others since the time of John Hunter have placed cells from a well individual into the plasma from a sick patient, and found that the normal cells in this plasma settled almost as rapidly as the sick pa­ tient's cells in the same plasma. Sasano, Ordway and Medlor (1936) thoroughly investigated this phase of the phenomenon by examining the blood of 200 patients, and concluded that the blood plasma was of greater im­ portance and significance than· the red cells in the sedi­ mentation reaction. Two individuals belonging to.the same blood group were selected for their experiment; one was normal and well and the other clinically ill. The cell volumes and sedimentation rate for each was r

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determined, and the plasma and cells of each separated. The cells of the normal individual was placed in the plasma of the ill patient, and vice versa. This was done after allowances had been made for cell volume. They found that when the cells of the normal blood was placed in the pathological serum there was an increased or accelerated sedimentation rate, and when normal plasma was mixed with the cells from the ill patient the sedi- mentation rate was normal. Hirsh (1936) contends that although there are many factors which influence the red cell sedimentation rate the precise mechanism' of the reaction is not yet known, but be believes that it depends on foreign protein: the rate in pregnancy depends upon fetal catabolism; in infection the rate is due to protein of bacteria; and in neoplasms or a disease such as coronary occlu- sion the accelerated sedimentation rate is due to the protein of necrotic tissue. Yardumian (1937) after investlga ting the physico- chemical factors influencing the red cell sedimentation, brought out the following: l. Factors which.do not affect the sedimentation rate. a. Various anticoagulants. b. Various techniques. · - 22 -

c. Va.ria. tions in tempera. ture between 20 to 30 degrees centigrade. d. Remixing ia:nd resedimenting. e. Variations in chemical constituents, blood sugar, non-protein nitrogen, calcium, phosphorous, carbon diox­ ide combining power, cholesterol, plasma and cell chlorides, and albu­ min-globulin ratio. f. Variations in the number of leukocytes and blood platelets. 2. Factors which a£fect the sedimentation rate. a. Delay over two hours decreases the rate. b. Variations in bore and length of the tube. c. Extreme temperature below 20 degrees and above 30 degrees centigrade; cold slow­ ing and heat accelerating. d. Albumin and globulin content of the blood, high values accelerate the sedimenta­ tion rate. e. Marked hyperglycemia of 200 mg. per cent slows the sedimentation rate. 3. Factors which markedly affect the sedimenta­ tion rate. a. High fibrin content of the blood general­ ly accelerates the rate. b. High total lipoid content of the blood in certain cases generally accelerates the sedimentation rate. c. The volume of packed red cells, the small­ er the volume the more rapid the sedi­ mentation rate. d. Deviation of the tube from perpendicular. The foregoing material bas presented maD.¥ theories - 23 ""

and speculative opinions as to the cause of the erythro­ cyte sediments. ti on reaction. It has not been definitely established, however, that any one factor is entirely responsible for the phenomenon. Therefore, it would seem logical to assume that the sedimentation reaction of the red blood cells depends on a disturbance of the physicochemi cal balance du_e to constitutional changes of the blood during a dise&lse process.. Tbe part that each .factor plays in this phenomenon would perhaps be governed by the area involved by the disease process, the type of process, and the extent to which it has developed. - 24 -

CLINICAL APPLICATIONS OF THE SEDIMENTATION TEST

The remainder of this paper will be devoted to the value of the sedimentation test as a laboratory aid in medicine and surgery. In order to avoid confusion to the reader, only the figures for the Cutler, Westergren and Linzenmeier techniques will be used. Where results are found, the method employed will be mentioned. The sedimentation test has a three-fold value, (.Bannick, 1937) namely: 1. To indicate the presence of disease. 2. To indicate the intensity and progress of the disease. 3. To aid in differential diagnosis.

NORMAL READINGS Cutler (1926) gives a normal range from 0 to· 8 mm. in men and 0 to 10 mm. in women. Westergren (1926) ·gives bis normal as 8 to 12 mm. I have found there is very little consistency in the normal readings for the Linzenmeier technique. Waugh (1923) employing Linzenmeier technique, observed that fully developed males in health gave a sinking time of 1,200 to 1,400 minutes to reach the 24 mm. line. Women during their - 25 -

sexual life have a shorter time, BOO to 1,000 minutes, ·except during menstruation when it falls to about 600 minutes. He also noted that the sinking time in the new-born up to the fifth week is 1,500 ·minutes and from then on there is a marked drop or shortening of the time up to the fourteenth year, and the readings during this period may be as low as 100 minutes. Friedlander (1924) uses the Linzenmeier method and records the time it takes the red cells to fall to tbe 18 mm. mark, which he reports as 1,000 to l,200 in 'healthy males and 600 to 1,000 in females. These wide fluctuation in the Linzenmeier tech- nique will not be found in the Cutler and Westergren methods, and the writer believes the latter two are easier to interpret. Ellenberg (1934) carried out a series of tests on babies varying from two days to 10 days, using the Linzenmeier method, and found the normal range of the new-born between 7 and 23 hours with an average sedi­ mentation speed for the entire new-born period being about 15 hours. There was also a tendency for the sedimentation reaction to become less prolonged as the infant grows older. The following table, which has been worked out, takes into cons id.era tion the affect of various pa tho­ logic conditions on the sedimentation rate: (Cutler, 7 1932) - 26 -

Diseases with abnormal sedimentation rates: l. Chronic infectious deseases, such as tuberculosis and syphilis.

2. Acute infectious dis~ases, such as ,pneumonia, septicemia, acute endocard­ i tis, and e:m.nthema ta and acute bron­ chitis.

3. JIIalignancy. 4. Localized suppurations, such as pelvic inflammatory disease, suppurative mastoiditis, suppurative sinusitis, empyema of the gallbladder, bronchi­ ectasis. 5. Acute intoxications, such as lead and arsenic poisoning.

6. Certain endocrine disturbances, such as thyroid toxicosis. Diseases ini'luencing the·· sedimentation rate very little; if at all$ l. Simple catarrhal ini'lammations, such as acute cata.rrhal appendicitis, simple rhinitis and colitis. 2. Chronic ulcerations of' small extent, such as gastric or duodenal ulcer. Diseases not 1ni'luencing the sedimentation rate: l. Functional diseases, such as the various neuroses, and neurasthenia. 2. Certain nervous diseases such as dementia praecox. ·3. Focal infections, such as abscessed teeth, diseased tonsils and chronic sinusitis. 4. Metabolic diseases, such as uncomplicated diabetes and essential hypertension.

5. Allergic di~eases, such as asthma and hay i'ever. - 27 -

6. Most skin diseases. 7. Simple growths, such as fibroma, lipoma and fi bromyoma • 8. Simple cysts. 9. Chronic valvular diseases of tbe heart. Cutler bas neglected to mention anemia and into which category it falls. This will be given consider- ation under a separate heading. Discussion of the various diseases and the value of the sedimentation test in each will follow:

TUBERCULOSIS

One of the first uses of the sedimentation test was to determine the activity of a tubercular.lesion. The opinions and conclusions of various workers will herein be given~ Morris (1924) observed a definite acceleration in the speed of sedimentation of the red cells in active tuberculosis. He also found that in the presence of defini ta symptoms of activity that the ra ta was always rapid, and in those conditions which were believed to be quiescent the sett1ing of the red cells was found within normal limits. However, he found normal read- ings frequently in women. At this time he concluded. that the test was of 11 ttle value in the diagnosis of tuberculosis. In a pa.per (Morris and Rubin, 1926) - 28 -

which was published two years later, while working in conjunction with Rubin he repudiated his previous state­ ment by saying, "the test has been found especially useful in tuberculosis as an indication or the degree of activity present." Westergren ( 1928) after thoroughly investigating the use or the sedimentation test in tuberculosis, was also of the opinion that it could be used as a criterion to determine the activity of the disease. Two years later a report came out (Cutler 1930) that the human equation could now be eliminated from the diagnosis of activ'ity in tuberculosis, which in the past was entirely based on clinical judgement, and by using the sedimentation test the three follow­ ing questions can be answered: l. How much consti­ tutional disturbance is the tuberculosis producing? 2. Is it active? 3. Does it require special treatment? It was in this same year that Banyai and Ander­ son (1930) brought out their report on 2,000 cases of tuberculosis, and found that the activity of the dis­ ease has a direct influence on the velocity of the sed­ imentation test in the majority of instances. In these cases 7.35 per cent showing evidence of active tuber­ culosis resulted in a normal curve. Nevertheless, they believed that the value of the test lay in observing - 29 -

the course of the disease, and could be used as a sen­ sitive indicator of complication of the development of new lesions and as a criterion as to the treatment. They suggested that it might be of value in discovering new foci of infection in the lungs, as many times these are not discovered by routine diagnosis. Other compli­ cations like intestinal or renal tuberculosis are often unsuspected, and an accelerated sedimentation rate might aid in directing the attention to the source of disturb­ ance. Although the test cannot estimate the extent of the lesion a rapid increasing rate for any length of time indicates an unfavorable prognosis •.

Roche~ (1932) ran sedimentation tests on 244 tuber­ cular patients, using the Westergren technique. His normals in healthy males were 4 to 15 mm. in one hour and in healthy women 6 to 15 mm. in one hour, but he regarded these figures as slightly increased, and placed the readings in three groups: 1. Normal, 4 to 6 mm.; 2. Medium increase, 15 to 30 mm.; and 3. marked in­ crease, 30 to 50 mm. He regarded his' low rates as a sign of good prognosis, although be found in emaciated patients where the disease was markedly advanced a re­ latively lower reading was almost invariably constant. This be explained on a basis of a diminished fibrinogen and a lower concentration of serum globulin in the - 30 -

blood plasma. He goes further to state that prior to the onset of relapses, such as a rising temperature or other signs of increased activity as hemoptysis or pleu­ risy, the patient's temperature, resting pulse rate, and general condition and appearance, and even bis exercise tolerance, may have been quite satisfactory. But with­ out any special means to prevent occurrences of this type these are apt to be considered unavoidable develop­ ments of the disease. He is of the opinion that in num­ erous patients such an occurrence could be avoided if, in the presence of normal temperatures and pulse rates, their activities are limited until the sedimentation rate has fallen within the slightly increased group. Stainsby (1934) brought out that in tuberculosis, however, s-econdary infection of the bronchi by organ­ lsms, other than tubercle bacilli takes place, especially in advanced cases. He finds thit the sedimentation rate may be of considerable diagnostic and prognostic value if one will keep in mind the question as to-how much of the increased rate is due to tubercle bacilli. and how much is caused by the secondary invaders. "In detecting early tuberculous infection, the sed­ imentation test is sometimes of value." "The sedimentation test is also of help in follow-. ing the course of the disease in any particular patient, - 31 -

and is of considerable value when patients are being treated at regular intervals by pneumotborax. When used in conjunction with sputum examinations and temp­ erature records, a satisfactory picture of the course of the disease is obtained. In the ambulatory treat­ ment of tuberculosis by pneumothorax, the sedimenta­ tion index is more reliable than the temperature for the obvious reason that the temperature varies con­ siderably during the course of a day, while the sedi­ mentation index remains constant. "A normal sedimentation test at the time when a patient with tuberculosis is considered to have reached an arrested or inactive stage of the disease affords assurance to the physician that bis impression is cor­ rect. A high index, on the other hand, does not indi­ cate activity of the disease, for secondary infection in the bronchi may be responsible." Lesser and Goldberger (1935) studied 50 cases of pulmonary tuberculosis and found that the height of the sedimentation reading is an accurate indication of the extent_ and activity of the pulmonary pathology. Similar­ ly in tuberculous peritonitis, high sedimentation read-, ings were obtained. Merritt (1937) stated that the sedimenta.tion rate is an especially valuable aid in determining the activity ------

- 32 -

ot tuberculosis. In July of the same year Blem (1937) reported that the sedimentation test serves as a guide to re-infection and an inactive process shows a normal sedimentation rate. It is the opinion ot the writer that the sedimen-. tation curve is a more delicate criterion of activity in tuberculosis, than either the temperature chart or the pulse rate. No case of tuberculosis should be allowed to exercise until the rate is normal· and has remained so tor quite some length of time. The writer t eels that a pap er of this kind would not be ccmplete without sane charts to demonstrate how the sedimentation curves can be graphically plotted. The curves on the graph illustrate clearly the severity ot the disease, and the reaction to treatment.

Illustration No. l is a record of the sedim~n tation curves of a man with a tar-advanced bilateral pulmonary tuberculosis in whom any type of pulmonary compression was out of the question, because ot the anatomical dis­ tribution ot the lesions. Fifteen months of bed· rest brought about quiescence ot the pathological process, and a corresponding decrease in sedimentation rate. (Ringer, 1934). Illustration No. 2 is trom the records of a patient with a unilateral cavitation who, after several months . . - 33 - .....

OUTLER BLOOD SEDIMENTATION TEST fame ____ ------\Jdres ---~-~~-.._.--~---- ,H-EC-1)'.·----G-RAP--H---.-C-o_r_r_e_o_"'p_o_n_d_i_n_g_, _C_l_i-i1_i_c_o._l______--·- ·------.~· ·- .. 1- - - ··-·-· .

Condition Sod im'3.:.1" J cc'cl -r.1. ~:· 1. 9 r Ho~tal Lin Normal or Absolute Index T~.n;..G Quiescenco DingonaJ. 'L!ne Quiescence ----MI.I. ----Hin~ : Diagonal Curve Slightly or moderately nctivc Vertical C'W:.,,-e Moderately or markedly n0tive

S0 d • ·in· TD/IE IN 1,iI:·HJTES i:.,..,>GC..o · · I MM.-~------...----.-~-T.;- . , TI · I . Irn.~(· L ; 0 5 lC 15 @ !25 -f-2- ·J-t-~_2-~.L·4~--t.5--f-~ ~ -=±j__ 5~-I ·-···-~~-~- --' -! 0 ! I ·--;-··--- 1 - ·r-----r··--· ·-·-·-·1·--·- · --: ·- ~; 0 '. ---~~-t----t---•---+- 1 ·---r------·---1··--·-· ' ---··1------· ·: +-Tlllil!!!~~I------.------r--·--l. ---..J .____ .,._ _ _ .._;_ - ---... ·--·---' -·-··· - -1 +-==:::!:'f;:--..~---:t-~::;;;s~::;;~:==:- ·r--·---- -• -- -··-r· ----- · ~- ·- -+-- ---~ - - -l ----- ~-·--- -·! +- , ...... --i--. ·-r-- - -- ~--;- - ·- ·- · ·i-· -·--;--· -· -r ·- - - · · ~ -·· - · ·-~·- .. - -- -- ~·- ,_ ... _ "' ...... __ . --~-...... ·------,-- --r ...... +---- ·r ··- ··-t·-· ·-----1 t---t---....io--...... ;...... ----~~.__...... y__ - - ·· - :_ --. _ ...._ .,.. _ . ~ ...... _ ~ · - ·--· .. -· ...... ,..._ ·-- ....- .tf I ' ~, '. - · --+- · --~ -- ~- -·· t - ·--- ~ · ·-··-+·--·._;.! l I " --·-+--- -· __,.. ___. _ _L._ _ -.,.· ·- ...... --,_~- -· ,.,__ ----1 ! ·'\.'I , ""- -~· - - :· -- I - ·· - -~ --·- ···+ ----·-·+·· ·-- •··- - ---·--·l9-J.3...33 10 +--_...,.__ __. __....., _ __,~ I --i--1-· - ·----!"·--·+·· ·-·· r-··--M· . -- .., i r\ ~---}---,-·--r- '··---4---- ·-·-L---+----·-· __d.• .Q_i \ I . f • • t I I --. -' -r---r---· J..... ••.. - I --·-;· -..--!------1 . ....,_..... __ ..,__....,._...,,.~,-+---. .--- - , - ....,. .. -· ·· +-- - · t-:-· · ·- ~ · -- --, -·--'···----1 I +----+----+--...... - ...... --·- >- - -,- - -+· _ _...__. ·- [ - ..... >-· - ~-· _,_,, ___ . ···---- I 1 .-----+---+---1---.....+-\.---y ·-- · - · ~- - - - ·- --+-- - ·f ·--·-·- - ---+ · ----~· ·-· 5-~ I .--~,~---+----+--~~\.---t- - +---+ --·-r···-- -t--- L--..., ... ··--- --+·-- ·- · : :r_-_-+----+--+-~f. ~ -+==t=~ : '- ·-·:: t=~ :;t:=j=,:.i=-=~1 t-~~~ I -1. -·-·t··---- -+·--{-- .. ------t·-·-·-t······· . a::i · -~--- --r-·-,-· -- -+ ···-·-+·---t·-·---·J.-- ·---i ,....-~--t----t---t----+ -i ··~--· I --·--;-·-- ···t--· I-· -1---J_____ . 20 I ------·---+· .I.. ·-j_ ·--;--·---·r ~···;- - --···~----- · ·- . , -· - , ---\ ·--·--""?--"--r~- - --,- ...... ·-- -- ·-11a~ 1 +----t---+----4--:---L·--·-t-- +- · -...:- ~ - - !-·- - ·-~r - -4-----t·-·· ! /~------1,--+- ·· ··--, -+-··t- ~- ·· "-r··----t·- -·- ! ...... , --+----+---+----- ·--r------~· ---+--- -· -·· -~ ~---{-- · ---f -·---;··---.:· ; r------4-+-- -!-- ---~·····" --...:..- ·1·-·--··t--· 7~ · +----+-- .·' i ~ --+----· -t-·- - I --+-·- --···i._.. --· . - · -·-· 'I . --- -- I +---+--- -'--·---· --+ ·- ·-+ ·- ·-+---r-- t-· --' - - --'-·----L-·- 30 ~---t----+--+-----1"'"---t- - ·--+-----t--·· I -··1---·' ___ __ J---t--·---- ::SO ' : -- i- l +------}--·-L-.1...--l---+--4--+-E- ·.-r--± I -- . ··r--- I t---·i----·------i J---L·--!-- ---t-·---;-·E' I ----·-----r--- I I I·-- - --,··------·------...... '---' I . ' . . l I l ; ' I _i.,__-+-~--~ ! I I +------·------I 1 I i ·-r--~-·-r-: .' ----· I ~------,-,~ ;-~f-,--- -r------·J--- ;.--.,.._---- _ _. ___ --+----~------J~ - l -L,---- . I ..____.___ I I - --~--'"---- ! l I I Illust. 1 ...... - 34 - · ·.'·· CUTLER BLOOD SEDI1IBNTATION TEST

:~ ~e ______\J.dres ---~~--~------~- GRAPH Co~responding Clinical Condition

Ho~tal Lin( Normal or Absolute Quiescence Diagonal 'I.d.ne Quiescence Diagonal Curve Slightly or moderately o.ctivo Vertical Oul-ve Moderately or markedly o.c.tive

·sad. ·.1n TIME IN J:,UNUTES Sec.o· .

MWi..------'--..-----....--- Index 1 o 5 l 1c 15 a> I .25 I 30 ! 35 140 1-r.5 [ 50 1 5~ 1 {o : 1 l I ;---; · ·- - -; · --~--~, __ =f-,, - ~-· ·1 ·------;-~.ot o .....--~------,---...... L tu- ·--·---t---:·- ; o ! ---~, ~~t;;:::t::::l==:t.:-=--,· '---t---L-- ~-i· · --- "'1 ------1--~--· !----i ...,._ - ---1. ---- ·~·- +----+- ~ --!- · -- · · ~ --· ·-- .• - _1 ~~,...._~'-=-~st~~~:::=:¢::::;;;::t:' =·- ·<- - - ~7• ·•-•- · ~- •· -· .. ;-- ·- j· - - - ' _ _ __..J •v- •-• - •l +. ~..,;:""'-'. :::::::.._-._,..__, -·..J_ ··--+ ··--··...__··-r·-· -+- -···.. ·-··-- --+ -• ·- -- ~· · ·- ··· -·· +-----f.11~....__...... ~~--+- -- - · \...:__.-... ~ --- _ .,;,, --·--··--+-.. --·r··- · --~-· · - ---j ' '- '"""""-. -i--_ . I ' i +--...... --~ ...... "".""'---+-""""o::~:+-- ...... ;::::- •;- ....- -..-t- ·- -j-·- ··r ····-·-r---- I - --r- -- · -~ - .. - ._..,...... _.._.._ ,. ·- ---·· .... . ~ -· ... __.. ·r··.. ·-·-·- I . ·" · ' ~ . ·· -· - · -·- - ~ .. -- .· ·-.. + ---,-)-·--· ·---- a5-331 " " -+-· ·-· . - l---.. - - ·-t· ·---· +--·-- -·r-·- ~ ~ · · .!.-.- - ·-'"=! lO ..___.....__...... __'\.~, ...... ,-""...... , ...... r-.... -- + · - -t- -- --;- . ---t---·--···-r-·- ·+··-·- '-j ., 0 ,.___...,...---t~_.....--*"i~--...... ,._,...,..,-t-~·--f--T·- ! ...-- ·1 -+···---r·-·-·-- , --:.·--~1 .,.__..,.._ _..., __~- ...... -- .."boooc~K.- · -· · I -,---1 ··-I--;- ,---_---1 ' +--·------.....----- ...... _J.. - ·-r-· - +--- *j-- ·- , -. - -·- 1 ---4]0.9~31 ·· ---- j ---1----- · '-- - - ·~- --- ,··---·- l .._.,_,.. ______~-,----.:; ·· ------!-- · --t-·- ·--t- ·- -·+-···- ·l- --- T- ·-----: ! , ------+-·-- .-, --.-r--·- --, ... __ ,_ • _____.. ? I i .. ).~-f ~ 4--- -·-+-· · - · ·+---- ·~ \- ----L-~--+-· - · -~ I t---1.-~..__...._.._------~ ~--~~--- - -r--.·--·- 1 · ·~-+- - ---t- ·- -!-__- .-1 .. -1-- ~· ---t·-r---···· 1 __ ... J.. __ I , - ~-- - ! - -.,.-- -~T - - ·+- ·----+-··- 20 l ., ' - · t----1 .. _J_ f -!. ., ·---+ ·--r- .... -1-. .,_7..;;,3 ' -·-·-·--' -.----~-~ ._...J_, ____-T..,___ ---T ,-...... ------, .. i ,, _ . ! _...--i,..__-+---___._---+---*~i.------~--+-L-+--·r--r-·-r---·--,- -r·3-- ·--- I ...._,----...... --+---~---+---- . ~--·-r· -- -·r---;- ···--- 1 r--~----,.-1-·----r- -- ~- . . -·-· -;---·- ··,-----i-- -· ' ---+--_.__ _..,_ t---...P' ----t-~- ·· · ---:+-- -~~- - . .. - .--.-,.. ---t-- ~-e'.7-33 l 1 ~o r------'-----=~::_-_. _-_-+_, =-+=~1 -- ·~t·-·-1= ---=f I ·- :SO ! I - ---- G ~ 1 ! __,. ~_.._ __.....__ __L ..-l.. +--+- ·-· -- -·-- I I • ! -1- . -L-· ---·+-' ·--~ ' I I I . I , 1 i - • - --r 1 ~ - I t I . -t---r , --· ··- ....____ ,______I ! ~- 1 - · -r-- · ,_....____ --! _____; .___ ; __ --+-+-=~-':-c=F·+- • i I I l I I

Illust. 2 - 35 -

of bed rest with no improvement, was given artificial pneumotborax, but, as so often happens, the cavity was held open by adhesions. An internal pneumolysis was successfully done, and the clinical improvement was grad­ ual but steady, as shown in the graph. The patient had a remaining plural effusfon, but was clinically well and entirely symptom free.

SYPHILIS

There has been very little written about the use of the sediments. tion test in syphilis. However, it is the consensus of opinion that the rate has a definite relationship to the activity of the disease. Rubin (1926) found in the majority of patients that the sedimentation rate in syphilis accelerates with the degre& of activity. Schattenberg (1932) found approximately 40 per .cent of patients with positive serology showed accelerated sedimentation rates, and in all of these be found some :form of open lesion or some form of syphilitic process. Those whose bl.cod gave a positive serological test with­ out an accelerated sedimentation rate appeared to have latent syphilis, or showed no activity.or outward ap­ pearance of the disease. M·erri tt. ( 1937) supports these views by bis findings - 36 -

that the sedimentation rate in syphilis seems to corre­ spond to the activity, and in latent syphilis a normal rate is .found. Fremming (1937) while investigating the sedimenta­ tion rate o.f 53 cases o.f cerebrospial lues .found a nor­ mal rate in only 20 per cent. These were mainly classed as paretics. The. rate was de.finitely accelerated in 50 per cent o.f the cases. A lower rate and marked changes in spinal fluid points to a more superficial .form of cerebral syphilis and constitutes a .favorable prognos­ tic sign, while a lower sedimentation rate and slight spinal .fluid changes indicates an older and more chronic process with very little possibility o.f remission after treatment with malaria. He also found that patients under malarial treatment give a Itllrked rise in sedimen­ tation reaction which occurs in different degrees. In some cases the rate .falls a.fter the .fourth or .fifth at­ tack o.f .fever in spite of continued rise in temperature. It is not known whether this is due to hepatic injury with consequent lowering of fibrin or not. The following sedimentation graphs (Bouton) clearly illustrate the varying degrees with which the sedimenta­ tion may react a.fter treatment with malarias (Illust. 3) "This patient, E.W., a muscular 41 year old white male, was admitted to the Springfield State Hospital, - 37 -

Maryland, on February 4, 1935, with general paresis. "His present illness began about two years ago with conf'usion, memory defect and grandiose delusions. "At the hospital he was kept in bed. He was rest­ less and disturbed and occasionally needed restraint. He was definitely clouded, but bis physical condition was fairly good. "The patient received malaria on February 26, but showed only a slight reaction with subsidance, so the. t be was reinoculated on Mar ch 2 9. There was no definite reaction. "on April 5, be began to have convulsions, and died on April a, exhibiting marked meningeal symptoms." The charts may also be used to show the increased rate resulting from meningeal symptoms. Westergren (1928) demonstrated that meningitic forms of cerebro­ spina.l syphilis show slight or moderately high rates. He also added that luetic aortitis, as well as gUmme.­ tous lues, is almost always associated with a moderate­ ly high sedimentation rate. I might add at this time tba t Newham (1926) found that the sedimentation rate in malaria was between 25 and 30 sm. with the Westergren technique. The effect of chemotherapy on the sedimentation rate bas not as yet been discussed in this paper. The - 38 -

SEDIMENTATION CHART Name_ _ E_ ._ w_. ______Da te 2 -2 9._-_,,3~5""----

Sed. I..__ 7_ 6 _____Tim e 1: 00 P • m • MINUTES 0 10 20 30 40 5 0 6 0 70 80 90 I

MM. 5 K -

10 ~ 15 ' \. 3) ' \ 25 [\ 30 \ 315 40 I\ ' 45 50 \ 55 ' I\ \ 60 65 I\. I'\.

'°75 '" '~ 80 ...... r--..... 85 ...... _ 90 f"-...

95

100

105

110

115

120

125

130 RBC 4 , 970, 000 __ HB 95 CI .95

WBC 4, 800 Polys 66 Lymphs 24

Berore inoculation Bnds 10 Yg. F . with malaria Myel. Monos. Eos. Bas. ~r-·

Illust. 3 .. - 38e. -

SEDIMENTATION CHART

Nam. ~__ E_. w_.______Date 2 - 2 8-_3_5____ _ Sed. J __2_5 _____ Tim e l : 30 P .m. MINUTES 0 10 20 30 40 50 60 70 80 90 I I I MM. 5 N I I I 10 ~ 15 I " I "-...... _ 20 I

2S

30 I 35

40 45

50 I 55 ! I ISO

65

70 " 80 85 ' 90

95

100

105 I

110

115

120 I 125 I 130

RBC 4 1 8001 000 __HB 87 CI . 90

WBC 10,600 Polys 87 I.ymphs 7

Malaria inoculated Ends 4 Yg.F. 1 Feb ruary 26 Myel. Monos. 1

Eos. Bas. ~fy

Illust. 3 ( cont) - 38b -

SEDIMENTATION CHART

Name_ __E_ ._w_.______~ ate~-2-_3_ 5 _ _ _ _ Sed. r __6_ 3__ _ __Ti me 12 :45 P .m. MINUTES 0 10 20 30 40 5 0 60 70 80 90 I

MM. 5 ~'" ~, 10 ~ I 15 I I ~ \ I 25 ' 30 \ 315 I\ \ ' 40 45 \. 50 "" 55 "', I "{ 60 . I ~ "' ' I '°15 '" I 80 '" '"" ...... , , 85 ' ...... 90 " 95

100

105

110

115 I m '

125 I 130 I R BC 417801000 __ H B 90 CI . 95

WBC 13,80 0 P olys 72 I ymphs 14 14 No parasites found Bnds Yg. F . in the blood Myel Monos. Eos. Bas. pf

Illust. 3 (cont) 38c

SEDIMENTATION CHART

Nam E.W. ate 3-7-35 Sed. I 90 Time 1;00 l2 .m. MINUTES 0 10 20 30 40 50 60 70 80 90 I MM. 5 i\ I \ 10 ,...__ 15 I--\ 3) I 25 \

30 \ l5 40 \ 45 ' 50 I\ \ 55 60 I\ ' 65 1\. I '\ 10 "'\

"80 ...... 85 ""' ~r---. 90 I I ...... 95 r----. ~ .....__ 100 -- 105

110

115

120

125

130 ' RBC 4 i 2l0 .2 000 __HB 50 CI . 97

WBC 16,200 Polys 81 I.ymphs 8

Bnds 9 Yg.F.

No parasites :found Myel Monos. 2 in blood Eos. Bas. ~tf-

I 11us t • 3 ( cont ) - 38d -

SEDIMENTATION CHART

Name. __E_ . -'-W'-·---~------Date~l3_--=3-=5::______

Sed. I · 36 Time lO:OOa.m. MINUTES 0 10 20 30 40 50 60 70 80 90 r---. MM. 5 ~

10 ""' ..... ,.~ . 15 ...... 3) ~ ...... 25 ~ 30 ...... r--...... lS ~.._ r--. 40 ...... 4S r--.... 50 SS I 60

65

'°75

80

85 90

95

100

105

110

115

13)

125 I 130 RBC 4l370t000 _HB 76 CI • 89

WBC 6~200 Palys 57 I.ymphs 2 8

Bnds 13 Yg. F .

First chill March 11. Myel. Monos. 2 Parasites .found in blood Eos. Bas. ~-

Illust. 3 (cont) 3 8e

SEDIMENTATION CHART

Nam._e __E_ •.-'-V'/ _.______Date 3 :-1 9 _-3_5_~--

S e d . I ··- --5 7- - - - T.ime _____ 10 : O 0 a _• m__. _ M INUTES 0 10 20 30 4 0 50 6 0 70 80 90 I M M . 5 K I " '- I 10 ' I I 15 ' \ 3)

25 i'\. JO i\.. l5 ~ 40 ~ I I 45 ~ 50 ~ "l SS ..... , 1 60 6' ' I ' 'I'...... '°'5 I 80

85 90

95

100

105

110 115 - 120 i 125

130 R BC 3 , 330 ~ 000 ._HB_7_2_ _ CI _ _l _._0_9__

WBC.__ -= l"""'0~,._7;_0..;._0__ _ P olys 70 J .ymphs 2 4

Bnd~s__ 5_ _ Yg. F.__ _ _

Para s i tes f oun d i n Myel._ _ _ Monos._~l~- t he blood Eos.___ Bas. ~~~ --

Illust . 3 ( c o n~ ) - 38f' -

SEDIMENTATION CHART Name E.W. Date 3 - 2 3_--=3-=5=------Sed. r_B_O______T ime 10: 00 a • m. MINUTES 0 10 20 30 40 50 60 70 80 90

MM. 5 ~

10 15 '"""'~ I 3) I\ 25 ' 30 \ 315 «> r\ ' \ 4S 50 I\ 55 \.

60 \ [\ 65 '\. '° '\ 75 ' 80 f' ... 85 '""' r-...... 90 """' ...... i-...... __ 95

100

105

110 115 120 I 125 I ! 130 I RBC 3, 540,000 __HB _5_2__ cr _ _ ._7_4_ _

WBC_ -..,.._l=-=3-J',._6_0"'""0-'--__Po lys._5~9~-~lymphs_,l,,,_6=--

No satisf'actory reac- Bnds 21 y g. F.__ 4.:;:__ _ tion since March 19 Myel.___ Monos ..__ _

Eos.___ Bas.~~

Illust . 3 (cont) - 38g -

SEDIMENTATION CHART

Name E.\'V . ate 3-30-3 5

Sed. I. 102 Time 10:00 a.m. M I NUT ES 0 1 0 20 3 0 4 0 50 60 70 80 90

M M. 5 r\I ' ' 10

15 \

I 2D ' I ! 25 \ ! 30 \ 35 \

40 \ 45 so ' \ SS \ I 60

65 \ ' [\ '°75 80 ' 85 I\ ' !IO I\ '\ 95 ""- f'...... 100 I ~ i--i-- 105 - . 110

115

12D

125

130 I I RBC 3 , 4 9 0, 000 ._HB 6 0 Cl_ ---.o.•....;;,.8_7_ _

WBC__ ~ l~l...... ,,_6_0~0~- -Polys 59 I ymphs 2 7

Bnds 13 Yg. F. 1

Rei n o culated March 2 9 Myel. ___ Monos.__ _

Eos.. _ _ _ Bas.~

I llust. 3 ( c ont ) - 38h -

SEDIMENTATION CHART

Name E. \111 . Date 4 - 4-35

Sed. I. 8 7 Time 10:15 a .rn. . MINUTES 0 10 20 30 40 50 60 70 80 90

MM. 5 ~ I

10 ' \ 15 \ ~ 25 ' 30 \ 35 \ «> \ 4S \ 50 I I 55 \ i 60 ' i ! 6S \ 70 ~ - - 75 ~ !'-. 80 ...... J'..... 85 i""- i--..~ 90 95

100

105

110 us 120

125 .

130 I-

RBC 3 1 4 10 ! 000 __HB 70 CI 1.03

WBC 12 , 600 Polys 7 0 l.ymphs 1 7 1 0 1 Die

Eos. Bas.~,

I llust. 3 (cont) - 39 -

following chart (.Hakansson, 1928) shows the result fol­ lowing treatment with arsphenamine and mercury.

"The primary stage with cban~e on penis and in­ guinal adenitis; Kahn 4•. Curv~ A, December 30, 1926: No treatment and has bad no fever up to this time. The diagonal curved line, with a rate of 23.5 mm. indicates considerable activity, and confirms the assumption even at this early stage the infection has spread throughout the body. Curve B, January 12; 1927: Had received three intravenous injections of arsphenamine and three of mercury. Curve C, January 25, 19271 One more injec- ticn of mercury and arsphenamine. Curve D, April 26, 1927: Further treatment, two of arsphenamine a?Xl five of mercury; Kahn 4+." (Illust. 4) The sedimentation rate in this case indicates that the tissue destruction bas been checked. Although the rate has returned to normal, one must not assume that th~ patient is cured; the patient's serology must be negative before treatment can be stopped. Hakansson observed the sedimentation rate after treatment in syphilis of long standing, and discovered that there is first an acceleration of sedimentation rate, probably indicating activity of dormant lesions.

This increased ~elocity may be in the nature of a Herx­ heimer reaction, and as more treatment is given the - 40 - CUTLER BLOOD SEDirviENTATION TEST b .me Dc:':;o Dec. 30 1. ~ 6 AJdre s a.... ______. .. _ .. -- - __, . .,._...... , ,,..... "' ! ~ ·-*- ---- Di.ctg:i: .. c~· i '3 -~.Ph~l1. $~, ... .; . [Jiwm:· GRAPH Corresponding Clinical I I-S od~~ -~!l~-- -!--;~~~~~i.:. ,~·---- - i Condition I Hor-:L:ronta.l Lin( Normal or Absolute Index _ I T 5.m.G Qu:tescenco ___MI.I , Ein, Diagonal ·Lif.ne Quiescence I Diagonal Curire Slightly or moderntely o.ctivc Vertical ClU-ve Mode rately or markedly uct:tve +--______...... ,, __ ...... , ______+------""------· , Sed. ·.in TI1ffi IN 1.IIHLTTES I MNi.-~----'.-.,._.-...... -----~ , · . [ 1 ; j • --;Inr.:. <:: ·;~: 0 5 110 15 aJ ! 25 3J ! 3:5 !40 '-!-5 ; f.)0 1 5~ ,._ () ' l : i---1 ---r ..-~---t ·;---·- -1--··- ·· ·------·-;-···-.' Q ~l - ...... ----+----+-----1,-- i --;--·--'-,. - ---r-~·-t-· -· -·-· -+ --- - ·· -: ---:-: 0 I ' • ....+--- -~---- ~ --+· --,-1-·-1- · -· 1 ·--·!----- .) ~ :.:-- - - : ; l -- ____ .i ·-+- --i - -·-+---·-J-·------j .. i=:::___ ~-~ -- - --~:;-....:. ::. -·;::-_: .. +---···-!--- '".:- · - ·~:::~~~ .;:::-..:...:. D -~ L - · - ~ --- .-l ...... j... •• " ••. 1- ·- ··+ . - --j +----t---+---...... ~~...... ---i .... ·- -1--..·- - -r : -· L1·····-- ·-,..~ · ··· - -.-· --....+- .. _ -: ..."- ...... io---+----+--, ~ ...... ~- --t-----r--·- ·-· - . . - ----·· t . ··- t- . -- ...... ·-· --1 1 ...... ·+-· ··--1-... -·-;--·-----+·-; . :..... -- . r· ~- --11 I ----f . -··-·· .,__...__ _.., _ _...... __,, ...... _ """".,....-.+ .... ~- - __..._, . - !-I -·· ------. +--· ·-- . . • ---·--.' C +--_....,.._ _.., __...... ,_ ...... __ _ - ---r--- }---'--- - -~ -·- - +--··-·· · 1 ·· ----~ ---t . lO --·1 ·· --1L---i---~· · --·+-- · r------~ -· - - BJ.Q_j .,.__,..__.....,.__ .,._ _ _...., __""{·- · -· ·- -r----r- - - ~- ·- --r---·-;· ----+---r- ----·-1-·: I ...·--~- ...... ---+--~---;', - --+ · ·--t-- - +-- - c' ~ · - ----1 - --- ! -- --~· · - ·--t I ~ --r-· - - ---!--- ·- .. _ __ J._ --1-~---+·------, ------, ·--+-~ - ----~------·- ·-·r·- - ·· l-··- ·l---- r--1-----; ! • ·-t----t· ---+- ·-·-r ··-·--··r-·--·:--•-••y •• - ---~i .. - -·---, I 1! --·-+ ·-·--r·-- --+---· f-·-···-·r·--- --·-t···-----.1:---r-·---- 1' +---+·--+---+-----t--±1- ·-:1-r--r-·------i •· ··-y-·--·-·i ---··->··r----l t-:-+->-~1------+------,..· -----1- .. --- . · - -··-t ·--·- -t •"'·-.. --'1 m· ------r-----..------. - ·· -·+-- --±·- -- ~- - J..------___, I ...... --+ ! -. -+-~------. 1. _ _ . ; · -~·-·:-·r --:-- I --1---· j 20 -~ 1 •• --~~ -:±_ ·----;-.. - r·- - l --T·---~-,--- - -·- I ~....,...... ,1--...... --+---+---+ ·--t·- --.·--+--1- _, ___ ---! _..... ___ I ,, -"--j·--·r----I-+- --~+---- -,~- -t· '· - .:.::--· A f --·-'-·--·- - --· ·---r-- · ·r- · -·r- · ·~-,-- -~ - I -, ---,..._ ____. ·--+----+-- ' --- ~ --·-r---r- c•---r ---+-- - l t--·r---t--"'*'-+-!---+---+-- -.------'--· ·-- ·:- --·---r----1-··--.-+--·--· i -----'·---···.... :__ ....., , --+---·- -1------+- · - - + · ~--- -l-- - ·-· · ·-- - · ---- +------I ---+------'---t·--+-- ---r--..-·-·t----'----1..__ .1.. _ __ :so i +----+-t,------r---+-·-·_,______-4-:=r=-. - --+-r' r--· }l -1-·- -- r----. ~o +-- . .--L_ -!------!---+--- ____.,. ~ r------I t-----i----1--· 4- --t - - ·:j - I t-·- 1 r 1 M~-t---,---,-=i- · -- I ' --4- I I ; --+---+----r I -- 1" - · '--- -=±--·- -- ~-r--~.---t *' --1--r- ·---t--~---· ~- - ~ i _ ------L I -=±-+-----r-·::-1 --- .___ ,..___ I : : I [ __.... 1_ _:-_-:_-_-_-_-_-_.... I I I I l I I Illust. 4 - 41 -

sedimentation rate will be brought back to normal.

PNEUMONIA AND COMPLICATIONS

Gallagher (1934) while studying such illnesses as bronchopneumonia found the test to be an aid particu­ larly in those individuals whose cough persists and whose convalescence is slow. In those patients a steady decrease in the sedimentation rate gives one assurance that the trouble is gradually subsiding, or a continued acceleration will compel. one to investigate more care­ fully for some complication. · Lesser and Goldberger ( 1935) in taking fl ve week­ ly readings in each of 60 cases revealed a definite prognosis in the course of the disease. The acute full­ bl.own case o:f pneumonia, regardless of type,· showed an average reading of 80 to 100 mm. ·per hour with the Wes­ tergren technique, and with beginning resolutions and convalescence the study of the patients showed a grad­ ual decrease in sedimentation readings. With the onset of complications, such as pleurisy, empyema or peri­ cardi,tis, a sudden sharp acceleration in sedimentation rate was noted. Nungester, (,1937) exper1ment1ng with type three strain.of pneumonoccus, prepared a specific polysac­ cbaride, and found that this material accelerated the - 42 - sedimentation rate, and followed this up by saying that an abnormally high rate is found in the disease. Illustration No. 5 (Hakansson) is a graphic repre­ sentation of four sedimentation tests taken .from a case of typical lobar pneumonia which terminated by crisis and the convalescence was without complications. "Graph A, taken January 9, 1927. Onset 5 days prior. Consol- idation of right lower lobe; temperature 104.6 degrees; white blood count., 18,000. B, January 12, 1927, crisis began 12 hours ago; temperature 99.2 degrees; white blood count, 9,ooo. C, January 17, 1927, temperature normal for 2 days; lungs clear. D, February 12, 1927, recovered•" In these graphs one can readily note a parallel between the sedimentation rate and the other clinical findings upon which the condition and progress of the patient is usually based.

ARTHRITIS

Boots (1930)-bas written an excellent article ex­ plaining the formation of the various classifications of arthritis, which is quoted in parts "The study of chronic multiple arthritis has demonstrated the exis­ tence of two separate and distinct disease processes which are conveniently grouped under the general title. The first of these represents a multiple arthritis with ,. .'. ,"•· 43 - CUTLER BLOOD SEDIMENTATION TEST \Jd'1~ree ...... s__ _ ----~--~------~~- - - -·- ·· - ··----·--·I-·- -··---·· pfilillr· GRAPH Corresponding Clinicul I' ~ :k· ' l I Condition sod i r.i')11" Jc(:. . l 9 I' r.1 • Ho!'izonto.l Linc Normal or Absolute Index .L J.n ...G Quiescence J.!iE Diagonal 'Une Quiescence MI:I. Diagonal Curv-e Slightly or moderately o.ctivc Vertico.1 Curve Moderatclf or markedly ac.t .ve . . , S(}d• ·.1n TIME IN I.a ~>JUT ES SeC..o MM. T-----:- · 1 ' · : · j . -Inde>e , . o 5 ;10 15 ID .2 L.: 3 J-+ -~~-)---+-.Li~~-f -!-5 - f-, ~- -±L_2~---r-···-~!L . +.---.' ..: 0 ~--t----+--...... ---t---+----r ---·+----··- --r--,----··-· .· ·-·-j·-- -·- -• I ---.,..... ·--f.--..L_l_ -i··--·-· --1 -· -··- ···.+-----· ·.L...Q __ ..__i ~ · . _ 1 ...L---+--- --i - .J.--. -.---- . _1 I . - ·-r· "...... !--- ... .;_ -: . I •. . 1-- - - -·I ,. -- ...... _. ____ -r...... -.. -t·--····.J·-··· ...,+ ...... - .•. • !... ·- --·--· ""' ...... l-. -+- I . ··r-· l. - - 4-·· ·-- --4- --~._.,j I J ' ' I --- -- · --t-·-- ·----·r··- _,...... ~.--t~ · - · ....I.... · · ·-·-1 n 1 ''\." I . " '{ - . .. i_. - -·-- .;-. l_ -I -····J--··--f- ••··- t•• ·•- ·--+••• -- ·--! !' .,_._...,._,...._ _....,_oir---t-·-.....!---. ---r·-· - - .·- ··- - - ... . ·- ·' ...... -·- ·· ,;.... --·· +. ·--- --I ....._....., _ _,.. ___, ___ "-..... -r-·-·+·~· ·- ·...... - ·.L. . •- ---- .· ··--·- -+--·-- ··~-- ·-· ·t----·---~ 10 t---+--...,_.-.....~--"~,...- - -+ · · - --t- -t---;-- -+.--- .. ······-r-··---1------·-; lC l ,....___,._...... ,._...,.__...... ___.v---·i-·--·l---1- · - -r ---i---·

additional evidence of a generalized tissue response to an infectious process; the second, a degenerative process involving the joint structures and appearing at the time of life when other degenerative changes are prone to occur. The existence of these two clini­ cal entities is clea,rly recognized, but the obscurity surrounding their etiology, l:Es precluded the adoption of an adequate and generally accepted terminology. "The terminology most generally accepted in America is either one of the following: I Chronic infectious arthritis II Degenerative Arthritis

I Atrophic arthritis II Hyperthropbi c arthritis

"The classification adopted by the British Minis­ try of Health is as follows: I Rheumatoid arthritis II Osteoarthritis" Stainsby, (1933) while working in conjunction with Nicholls, after running sedimentation tests on 597 patients with atrophic arthritis found the test to be a reliable criterion in gauging the activity of an artbri tic process, and would indicate any change in the clinical picture. stainsby (1934) mentions the fact - 45 -

that the temperature, although not .elevated, and the leukocytic count within normal limit.a, the patient •s symptoms are not a reliable.. index of the activity or progres.s of the disease, as· they are readily influenced •by climatic ccnditions, rest. and exercise. He goes f'urther by adding that even specialists in this field are many times deceived, as some of the most severe. cases m ve few clinical signs such as swelling and tenderness. Three questions are asked by him whicq can be answered by the sedimentation test:· "Is the disease active? How active is it? Is the pitient improving or getting worse under the treatment administered to him?" He classifies the results of treatments as follows: A sedimentation rate near normal means the case is inac­ tive; if the rate is above normal, the disease is active; a decreasing rate indicates a .favprable response to treatment. Another investigator (Weiss, 1931) while studying 150 cases of atrophic arthritis found the sedimentation rate to be accelerated in this disease, and it did not return to normal with the disappearance of the arthritic symptoms. Three to five per cent of his cases did not show a normal rate for three to seven weeks af_ter the patient was free of clinical symptoms. .He points out that in his patients be did not find the severity of - 46 -

the joint inversely proportional to the sedimentation rate. Kling (1932). conducted a series of very interest­ ing experiments by removing the synovial fluid from arthritic joints and placing red blood cells in this fluid. He did a sedimentation test with this mixture, and compared the readings ~1th a sedimentation test of the true blood of the same patient. In synovial fluids from an infected joint there is an increased fibrinogen. Those which a re not infected, are non­ inflammatory, have a low protein content and have a low comparative sedimentation index and a low viscosity. This was also the case in transudates. On the other band, it was found that nuids with a high content of mucin showed a low comparative sedimentation index but a high velocity. He demonstrated tba t the severity of the infection of the joint is indi ca tad by the sedi~ manta tion curve in the synovial fluid. The general reaction is found in the blood curve. Using a compar­ ative sedimentation test. in monarticular arthritis, a high increase in the blood sedimentation rate is found and a low rate in the synovial bluid, which indicates a foci· of infection outside of the joint as .the etio­ logical factor. The same may be used in polyarthritis. Kling is of the opinion tl:&t this may be a valuable - 46 -

the joint inversely proportional to the sedimentation rate. Kling (1932) conducted a series of very interest­ ing experiments by removing the synovial fluid from arthritic joints and placing red blood cells in this fluid. He did a sedimentation test with this mixture, and compared the readings ~ith a sedimentation test of the true blood of the same patient. In synovial fluids from an infected joint there is an increased fibrinogen. Those which a re not infected, are non­ inflammatory, be.ve a low protein content and have a low comparative sedimentation index and a low viscosity. This was also the case in transudates. On the other hand, it was found that nuids with a high content of mucin sbowed a low comparative sedimentation index but a high velocity. He demonstrated that the sever! ty of the infection of the joint is indi ca tad by the sedi­ mentation curve in the synovial fluid. The general reaction 1 s found in the blood curve. Using a compar­ ative sedimentation test. in monarticular arthritis, a high increase in the blood sedimentation rate is found and a low rate in the synovial bluid, which indicates a foci of infection outside of the joint as .the etio­ logical factor. The same may be used in polyarthritis. Kling is of the opinion tm t this may be a valuable ,..---·····

- 47 -

aid in differentiating the atrophic type from the hy­ pertrophic type of chronic arthritis, and that the underlying process can more accurately be diagnosed by the.comparative sedimentation test. Various authors (Merritt 1927, Oppel 1933, Keefer 1934, Stainsby 1934, Hirsh 1936, Lautmann 1937) agree with the following statements:

1. Active cases of atrophic arthritis usu~lly give accelerated sedimentation readings of 30 mm. or over in one hour (Westergren technique). 2. A relationship usually exists between the activ­ ity and the extant of the disease. 3. Increase in symptoms almost without fail causes an acceleration in sedimentation rate, and remissions a retards. ti on. 4. In arrested cases the sedimentation rate is inclined to remain normal. Short, Dienes and Bauer (1937) comparing the

Varnes• resorcinal test, Schilli~g cotm.t and strepto­

coccus agglutination and sedimentation rate in 49 pa­ tients to determine the degree of activity of the dis­ ease in atrophic arthritis. They found the sedimentation rate positive in 92.2 per cent of the cases, the Schil­

ling count in 87 per cent, and the remaining in 50 per cent. - 48 -

Oppel (1933) and Keefer (1934) agree that patients with gonococcal arthritis invariably have an increased sedimentation ra ta. They find the examination is of no specific diagnostic value in these cases, but both are of the opinion that it is of great value in showing the clinical course o:f the active infection. The relationship which exists between bacterial activities and chronic arthritis still requires con­ siderable study. Regardless of the type of artbri tis, some time during the disease evidence of bacterial in­ vasion can usually be found. In the atrophic arthritis bacteria are usually believed to be the outstanding etiological factor. On the other hand, hypertrophic arthritis is usually regarded as due to senility, wear and tear and metabolic disturbances. (Lautmann, 1937). Westergren (1928) finds no increase in hypertrophic arthritis, osteochondri tis and Perthes' disease. He also finds that the sedimentation re. te is often increased before the temperature, and its chief importance lies in its ability as an indiea tor of the intensity of the disease. Others {Dawson 1929, Oppel 1933, Merritt 1937) are in agreement with Westergren on the following: 1. In cases of hypertropbic arthritis the sedimen­ tation rate as a rule is slightly elevated but rarely attains a greater value than 30 mm. in one hour. - 49 -

Boots {1929,, 1930) observed that all cases of non-articular rheumatism such as myos1t1s,, fibrositis,, neuritis,, showed normal or only slightly elevated sedimentation rates. The following chart is an illustration of the patient,, Mrs. O.E.J.,, who entered the Clarkson Memo­ rial Hospital October 14,, 1937,, suffering from chronic arthritis,, which at times would assume an almost acute form. The patient was diagnosed by the committee on arthritis as a very active form of hypertrophic arth­ ritis. This patient received seven treatments in Kettering hypertherm. (Illust. 6)

RHEUMATIC FEVER

Rheumatic fever bas a variety of names: acute rheumatic fever,, acute articular rheumatism,, acute rheumatism,, and polyarthritis rheumatica. The etiol­ ogy of the disease is probably infectious,, and seems to be closely rela tad to an invas1 on of the body by hemolytic streptococci,, and is characterized by febrile and toxic states. It also invades the synovial cavi­ ties and joints,, and may produce in the cardiovascular system and joints numerous disseminated focal inflamma­ tory lesions. Rest,, relief of pain,, well-regulated diet, and convalescence,, are the chief therapeutic in- .. . - ·so .-:·

CUTLER BLOOD SEDDv!ENTATION TEST i~e O. E. J, De. t;c .. .2~~~eE-.~4.J. .... 1. ~i._3.1 .. Udres ---- DL:tgJ·.. oe l -------· - ·-4£J; trri_ . J._~ .. J~ · GRAPH Corresponding Clinical , Condition Sodim

in ~ :;.rr~~JTES Se d • •. TIME IN >''"'e,.:i> '-·· · MN~ ------'--,.------.....------....,....------.---"'t'----In<.'~ €· X: : I 0 5 ! 10 15 @ !. 25 ! 3·J-+ .~ ~---P,-0-·~ -!.5-i_5 ~. --iL..--2~ -!- -- ~~~~#- ~- --:'~ -----+---+---+-----+----+,---+-----+·- ·.. -r---r·-~- 1 --·---+ ------~ 1 I O l -· ; -!,_ ___ t___ L __ --f··---·-t-- ·---t- · - ···-~---~L__Q ____, -...... "-- ~ --1-·· .. 1 -·- --~---· - +----1- - ---t·- · ___, - .·-. -~ ·- _1 I ._ ...... ·c.. ·---·-· - ·- · r ------t--·---+-- - -r------i ----+·- --·---·! I "'""' --...... -.::.- " - --"'1- ··-·-.. ,--·-··· - - "-t··- - ·· ·······- --~-- ____ _..., ___ ··- ·-· - -· I - . - !_. . -~ --- -~ - - ~- - · -+· - -- ·r ·- -- -4·- ____, "'-I"".. -...... · - _.)·---· ~---:::::-::: i ... - -f .... --·-l--·-·-- - - ~ ·- ·-- .. -~ I ~' - I ·-·-4-·- . l _ •. i "-·- +••• ·- _...:., j +-_...... _ _..,_.~~+rx....'"'r'-_,._, __ ..J.... -- ..... - -'·---·- · ••.•. ••• ·-- . • ;... . "· ·-· _._ , t---...---+---~':--"-~+'--- -·r .. - . -t- i_ _ __ L_ __ ·-t --- . ·:-- - ·M- r3-15-Vl7 ...... , , ! I • I Tl r.I _'1f111 ,...___....,_._....,.__ ,.._""',-~"\.. . - -i-·- 1 .---r-·-r ·-- ·· t-·"- ·;-··----l..u.J.0....,1 ljoiiilO.._+---+---t---+----· ;i...... ,~~~,· · 1--~ ---t---T · ·--r· - ;·-·-·-+·-- ·. ~ -- ---r- -··-· w ~ . '- 'l--·-:t---r-·-r- - ·1 ·-·· .- ·--r--f--==t ------...."~: -....-.. - r-·-r-·- ·+·-r····- ·; - - ·-J"'... --1 I .___....,__-+---...... --+-- - '"''{-+ -, ---, - - - ~ - ·r--:-·--.- ···- .-·---- ; , l · - · -f-~-- -f--·- · ···-t- --.. ~ -- ··-; - ---+-- ,· -...... ·]2 I ' I f - -·· ---+---·-r----.·f--_j-··-· ...:- ·· ---·~ t· - - ...-...... ; -14-37 . ·------t - :.. --+ ··- ··--i- --··· \~-.. . ·------r-·-- : ------+--~ · - -- ' - · .,.-· -~-{- - .. --iL ___ .J ·--..· - r--- l I - ---1·--±--· -+· -·-- ·-- .. - - :·-- - - · --~-t - .. ·• -ll."'6-37 1 ar r-- - ~- _..___-r __ : --=--,_.- -::_·:_ t:,- _J~- --- ~~- · 20 1 ! • , · g= · i I ! 1 • - • ..--..:i _...... r - ... --r-- --·- I • . • ' ' f l __ ~ . l r-- . .. .. _ --;----' ~ - - · ::-i · ·------·-- ~ t-· T . ---··L----1---' : +-- -.. -;,-- . .--=:-! ---- -' ..--- i i ' L.- ---L--+---+---- -.· - -·J..·-=r_ -·-~0-1 . i ~-=r= .I ~t~-=l=--=l=-1.-~c-::.:.±=:·:.·±:_:_~=-~+==-: l ·- ,,I. ·--+----·-+- - --+-· ---+-·~ - - ··'-- ~ - ~- ; .. ' - ·· - -·-··+"·... -- 1· It------+ --- '-··---. - --+-·-t··---r-- .--· - t------·-.. - ----1._ _ __i... __ 30 ~ 1::-E- I. _-+=- ·-r-.... J + · Ee·=~-=--!-==±=·--- ~o · +--· ---i-..--L - --l--- --t----i---1----· t--- .. -~ : ~-1...--+-- -·-r---+.. - ---i------1 '--- I _..._____ --,------l----· -- l· I l I ' - -t-.....--oy·--+--J_ ___ , • I l I I I I I ~ -- j -~--.-' . i - 1---.I ------+-' ·-·-·-· :::::.· -_--__-----:---;- ·--=± : __:: ~ f-~ ·=F-t--- - t t t I f- I J I Illust 6. ~------~-~---~------~--_...--~--~~~---~--~----~~~~~----~·--- - 51 -

dications. It bas been stated that during the period of convalescence extreme caution must be exercised, and that the rate of recovery is roughly proportional to t~e length of the illness. Before the use of the . sedimentation test the patient was required to remain in bed until free from fever and other signs of inf ec­ t ion for two or three weeks without the influence of salicylates. The white blood co'lm.t must ·have returned to normal, the heart rate must be fairly slow, and the patient must have regained his normal weight.(Cecil, Third Edition). There exists a close relationship between the clin­ ical .findings and the sedimentation rate, and almost every variation in the curves will show a corresponding clinical change during the disease. The most practical use o.f the test lies in its value as an indicator of the patient's progress, and will decide for tbe physician the course of treatment to follow.(Payne, 1932). Lesser and Goldberger (1935) studied 40 cases and averaged five readings to the ease. During acute clin­ ical stages, the average readings were 90 to 100 mm. per hour (Westergren technique). They took weekly readings of the ·cases which gave a prognostic indication as to the course in these febrile conditions. For example, with a regression of joint symptoms, a normal white count - 52 -

and temperature, the sedimentation rate was definitely decreased. On the other band, with an increase in car­ dia e or joint symptoms, the rate persistently remained above normal.' Other investigators, (Mossell and Dueket~, 1936) after studying 178 cases, came to the same conclu­ sions as Lesser and Goldberger, but went further and compared the white count to the sedimentation test as indicators of the course of the disease, and folmd a close relationship between the two. British investigators (Bach and Hill, 1932) stressed that in a clinical picture of active juV'enile rheumatism the sedimentation rate was decidedly increased, or when it is a quiescent rheumatism or rheumatic heart disease without any signs of activity the rate was wLtbin the range of normality. In children with a sedimentation rate of' 11 to 21 (West.ergren technique) or over without the usual clinical signs of activity, the active disease should be suspected. Mer~itt (1937) concurs by stating that in order to prevent a convalescent juvenile patient from ·getting out of bed too soon, the sediment.a tion rate should be the deciding factor in establishing whether the child should remain in bed or not. Stainsby (1934) bas a similar opinion, tl:lit a case should not be con­ sidered inactive until the leukocyte count, temperature chart, and.sedimentation tests are normal. - 53 -

White (1937) is in agreement that there is an al­ most direct correlation between the activity of the dis­ ease and, the sedimentation rate, and that this may be the only indicator as to the extent of the infection. Others (Hench, 1934) have confirmed the work of Payne, and Bach and Hill on the value of the test in determining the difference between an improvement due to the abating of the disease or a false one due to such antipyretic drugs as salicylates. An article on this subject (Hench) is quoted in part: "The rate is elevated in rheumatic fever and rheumatic carditis; it varies with the activi;ty of the disease and affords one of the most delicate gauges of activity. It is normal in cases of uncomplicated chorea. However, it is accelerated in cases of chorea with cardi­ tis, and chlnges occur even before carditis is distin­ guishable. Because uncomplicated chorea is associated with a normal rate, Elgehammer suggested that it may not be a true rheumatic lesion, and Warner suggested that chorea was not an infective process although associated carditis is. According to Struthers and Bacal and to Perry the rate returns to normal or goes to less than normal with the onset of cardiac failure with edema, a sign of bad impart. Elgehammer stated that when the rate increases after removal of foci of infection he suspects - 54 -

reactivation of the infection." Lyon (1935) states the prevention of disability from rheumatic heart disease lies in the early detection of the presence of the rheumatic infection and of its sub­ sequent periods of activity. The heart in childhood is especially susceptible to rheumatic infection. If the infection in its early stages goes unrecognlz ed and un­ treated, cardiac incompetency may develop. The following chart, illustration No. 7, ls a graphic presentation of the sedimentation curves, showing the pro­ gress of a patient during and following treatment: C.T., a white male, age 12, entered the Clarkson Memorial Hos­ pital April 21, 1937, and was diagnosed as having rheumatic fever with rheumatic endocarditls and associated chorea. On the day of admittance the patient received three hours of fever therapy. He received five treatments, totaling fifteen hours, at temperatures of 104 to 109 degrees F. The last treatment was May 1, 1937. The treatments were .well tolerated, and there were no complications. During treatment the patient showed very little change in sedi­ mentation rate, but had remarked of subjective improve­ ment. During treatment there was a marked improvement in objective findings in the knees and ankles. On dis­ missal the patient bad no involuntary movements; the heart had only a slight systolic murmur after exercise - 55 -

with occasional rhythm changes.

CARDIA. C LESIONS

The first condition to be discussed will be coro­ nary occlusion, also known as coronary thrombosis and cardiac infarction. Angina pectoris, which is also called stenocardia and breast pang, will also be taken into consideration. Coronary occlusion is defined as an obstruction, usually acute, of one ·of the branches of the coronary arteries resulting in an infa.rction and dea.tb of the heart muscle supplied by the occluded vessel.(Cecil).

Angina pect~ris is not defined as a disease in the true sense of the word, but as a clinical syndrome which is characterized by paroxysmal attacks of pectoral or precordial pain, syncope, and a sensation of intense anxiety. (Cecil). Riseman ( 1937) pointed out that the sedimentation test is frequently a help in differentiating between coronary thrombosis and severe paroxysms of angina pectoris. He finds this especially true when the pa­ tient is seen for the first time several days following an attack, and under such adverse conditions it may be impossible to ascertain whether the fever, white count, ,or changes in the electrocardiogram have taken place. - 56 - ......

CUTLER BLOOD SEDIMENTATION TEST h me _ _ c . T . - ·- - Da.to. ..P ~J?...ril _g_! ...... ~ ··-· l. '}, _~_'l_ \·ldress..__Q_+,gkson HosQitaJ, Di. ne;r ·.O el ·'3 _ R,b .fH?.-~ .:t.i c. .. .t: e.v er ~------~!.~h..Jpqoc~ygJJii,» -~. chorea 1J I:IEalr GRAPH Corre s ponding Clin ical 1 j ., "'(0 ·1 1·11 '.,~ Con d ition Sod i rrv~.:.1 ~ > •.•)" I..-·~ .I l9 HoN.zontnl Lin Norm.al or Abso lute Inde x I T!.n!G Quiescence MI.I. p ; r . DingonaJ. ·'Line Quiescence ---- ··-- !~ --- I Diagonal Curve Slightly or moderately a ctive Vertical Cu:Mre Mode rately or markedly ac.ti ve

Sed. ·.1n TIME I N i.IINUTES I 11M.--~---...--_,...... _.--~..--~ 0 5 : 10 15

0

10

; t-, 20

4-26-1~ 4-2 ' 5-1 4-2~ 4-2l r-- , ... I

,,_ '- 0 I 0 I_ +---· r--- - j-· - I I ....__ =!= . I

~- - ,...-- ;.....__, -+

Illust . 7 - 57 -

A persistently normal or only slightly accelerated sedi­ mentation rate between the fourth and twelfth day after the attack is strong evidence that there has been no myocardial infarction. Conversely, a marked a coelera­ tion in rate, especially if it shows progressive changes from day to day, may be a distinct aid in establishing the diagnosis of coronary oc_clusion. They believe the test to be of little value in foretelling the outcome of the disease, but found that the period during which the sedimentation rate is most rapid corresponded to the period.when the maximal myocardial softening occurs. The period of recovery and healing was accompanied by a retarded rate. The mortality of the patients who were discmrged from the hospital with accelerated sedimenta­ tion rates more than doubled those discharged with low rates. In the past the gauge for determining convalescence has been the absence of an increased white count, the return of the blood pressure to normal or thereabout, and the disappearance of abnormalities in the electro­ cardiogram, but this was not necessarily a proof that the lesion had healed and that the patient was ready to assume a normal mOd.e of living. In the event the patient gives a history of angina pectoris which has occurred several days prior to his examination, one should be - 58 -

suspicious of a recent coronary artery thrombosis. The temperature and blood count are usually normal in such cases, and the electrocardiogram is indefinite. In cases of this type the sedimentation test is a valuable aid in differentiating between coronary thrombosis and angina pectoris. (Biern., 1937). Hoffman (1936) does not entirely agree with Biern, as he feels that the degree of accelerated rate is no indication of the severity of the injury, and although a return of the rate to normal usually means healing of the infarction, this is not invariably true. Shookhoff, Douglas and Rabinowitz (1936) using the Linzenmeier technique, made a study of twenty-nine cases of acute coronary thrombosis. All diagnoses were con­ firmed by electrocardiogram. Nine patients died, post- mortem was obtained on five of the patients, which con­ firmed the diagnoses. The sedimentation rates were bel9W 60 minutes except one the fifth day, and the one case was abnormal after the end of the first week. In two cases the temperature and leukocyte count were normal throughout, while the sedimentation rates were abnormal. The major! ty of patients showed a fever and leukocytosis the first few days; during this time the sedimentation rate was normal. Toward the end of the first week the temperature and leukocyte count returned to normal while - 59 -

the sedimentation rate·was definitely abnormal. This enables one to gauge the rapidity of h ea.ling. Hottman agrees with Shookhoff that in the majority of cases the leukocyte count and the temperature rises before the sedimentation rate. Therefore, in the first few days following the occlusion its diagnostic importance does not rank with the temperature and white cell count. Its real value lies in the fact that it usually persists for a much longer period than either of the above men­ tioned factors, which are often quite brief in duration and are occasionally absent. Wood (1936) studied 22 cases of congestive heart failure, 21 of which were treated with salyrgan, and the sedimentation rate was measured at intervals after admis­ sion. He noted. in all instances except one that the rate in congestive heart failure was slower than when the cardiac efficiency bad been restored. In some instances the rates were fast. These were diagnosed as rheumatic cardi tis. Wood gives a clihi cal picture of a girl, age 16, who bad rheumatic carditis. The initial sedimenta­ tion rate was 96 mm. in one hour (Weatergren technique). Three weeks later it returned to 18 mm. in one hour. A.t this tipie this was believed to show improvement. A. week later signs of congestive failure appeared. The body weight increased as edema aecummulated and the sedimenta- - 60 -

tion rate slowed to 10 mm. in one hour. The patient was at this time critically ill. She showed a sudden rally, and when all signs of eariac failure bad dis­ appeared the sedimentation rate was found to be 89 mm. in one hour, almost its initial level. Immediately following a steady improvement took place; she bad lost her edema and showed a natural_ gain in body weight, and the sedimentation rate was finally 15 mm. in one hour, showing a true improvement. It must be noted that the sedimentation rate bad slowed before there was any evi­ dence (clinical) of congestive heart failure. In addition to the above, the sedimentation test may be an aid in differentiating between old rheumatic valvular disease, atherosclerosis, and syphilitic aortitis. It is norm.al in the first two, and increased in the la.st. Rapid rates may indicate a guarded prog­ nosis in cases of syphilitic aortitis. He agrees with Hakannson (1928) tlE.t antiluetic treatment decreases the rate of blood sedimentation, and may be used in fol­ lowing the progress of the case. Malignant hypertension is associated with an in­ creased sedimentation rate which may be due to the degree of renal impairment. Angina pectoris is associated with a normal sedimentation rate. The writer believes that as long as the sedimentatim - 61 -

rate re.mains accelerated there is an absorption of pro­ ducts of heart muscle degeneration, and that healing is completed when the rate has returned to normal. The observations of Wood that the sedimentation rate decreases with the onset of myocardial failure must also be kept in mind. Goldbloom and Libin (1935) attempt to explain the cause of most sedimentation rate retardations in conges­ tive heart failure by the fact that the circulating blood volume is increased in polycythemia, essential hyperten­

sion,, left ventri cula.r failure,, chronic disease o:f the coronary arteries,, and mitral valve disease.

MALIGNANT DISEASE

The value of the sedimentation rate as a diagnostic and prognostic test of neoplasms l:::Bs been studied by

many investigators. It is the consensus o:f opinion that the test possesses considerable value if the results are correlated with the balance of the clinical picture.

However, one must always keep in mind the limitations o:f

the test, and above all r~member that the test is non­ specific. Rubin (1927) studied the sedimentation reaction in 127 patients with diseases of neoplastic origin. In the study of carcinoma .of the breast, all sedimentation read- - 62 -

ings were high. The sedimentation rate was found to accelerate with the growth of the tumor, and was even higher when weakness, anemia, loss of weight, body pains and occasionally fever were present due to toxic action of malignant cells. All cases in wbich metastasis bad taken place, the readings were found exceedingly high. There was no correlation between tempera tu.re and sedi- mentation rate. Similar results were obtained with carcinoma of the esophagus, of the rectum, and of the stomach. It was mentioned that there might be a low sedimentation rate in cancer of the esophagus due to an increased blood concentration -which seems to develop in these cases. It was observed that cacbectic individuals tend to have a retarded rate. The test was found to have little value in differential diagnosis. Repeated tests, however, were found to be valuable in prognosis and the severity of the disease was in proportion to the accelerated rate. Rosenthall (1928) in the study of 18 cases of new growth, accompanied by a complete or non-obstructive jaundice, all diagnoses were confirmed by autopsy, X-ray, or biopsy during operation, and the sedimentation rate was accelerated in all but two cases, and one of these had polycythemia. His results agree with Rubin. Nitscbmann (1927) does not agree with Rubin on the , - 63 -

use of the test in differentiating between benign and malignant tumors. However, be feels that this is a method of differentiating between benign and malignant tumors of the female genital organs. Reichel (1936) and other investigators (Rubin 1926-27, Biern 1934, Miller 1935, Hirsh 1936, Merritt 1937) are of the same opinion, that the acceleration which is brought about by neoplasia is evidently not a reaction to the tumor as such but likely to the pro­ duct of cell deaths, for both malignant and benign growths are accompanied by increased rates once they have become necrotic or infected.- Small tumors, ac­ cordingly, are apt to be without influence, accelera­ tion being an indication of tissue destruction. Reichel limits his material to tumors which have been proved malignant by operation or autopsy, and found the rate increased in 90 per cent of 76 patients with such neoplasms at one site or another. Therefore, in a doubtful diagnosis, a normal rate strongly sug­ gests the absence of malignant disease. Blem (1934) agrees with Reichel (1936) and Schiller (Biern 1934, Hirsh 1936) that the sedimenta- tion rate accelerates after irradiation, which is probably due to the decomposition of the tumor with a resulting increase of the amount of foreign protein in - 64 -

the blood. Schiller and Reichel .find that a.fter rad!- cal operation tbe ~edimentation rate should return to normal within .four to eight weeks. It will be noted the. t a sedimentation increase is .found a .rter any surgi­ cal intervention, which continues until all inflamma­ tory exudate, necrotic material or blood bas been ab­ sorbed, and a rate that does not return to.normal with­ in six months after the removal of a tumor is a sign either of incomplete extirpation or a secondary recur­ rence. Witb the extension of the neoplasm by metas­ tasis the sedimentation rate gradually accelerates and this generally occurs before there is any clinical evi­ dence of a recurrence. This may be used as a guide by the radiologist as an index to therapy. The foregoing evidence clearly points out that the diagnostic value of the sedimentaticn test can be of only secondary importance. The primary value lies in its use as a gauge of the patient's clinical condition and the severity of the disease •. Repeated te~ts are very valuable in determining the prognosis.

OBSTETRICS, GYNECOLOGY, MEDICAL AND SURGICAL CONSIDERATIONS

Since Fahraeus (1929) ran sedimentation tests on 1 the blood of pregnant women in an attempt to diagnose - 65 -

pregnancy, much work bas been done on the subject, but it is now generally agreed that the test is non•specific in pregnancy but merely indicates the destructive meta­ morphosis of the fetus. Many agree (Biern, 1934, Lesser 1935, Grodinski

19331 Falta 1927, Ringer 1934) that from the second to the fourth month of pregnancy there is a low graded acceleration in sedimentation rate up to term. Illus­ tration 8 shows tbe effect of pregnancy on the sedimen­ tation rate.(Ringer 1934) Biern (1934) finds the sedimentation test useful in diagnosis of retention of secun.dines in abortion and 'i in the diagnosis of ectopic pregnancy and other abnor­ mal! ties which are characterized by hemorrhage or infec­ tion. Here the rate will be defi n1 tely increased over tba t which would have been the normal rate for the cor­ responding month of gestation. In incomplete abortion with the sepsis Lesser and Goldberger (1935) find the blood sedimentation rate only slightly increased .fran the normal or the corresponding month of pregnancy, but agree with Biern that with the.retention of secundines and the onset of sepsis a sbarpe rise in the velocity of the settling blood will be noted and in unruptured ectopic pregnancy the reading is only slightly higher than· the normal for the corresponding week of pregnancy. - 66 -

With rupture or free hemorrhage into the peritoneal cavity, the sedimentation reading is accelerated to 80-100 mm in one hour, (Westergren technique). Schattenberg (1932) agrees with the above, and uses the test in differentiating between ectopic pregnancy and acute e.mcerbation of a chronic infiam­ matory process. A rapid sedimentation rate points toward infection, while a slow rate may indicate ectopic pregnancy. Ni tschmann (1927) in tubal pregnancy finds the rate is not accelerated unl ass there is an· inf'lam­ ma tory reaction, and uses the test in differentiating between intact ectopic pregnancy and salpingitis. Falta (1927) states that with an impending abor­ tion the sedimentation speed is more marked. The same is true with endometritis. He adds tbat the first eight

or,ten days of puerper~um the sedimentation rate remains the same as during labor, but returns to normal within three weeks. The sedimentation rate has been used quite exten­ sively in the field ·of gynecology. Most writers on the subject (Friedlander 1924, Baer 1925, Nitschmann 1927, . . Polak 19'28, Scbattenberg 1932, Grodinskt 1933) believe that the test is of value in determining the most favor- able time to perform an operation. In the past, ope.ra­ tion has always been deferreq until the temperature 1a " I'". - 67 ~ ·'·· ' I

CUTLER BLOOD SEDIMENTATION TEST ~ '.1nl0 __,,.._ --- D~t o lg ______...... -..,.. .. - --... .._... ~,... ,,. ·~ ..__ ...... \Jdre s ('.! Di:i.g.r ..c~i r; _P..r.e£I:la..O.~CY~ ..:. ----~~~~----~~--- Gill_!_..cm:_ ·____ G_RAP--H----..~C-o_r_r_e_s_p_o_n_ . _d_i_n_g_C_l_i_l_1i_c_a_l__ --- - - · - · -- - ·-- ·-1--- --···· ! Condition I Sod ir.i'?.l" 3ec:..iY. 1• :~1 . Ho:N.z-ont.nl Lin< Normal or Absolute Index T 5.n.:..G Qu:!.escenco MlI. Diagonal "Line Quiescence --- Diagonal Curv-e Slightly or moderutely o.ctive Vertical Curve Modero.tcr ly or markedly ac.tive

Sed. ·.1n TIME IN :.IIlfUTES Sef..e I Mlft.-----...... -...-- ...... --.- . --, ~- ! TI , I j . -In(~. (·:·: , i Q 5 ; 10 15 :IJ 1I 25 : 3J.+ zi_.fi:~-?J2 :t.; (J --t--2\- - --~~--: --:'' i 0 I I I -; -· I t----r··--.. ·-· -r· --·-·-t·- · -:-~ : 0 I . ·~ --+...... -·--t---1---1 - --J···-·-·-t-·-l---··--r- .l,---- ··l ~ ~--.. - - ,--.---;-·· . ~ - - ·+-- .... +----1- - --..J.·---··· -' -·-... - - ; .....,._ . .... _ .... _ .... . - .... -r...... - .. ... t• ... .. - ., .. ~-. ...- , ...... - - ·-1i __... _ ... i ·-·~ ...... 4I I. __ ._ .. • ..... , •• ,.,.. _ , ~ -...... ;....- -·• ""·••,.,...... ,.,."'!"a• •I- , .. t ., 4 - o,.••- •~ ~~:::: :::::- ·--!-.. ---·-+-·· ,. . ', - ~ . --~+·· - ·t- ·- ··t·- ·-- ~--1 i +---...... --+-~~-~"'"=-- · ·- _,L.. ..-_ . ..-.--..-...... 1 .. ~ .. -t- ·- ...... ,...... ,...... ~ ' I '-.. ..:;:- ~~ • ·•• - ·-.;_ ·- I ..-· +- -·j• ---···i- ··-- . t·· .. _.. t-- - · I 2nd ~o +-_....., _ _.. __..._.;:,,,,,...... _--1 ...... ~....,,...... }- .. -- .... ---,------:· -·- ·-+- -- ·-·i-· --· ~...... ---~-1 i •· ·- .. ,. c- · - ~ - - .. , --- +-· ·-• -- r·-··-· ·r----·-_j·, I io · -+-.. -- ·---,·-· .---r-·--·T· -· ··-~· -r----·· , 1c j .....- ....-~!----+---+-·-+-- · · · -·--") ·- :, I ·• - ·{---··)..-.,. - - --·- - ·-···-1 • • I ! I 4l • .--.....---+--+----i---~ . _1 ·------.!.....--·--· __, --+- - . 2 mo I I I ! ' I ..---+----+--+----t----.--• ·-·-i-. ·- . -- -c· - · ·~' ·--.__J ·- 1··-- I --r-- - I -- '-- - ~-· - . -··-"'!-·· I ---- . ----, 6 . ------·---;-·- -~ - · - -+- - ·, -- 1 -- -f- ---~· - mo I , ---+---·1 · -·-·-,-----·· f----. ---,· ...... _+ ·- - . . +----;;.----+-"--~~-~ ·-·-+ - ··- --t------+-·. ···1- ···-.I·'"-- _,....l.. ______.,. 1 t +----+----+--+---·--·- r·- ·-r-- --r ·--· --t--· ~-~- ----~ --f ·--·---r- . 7 2 me ----- ·-~-L-----~ ·--:t..._-- --1--- -~ · ---1- - r--- ·· -'-·- --f ·-·-· -t ··~ -- aJ .. ----'- - -t--1-----~ ------f--- ·-r-··-·-- 1 - ---·1L-_j---··- .J..- -- +-----1---+--...._------·- -·=I----,---·-+---.. , . --·-- _ _J_ 20 -, --.:------·-. -j_ -~· ·- - r ~--1·- -' ~··------+-·-. ---··--·~b----+-· · --. mo ·=r=·- } ' • I -· ...... _. __ 8 ---·-----1.....· __..... ·, --·-·· ---+- --:.-~ --· t. ··- .. -...... :-..- -..-+ -----...J·-··-· ,, ______t___ , - -··- -+--+-- -·t-·- 1- .. ~---r----4 -··· ·--: ...1-----,---- ·--+----+ - -L ---l--·-1·--r·,...... _.,---1···---- r---·1---,------+-----.--- -+----~ · - .... -~ - ---4---- i - ~- ...,_ .. ____ ----r--~.. . ·t----·+ ·---t-· ----+----. J.- --- · ·--- ···-· ..--1--­ +-I--+ ··--_ _,. __~ --+--+·- --t---:-· - t-· ·-· -' - · -~-.l. · -- .. --- ;so ~ : ----t--.. -r-.. . -r·-i,-·-l1---1-·-·----- ;so l ---+-- . --t--~-1- · -1 - --, - --- , +---+---+----f-__.,...__ .-+- .__J_ _ __I,... _ _~ - -1-- 1 -1----1---1 r------+---+----1-----t--!=: -+--+-..+- -t j--· - J.J ---+----+--·r--....j ------+-i-----1~. --+ -t-,--1-- - ·--·· ,- ---t-·-+----t-,, --~--~;. --! ! I - -t--i-- ,--1··--·- j..._. - - ~~--+-- -i..---1--'----.- -t----;--r---i..·--·-· r-- ·'--- I i I i ~-- _____J _ __~ ... t' ---- . - - L I -+ -1-' I !_ ___ ,._.____ -----, : - I -~ -=c:- · 1·--- I }'-----·--;---+--+,---1-- I l "f -r---+1---+ Illust. 8 - 68 -

normal or" nearly. so for some time wi th a stationary or falling leukocyte count. Such observations coupled with

the general clin~cal picture and local findings were the . guides in determining when to operate. Polak (1928) states that .he previously· felt safe. in discharging a patient when she had a normal t.empera ture. for OI?-e week and leukocyte count even in the presence of a pelvic ex-·

udate.· _His statistics show.that many of these pat~ents

·on, retµrning home have been seize.d with severe pel v~c pain .a cccmpani ed by a rise in temperature, and most of

these women were returned to the hosp~tal. ·He believes

this could ha. ve been avoided had their sedimentation rates been normal before their dismissal. It. is also· the consensus of opinion ot the above men.that a patient

showin~ a sedimentat.ion rate ·of, over 18 mm. in one hour, I (Cutler technique) if operated is apt to have a stormy convalescence. In pelvi e infections, a ccor.ding to certain fnvesti­ ga tors. (Schattenberg 1932, Grodinsky. 1933, Nitschmann 1927) the sedimentation test is far more reliable than the leukocyte count, and tm.t the acceleration of the sedimentation rate occurs before the .rise in temperature and increase in leukocytes, and remains for a time after the others have gone down. It is well ·known that the leukocyte count flucuates during a 24-hopr period, and - 69 -

herein lies the danger to the surgeon who might take a blood specimen at the lower level and make the mistake of operating at this time. Had the count been repeated in several hours it would mve been found dangerously high. Polak ( 1928) states that an error of this kind would never happen if the sedimentation rate is taken, as it never yields to erratic results. The sedtmenta­ tion rate is of value as a prognostic aid which shows a gradual slowing as the patient •s condition improves. The regular fluctuations in these tests do not occur as they do in leukocyte counts. Baer and Reis (1925) state that the rate is direct­ ly proportional to the virulence of the infection. Williams, (1927) however, does not express the same opinion as the other investigators mentioned here. He concluded that a rapid sedimentation time did not guage to any unusual degree the postoperative morbidi t7, and that the temperature chart and leukocyte count are the more stable and reliable criterions in determining the diagnosis and prognosis. Much has been written in the past on tbe value of the sedimentation rate in differentiating between ap­ pendicitis and salpingitis. Many writers (Grodinsky 1933, Smith 1935, Schindler 1935, Lesser 1935, Bouton 1937, Biern 1934) find that catarrhal or suppurative - 70 -

appendicitis cause no increase in sedimentation rate un­ less they are well established cases of either abscess or generalized peritonitis. These men have all confirmed the results by operation. The following graphs (Bouton), illustration 9, are an excellent example of the accel­ erations in sedimentation rate which result from an acute gangrenous appendix: "E.B., a female nurse of 19 years, suf­ fered an attack of acute appendicitis during February, 1934. Prior to this she had been in good health. "She underwent an operation on February 14, at which time an acutely gangrenous vermi­ form appendix was removed. No other pathology was found. "The patient's post-operative course was uneventful, and she regained her usual good health within a normal time limit. "This series furnishes a clearcut illus­ tration of the change in the rate of sedimenta­ tion of the red blood corpuscles in an other­ wise healthy individual, brought about by an acute inflammatory process in the body, with a temporary slight rise of the curve follow­ ing surgical intervention, a renewed marked .·

- 71 -

SEDIMENTATION CHART

Nam E· I3 · Date 2-13 - 34

Sed. I 31 Time 11;45 e. .m. MINUTES 0 10 20 30 40 50 60 70 80 90 I I - ~ r--. I I MM. s :--,,,.,, I ~ r-..... I 10 I I 15 ~~ ...... I I I i 20 I ! ! '."'-., I 25 ...... ~ 30 I ~ '-.... 31!1 ...... ~ «I I 45 ~ I ...... - 50 I'-.

I SS I 60 ' 65 I

70 l I

"80

85 !IO ! 95 I 100

105

110 115 120 125 I 130 I I RBC 4,440,000 __ HB~_8_5~CI . 96

WBC 13,600 Po l ys._7_6_~1 ymphs 11

Bnds 13 Yg. F.___ _

Acute gangrenous Myel.___ Monos. __ _ a ppendi ci tis Eos.___ _ Bas. ~-

I llust. 9 7la.

SEDIMENTATION CHART

Nam E . B . ate 2-14-34

Sed. I 62 Time lO:J.5 a.m. MINUTES 0 10 20 30 40 !50 60 70 so 90 t--..1 r-. ._ MM. 5 • -f--· - - -1 l ~~ I 10 ·- - l\. 15 l - - ro - - 1 ' l\J--- __ ,_ 25 30 .. 35 ' ' \. - - ·---- 40 -- 45 "~ - - I\._ I 50 55 ~ 6'0 I "" ~ I ~ I I"

'°75 I'-' r-...... ~ 80

85 I'

!IO 95

100

- 105

110

115 120

125 j I 130 RBC 4 , 440 , 000 __HB 85 CI . 96

WBC.______Polys. ___~ymphs. _ _ _

Bnd Yg.F.. ______

Two hours prior to Myel_ ___Monos.~ ~ o per~tion 1 Eos.. ____ Bas.-W"J

Illust. 9 · ( cont) .·

- 7lb -

SEDIMENTATION CHART

Name~~~-E_._B_·---~~-~~-~ate~_2_-15_-_3_4_~-- Sed. r_5_3___ __Tim .....e _8_:_4_5_a_._m_.__ _

MINUTES 0 10 20 30 40 50 60 70 80 90 I MM. 5 K l l 10 I

15 " I 3) " ' .... I " I 25 "" "l 30 "\., 315 I '\ 40 45 1'- !O I"-. I S5 1""' ~ ]'.... 60 I 6' """" i'-... I""""' t"-..... '°75 I 80

85 !IO

95

100

105

110

115 120 I 125 I

130 I I .95 RBC 4 , 290, 000 __HB 80 CI-- --- WBC.___ 7~'~2_0_0 ___ Po lys 6 3 I ymphs 2 6

Bnds 9 Yg. F. 2

Day following opera tiori\1yel. ___Mo nos._ _ _ Eos. ___ Bas~

Il lust . 9 ( cont)

"- . - 7lc -

SEDIMENTATION CHART

Name E.B. ate 2-16_-_3_4 ____ Sed. l __9_l __ ___Time 8:45 a . m •.

MINUTES 0 10 20 30 40 50 60 70 80 90

MM. s K ·- [\... 10 .,. 15 \

20 \

25 \

30 \ 35 \

40 \ 45 \l ;\ I 50 55 \ 1 60 \

65 \ ·- I\ '° \ ' ' 80"

85 I". !IO " -r-- 95 - 100 -

105

110

115 120

125

130 RBC 4,120,000 ___HB 79 CI . 96

wBc__ _1_2 _,,<--so_o__ p 01ys 72 I .ymphs._1_3__

Bnds 13 Yg. F. l Drop caused by surgical trauma

Illust. 9 ( cont) .· - 7ld -

SEDIMENTATION CHART

Name E.B. Date 2-22-34

Sed. I 61 Time 9 :10 a . m. MINUTES 0 10 20 30 40 50 60 70 eo 90 I ~ I I I MM. 5 I I I

10 .... - >---- I ' I 15 "'- I I I I I ' I I I 3) \ r\ I I 25 , \. I 30 JS 1\. 40 \

~ I !'\. 50 ' '-..,.. 55 I I 60 I ~ '"' !'-.. 65 I .... I'--...._ .._ '°75 l'--- I - I -- I 80

85 I !IO I 95

100

105

110

115 I 120

125

I 130 RBC 4, 120, 000 HB 85 CI 1.03

WBC 10,200 Polys 62 I ymphs 29

Bnd 7 Yg. F.

Myel Monos. 1 Uneventf'ul Eos. 1 Bas.~-

Illust . 9 ( cont) - 7le -

SEDIMENTATION CHART Name~___ E_._B_. ______~at~e _2_-28-34

Sed. I.__ 1_7 _____ Time 10: 30 a .m •

MINUTES 0 10 20 30 40 50 60 70 so 90 I I LJ_ ' I I MM. 5 -- --...... _ 10 I-- ...... - ...... I 15 ...... r--..... I 3) ,...... ___ I 25 :-- .J) I 315 40 45 50 55 ' I 60 65 70 I I --- 75 80 85

!IO 9S 100

105

110 115 I 120 I 125 I I 130 I RBC 4,070,000 __HB_8_2~_cr i.oo WBC,___ 8__ ,_1_o_ o___ Polys 7 8 Lymphs 17

Bnds,___ 5 Yg. F.___ _

Good prognosis Myel ___ Monos.___ _

Eos.___ Bas·-~--~--~~·

Illust. 9 ( cont) .· - 7lf -

SEDIMENTATION CHART

Nam...e ___E_ ._B_. ______Date~ __ 2_-ll -34

S e d . I ··------9 T.1m "'e______10:30 e. .m. _ M INUTES 0 10 20 30 4 0 50 60 70 BO 90

~ I MM. 5 I -U I I ' -r--.!-._ 10 -~ I

15 - ~- I 2D I ' 25 I

30 35 40 45 50 I I 55 I I 60 I 65 I

'°75

80

&

!IO I 95

100

105

110

115

120 j I 125 I I I I I' I 130 l I RBC 4, 510, 0 00 ___HB_s _2_ _ c1_ _ ._9_1__

WBC.______Po l y~ ___Lymphs, _ _ _

Bnd~___ Yg.F~- -- Patient clinically i n Myel.. ___Monos .. ___ g ood h e al th. * · Eos. _ __ Bas~/

Illust . 9 ( c o nt ) .· - 71g -

SEDIMENTATION CHART

Nam.,.~__ E_._ B_.______Date 1-2 9_-3----"-5_ ___

Sed. I._ _ 9_____ Ti me 10:00 a.m.

MINUTES 0 10 20 30 40 50 60 70 80 90 I I I I I .MM. 5 ---,...... _ ___,...__ I 10 I I N-: 15 I I I 3) I 25 I

30 I 35 I I I I I 40 ' - 4S - ·--- -- 50 55 i 60 155 I I I \ '°75 - 80 I 85

90

95 100 ' I I 105 110

115 120 I

125 J I 130 RBC 4,610,000 ___HB 90 CI . 97

WBC 8 1 100 Polys 7 8 I.ymphs 17 Bnds.___ 5 Yg . F.__ _ _

Normal cha ck up Myel._ _ _ Monos.__ _

Eos. Ba~-

Illust. 9 (cont) - 72 -

drop reflecting the trauma of the operation, and gradual definite return to this indi vid­ ual 's normal. "The fact that the curves showed no marked initial drop gave added assurance, in conjunction with temperature readings and white cell counts, the. t there was at no time serious pus retention or excessive tissue destruction." Blem (1934) felt that the test was an aid in dif­ ferentiating between salpingitis and appendicitis, as salpirigitis gives an increased rate. Smith, Harper and Watson (1935) found that during the first 24 to 48 hours after the onset of symptoms the sedimentation time is apt to be shorter in sal­ pingitis (Linzenmeier technique). The reason for the shorter time in salpingitis is attributed to the fact tba t salpingitis is a, slower disease process, which tends to be chronic and that the appendix does not have the ability to distend as rapidly as the fallopian tubes. Therefore, the earlier symptoms in appendicitis. Lesser e.nd Goldberger (1935), after studying 1,000 cases with an average of l to 12 readings per case and using the Westergren technique, observed that if the sedimentation rate is less than 20 mm. per hour this - 73 -

could be considered an absolute assurance that no acute pelvic i.nfection was present. All cases which were clinically typical were found to have readings from 40 to 50 mm. in one hour to a high of 140 to 150 mm. in qne hour, depending upon the severity and extent of the acute pelvic pathology. They also took readings every week or two to determine the progress of the dis­ ease under treatment, and the optimum time for operation. It was consistently observed thit long after temperature, leukocyte count, pain and tenderness had subsided, the sedimentation test became a much more accurate prognos­ ticator of the best time to operate. No cases were brought to surgery unless the sedimentation rate was be­ low 25 mm. in one hour, and as a result in several hun­ dred operations no a cute process es were encountered, and this was also supported by a low post-operative ~ortal­ ity. Grodinsky (1933), Lesser and Goldberger (1935), and Biern (1934) found thit the accelerated sedimentation rate in pyonephrosis, pyelitis, pyelonephritis, pros­ tatitis and perinepbritic abscess, and seminal vesicul­ ities, do occasionally resemble acute appendicitis, and in these cases the sedimentation rate was high. Murphy (1937) has found that the erythrocyte sedimentation test is an important aid in determining the degree of activity - 74 -

of the kidney lesion. Although the reaction is not in­ fallible as a criterion, it was found that if the rate is normal tm.t the chance of the complete healing of the kidney is good. But on the other hand if the rate is rapid it may indicate progressive renal damage. Lesser and Goldberger ( 1935) found that acute sur­ gical gallbladder, varying from acute suppura ti ve to rupture, gives readings from a moderate 25 to 40 mm. in one hour to a high of 60 to 80 mm. in one hour (Wester­ gren technique). Ruptured peptic ulcer accelerates the rate, de­ pending on the duration of the rupture. Biern (1934) finds the rate is retarded in peptic ulcer unless peri­ tonitis is present. Tuberculosis peritonitis (Lesser 1935) gives a rate from 75 to 90 mm. in one hour, differentiating it from appendicitis. They added that the group of acute chest conditions with referred abdominal manifestations also enters into the differential diagnosis· of the acute surgical abdomen. Tbe several cases with apparent acute surgical conditions of the abdomen and high sedimenta­ tions have subsequently proved to have acute pulmonary pathology such as pneumonia and acute tuberculosis. It was believed that rheumatic fever might be differ­ entiated from appendicitis as every case of the fever, - 75 -

if in its earliest incipient stage, shows a sedimen­ tation velocity· of a high 60 to 80 mm. in one hour to a severe 70 to 140 mm. in one hour. r-11ustration No. 10' clearly demonst:re.tes the non.­ specificity .of the test, 'which may be of value in giv­ ing the approximate readings for the diseases listed. Lintz (1935) made a determination of the sedimen­ tation rates of 30 chronic sinuses, 13 cases of chronic tonsillitis, 5 with both tonsillitis and sinusitis, and 27 with dental periapical infections. Of these cases 92 per cent had normal sedimentation rates. Westergren (1928) found that there was little or no effect on the sedimentation rate in influenza. Gallagher (1934) found little acceleration of the sed­ imenta_tion rate in common colds. Gold (1936) studied whooping cough and noted that the rate is reta·rded and remains normal or subnormal in the ordinary uncom­ plicated case without fever. He believes the sedimen­ tation rate completes a diagnostic triad of symptoms which are; suspicious cough, lymphocytosis in asso­ ciation with leukocytosis, and a retarded (subn~rrnal or normal) sedimentation rate. In general, apparent­ ly healthy children were found to have a slightly in­ creased sedimentation rate. This he explained was due to some unrecognized minor _pathology as tonsils~ - 76 -

No. Norm. Av. 15 min Av. 45 min Average cases Diagnosis read. reading reading rate

26 Broncho- pneumonia 0 8 43 32

7 Lobar pneumonia 36 12 Bronchitis 25

9 Acute upper resp. inf. 20 2 Pleurisy 0 26 77 29 7 Acute rheum. arth. 0 42 96 48 13 Rheum. heart disease 17 4 Subacute bacterial endocard. 1 7 40 16 2 Atrophic artbri tis 0 37 97 41

8 Non-acute appendicitis 4 13 5

3 AP pendi ci tis & peri toni tis 1 6 29 11 7 Oti tis media & mastoiditis 0 15 55 21

7 Sinusitis 0 29 69 34

2 Tonsillitis 0 38 92 41 12 Abscesses 0 20 69 29 7 Acute genito urinary inf. 0 31 76 34 12 Local infs. 2 17 50 22

Illust. 10 - 76a -

No. Norm. Av •. 15 min Av• 45 min Average cases Diagnosis read. reading reading rate

3 Burns of extremity 1 12 40 14 5 Ulcers of extremity 1 16 47 18

13 Peptic & duodenal ulcers 6 4 16 7 8 Stomach carcinoma 1 12 45 16 12 Other carcinoma 2 13 41 18 4 Benign tumors 1 22 49 22 10 Gen. A.rterio- sclerosis 19 8 Cerebral hemorrhage or thrombosis 1 4 25 10

24 Hypertension & .~rdiovascular renal disease 11

9 Syphilis 14 Pernicious anemia 3 a. RBC above 2.6 million 5 19 7

5 b. RBC below 2.6 million 11 48 19 7 Diabetes mellitus 1 7 31 1·3

3 Enteritis & Coli tis 0 16 77 31 Illust. 10 (Cont) - 76b -

No. Norm. Av. 15 min Av •. 45 min Average cases Diagnosis read. reading reading rate

2 Amebic dysentary 0 24 60 25

3 Meningitis 1 5 27 22

4 Ta bes dorsalis 3 3 9 4 12 Post-opera- ti ve o 26 80 33

19 Hernia 14 4 10 4

14 Fractures 20

9 Hypertrophy of prostate 15 6 Non-acute gonorrhea 3 3 13 5

10 Chronic cholecysti tis 8

7 Kidney dis. non-nephritic 2 11 39 15 15 Tuberculosis 22

6 Misc. lung cases 2 5 27 11 11 Non-infect. heart dis. 6 4 29 12

11 Thyroid · 4 6 25 10 13 Misc. mental & nervous 5 20 8

6 Misc. eye diseases 4 3 17 7 Illust. 10 (Cont)

The above results were obtained by the Westergren

technique, and are quoted in part. (Haskins, 1930-31). - 77 -

adenoids, dyspepsia, or flatulence. There bas not been much written on catarrhal jaun­ dice, but .Rosenthall ( 1938) supports the work of Gram

(1921) by stating that he found a normal sedimentation rate in ca tarrhal jaundice. At this point I will brief­ ly give a case history of a patient on whom I had the opportunity to do four tests. These tests had an un­ usually high sedimentation rate, which clearly indicated tmt there must have been an extreme amount of tissue destructi an. This conclusion was later confirmed in the autopsy report of Dr. s. Miles Boutona A physical examination of the patient, S. w., in July, 1936, revealed obesity, a blood pressure of 220/108, rectocele, arthropathy of the fingers, with little else of note. The blood Wassermann was negative in 1934. On January 22, 1937, the patient appeared jaundiced and was put to bed, with a temperature of 99.2. Urine was dark, stool normal, the liver enlarged, the abdomen distended. The urine showed a low specific gravity, and the white blood count was 20,200 with 3 per cent lymphocytes. On February 3 her white blood count was 8,600, with a normal differential count. In May the patient was reported as up and dressed. In June her weight was recorded as 132 pounds. In August, 1937, she was put to bed again, when edema of the feet r-·····

- 78 -

and eyelids were noted. Blood pressure was 110/60, rate 84. There was marked jaundice, some weight loss, and a mild temperature, usually a bout 100 plus to 102 on ore occasion. Urinalysis early in August showed one pus albumen, with nothing else of note. In September gen­ eral edema was present, the abdomen was markedly cis­ tended, and 2500 cc. of fluid (clear, amber) were re- moved by paracentesis. The patient appeared more com­ fortable, bowels and kidneys were functioning, but she was drowsy most of the time and slept much. The ascites increased, and a second tap relieved her of 3500 cc. of bile-stained fluid, in October, 1937. On October 9 and 10 the patient received morphine supbate, because of unrelieved discomfort. She died October 11, 1937, at

1 A. M. CLINICAL DIAGNOSIS: Dementia precox; Carcinoma of the liver (?} ANATOMIC FIN DIN GS: 1. Obesity. 2. surgical scar hernia of right abdominal wall. 3. Chronic cholecystitis and cbolelithiasis, with periportal fibrosis and adhesions, chronic hepatitis and beginning cirrhosis. 4. Ascites. 5. Edema of external genitalia and perineum. 6. Pulmonary compression atelectasis, with pleural transuda ti on. Myocardial degen- - 79 -

eration with hypertrophy and dilatation of heart. 7. Moderate cerebral edema. CAUSE OF DEATH: Chronic cholecystitis, with periportal fibro­ sis, hepatitis and cirrhosis, and ascitis. Myocardial degeneration. (See illustration 11.)

ANEMIA

Since Fabreaus (1929) first demonstrated that by diluting red cells with plasma the velocity of sedimen­ tation was accelerated, much of the research has merely confirmed his work. After a careful review of the lit- erature I find that very little has been added to bis work concerning anemia. Gram (1921) was perhaps tbe first man to follow the work of Fahreaus. After analyzing the fibrin count of 542 plasmas, it was his belief that the velocity of sed­ imentation was due to the amount of fibrin in the plasma, and found a decreased fibrin count in diseases having aretarded sedimentation rate as in polycythemia. He also did concentration and dilution experiments, and pointed out the influence of the number of red cells on the sedimentation rate. He described a method of cor- recting the sedimentation rate by fixing a certain heme- .· - 80 -

SEDIMENTATION CHART

N am'°'e--=S-'.'-'W-'--=-·------'-'ate 8-2 0<---'3""-'-7___ _ Sed. l.,_ _7 _3_ ____T im'°'e__ 9~:_5_0 __ a_.~m=..:.• ~~- MINUT ES 0 10 20 3 0 40 so 6 0 7 0 eo 9 0 I I _,_ MM. s N ·-"- - - .__ ,_._ 10 \ ._ - - I 15 \ 1--- ~ :a:> \ 25 --- \ _,_ lO - - \ - ,_.,_ • \ - -- -- f- ,_ ,._ 40 ,, - 45 \ ,_ _ 50 .__·- - - 55 \ '\ 60 -- i-- 65 '"'- r--...._ I ,_ 70 " -- 75 --r- -I-- 80 85

90 I ' 95 100

105

110

115 120

125

130 I RBC 2 , 850,000 HB 7Q er _ _. _ __

WBC 9 , 300 Palys 61 I ymphs 19

Bnds 17.1 Yg. F .

Myel. Monos. 3

Eos. Bas. ~~·

I llust. ll - 8 0a -

SEDIMENTATION CHART

Nam~e ___s_ ._V~'-· --·------~at~g_4__ -_ 3~7___ _ Sed. I 149 Time 2 : 57 p . m . MINUTES 0 10 20 30 40 50 60 70 80 90 I MM. s I I I --r- 10 ~ I , I 15 1--f- j -t I I 20

25 I I 30 I I I

I- I • I I 40 I 4S I 50 - I 55 I I I I I 60 -l\ 65 I I I ""' I I 70 ' 75 \ 80 \ I 1 85 I 90 I\ 95 . \ i- .' . ·- ·-" - \ - ·- - MM. s -, 10 \ 15 i--I-f- I- I 20 25 \ I 30 • -\ 40 \ - -f...--

4S - ~ ... I- I " 50 --- ~ 55 I I 60 I 65 I 70 75 80

85 90 95

100 I-I- I - 105 . --- I 110 I -..- - --- 115 -- ! 120 1~ I I I I 125 £µ1-- \ I I I I 130 I I RBC 2 . 170 . 000 _HB 50 CI

WBC 6 z250 Polys 41 I ymphs 9 49 F ra.g ili ty 27% Bnds Yg.F Myel Monos. 1 Eos. Bas.~~- - 80b -

SEDIMENTATION CHART N ame.___S_.W_. ______....,a te 8-2.5--.-=3-.7___ _

Sed. I 133 Time 9 : 55 a • m • MINUTES 0 10 20 30 40 !50 60 70 ao 90

MM. s \ 10 \ - \ '++ 15 r-- ·~-- 3) ~-t- ·- T1" r + 2S I ' I I I 30 \ I I I I SS \ I I I I I 40 \ ~1- I I 45 \ I ·- ~ I- I I =f 50 55 \ I

SI I I 65 '° \ - 7S -· ·I-~- I 80 85 \ I I 90 \ I

95 \ I \ 100 I 105 \ 1 I 110 \ \ 115 \ 120 """- 125 "' I '-.L__ 130 RBC 2, 930, 000 _HB 80 Cl ____-_

WBC 7 1 l 50 Polys 3 8 I ymphs 2 2

Ends 40Yg. F ____

Myel ___ .Monos. ___ Fragility 27% Na Cl Eos. ___ Bas. 2 ~ .~ ~r--

Illust. 11 (cont) soc

SEDIMENTATION CHART

Nam~__ _s_._w_. ______Date 8 - 3 ]._-__,,3~7_,______

Sed. I. J.57 • 5 Time 2 : 0 0 p • m • MINUTES 0 10 20 30 40 5 0 60 70 60 90

MM. 5 i\ \ 10 15 \ 20 25 ' 30 315 40 45 50 55 \ 60 \ I 6S \ 1

'°75 80

BS 90 \ 95 \ ..... \ MM. 5 ' 10

15 -~

20 \ \ 25 ' 30 315 \ 40 \ ' !'-... 45 ~1'.. 50 r----.. _ 55 60 6S '° 75 - 80

BS 90 95 100 105 · uo 115 120 I 12S

130 RBC 2, 810,000 _HB 60 CI 11, 450 8 WBC~~~~ -<-~~~-Polys 55 I .ymphs

Bnds 37 Yg. F.

Myel Monos.

Eos. Bas.~.. - 80d -

The hemoglobin values given in these graphs were determined by the Tallqvist method and are therefore not dependable. The relationship which exists between the red cell count and the acceleration in sedimentation rate is neg­ ligible, as is demonstr~ted by the preceding charts. - 81 -

globin percentage as normal, using 100 per cent as the standard of normality. Rubin and Smith ( 192'1) found that a low er hemoglo­ bin frequently accelerates the sedimentation rate, and believed this could be correlated to the red cell count, and a low red cell count gave a corresponding accelera­ tion in sedimentation rate. Hubbard and Geiger (1928) allowed blood to stand in settling cylinders, and as soon as the cell had settled sufficiently they pipetted off some of the clear serum and a sedimentation test was done on the remainder. To some of the cylinders they added serum. Increased concentrations were found to retard the rate and vice versa. They al so mention that in many di seas es anemia is present, and if the effect upon the infectious pro­ cess is to be studied adequately some attempt must be made to differentiate the effect of this secondary fac­ tor from the primary factor, anemia. Morris (1924) found no relationship between the rate of sedimentation and red count, white count, or hemoglobin count. These investigators (Morris 1924, Hubbard 1928, Rubin 1927) found the velocity of settling to be re­ tarded in polycythemia and rapid in anemia. Foster (1921) in attempting to explain the various - 82 -

factors causing accelerated sedimentation rates stated that a stimulation of fibrin production, or at least a rise in fibrinogen values, was caused by the following factors: Food, hemorrhage, any type of inflammatory or tissue injury, and even certain general intoxications without obvious cell injury, and also added that poly­ cythemia inhibits the production of fibrinogen. The various factors, such as temperature, antico­ agulants, deviation of the tube from vertical, etc., have been discussed under the Phenomenon of the sedi­ mentation rate. Walton (1933) applies the original formula of Blacklock (1921) which is as follows: x/Y-1. X repre­ sents the original percentage and Y the desired percent­ age. He applied this to blood by substituting the number of millions of red cells for X, and 5 million for Y. Schindler (1935) also uses this method. Thus, if a patient bas an erythrocyte count of 4,000,000 the calculation would be 4.0/5.0-1 equals 0.2 ccs., and this 0.2 cc. of plasma per 1.0 cc. of blood would be removed after centrifuging the cells. If the count should be above 5 million, the calculated amount of plasma would be added to each cc. of blood. Many (Newham 1926, Hub be.rd 1928, Wal ton 1933) have done dilution experiments in vitro, and demonstrated - 83 -

that the sedimentation rate accelerates proportionate­ ly to the count of cells added or subtracted from the plasma. Others (Rourke and Ernstene 1930, Rourke and Plass 1929) have worked out correction charts using hemato­ cri t readings for standards of comparison. Wintrobe and Lansburg (1935) used norm.al blood with dry potas­ sium oxalate as an anti-coagulant in their experiment. Dunn and Sharpe (1936) constructed nomagraphic align­ ment charts to correct the volume of packed erythro­ cytes for the amount of shrinkage due to the anti­ coagulant, and to calculate the mean corpuscular volume ot the cells, the mean corpuscular hemoglobin count, and the mean corpuscular hemoglobin concentration. It b3.s in the past been the general consensus of opinion that decreased number of red cells caused an accelerated sedimentation rate. It will, however, be found that the majority of investigators have done their experiments in vitro and very little work bas been done in vivo. Gregg (1937} bas recently completed a series of experiments using the blood of rabbits made anemic by repeated bleeding. He uses the dilution method of Walton (1933), setting up a series of four sedimenta­ tion tubes containing blood in descending concentra- - 84 -

tions from 5,ooo,ooo to 2,000,000 cells per cmm. The hemoglobin was also determined by the Haden-Hauser bemoglobinometer. Whole blood was sedimented in com­ parison with the dilution. His results show that the whole blood did not settle as rapidly as the diluted blood. Other investigators. (Bannick, Gregg and Guernsey, 1937) have found that in a number of anemic patients who had diseases which are generally characterized by accelerated sedimentation rates that the uncorrected rates were high, but that frequently the corrected rates gave normal readings. It was also found t!Et in longer tubes, such as the Westergren tube, that the packing o:f the red cells did not occur as soon as it occurs in the shorter and stouter tubes. They con­ cluded that i:f single readings were to be taken at the end of one hour a Westergren tube should be used, as shorter tubes require more frequent determinations. It is also ad.mi tted that anemia causes an acceleration in sedimentation rate, but that it is not always neces­ sary to make a correction, as the increase in velocity caused by the anemia can be allowed. One may correct for the anemia, but it should always be kept in mind the possibility of over-correction. Bouton (1938) substantiates the work of Bannick, - 85 -

Gregg and Guernsey (1937) by stating tm.t in not in- frequent cases a low cell count in the blood bas little affect on the sedimentation curve, and that any correction of the sedimenting rate and especially the use of conversion charts leads to pseudo-accuracy and may nullify the results, but if the sedimentation , curve is graphically recorded and used in conjunction with other clinical and laboratory data, it is very val ue.ble. He further states that pernicious anemia and various leukemias have a definite and constant effect on the sedimentation rate, which is quite different from the velocity caused by an uncomplicated secondary ane- mia. He adds that if one takes into consideration the initial velocity of settling and the fluctuations in rapidity during the period of reading, the.curve can be directly interpreted from the results of the one hour reading and the final reading after the settling has been completed. However, corrections for anemia do not take into account the character of the curve.

DIABETES MELLITU S AND HYPERTHYROIDISM

Diabetes mellitus is a disease which occurs most often between the ages of 50 and 70. However, many - 86 -

cases are found in younger persons. The sedimentation tests in younger pa. tients (Kramer 1935) show a hori­ zontal or only a slight increase from normal. It was found that the blood sugar had no influence on the sedimentation rate, but tm t out of 346 patients 6'7.8 per cent md accelerated rates, which is probably due to some underlying pathology. Miller (1935) .found tm t 52 per cent of 29 cases md increased rates, and stated that the daily wear and tear on the body tissue causes only slight varia­ tion in the sedimentation rate. Buchanan ( 1935) studied 22 cases and concluded that the sedimentation rate is not indicative of pathology or tissue destruction. Inasmuch as he bas obtained high readings which have remained accelerated for some length of time even in tm absence of obvious disease processes, be maintains that the test leads to false conclusions. However, he neglects to take into consid­ eration that women have a much higher sediments. ti on rate tmn men, and of 122 cases 6 were men and the highest reading was 24 mm. in one hour and the lowest 6 mm. in one hour, and for the women the high reading was 27 mm. in one hour and the lowest 6 mm. in one hour, and that 12 of these cases bad complications and the remainder had comparatively low rates ranging fran 12 to 16 mm. - 87 -

in one hour. Cutler (1932) and Biern (1934) agree that metabolic diseases such as uncomplicated diabetes influence the sedimentation rate very little. Mora (1926) did sedimentation tests on 30 cases of thyrotoxicosis prior to and following operation. Prior to operation all patients showed a marked accel­ eration in sedimentation rate. The operation did not uniformly retard the velocity of the sedimentation re­ action. He gave 11 of his patients iodine prior to surgery, and noted the affect on the sedimentation rate. Six tests showed a retardation in velocity which was proportionate to the drop in the basal metabolic rate. The remaining 5 showed a marked acceleration. He also found that after maximal removal of the gland that three showed little change in sedimentation rate, 13 were ac­ celerated and 14 retarded. He concluded that there was little relationship between the sedimentation rate and the basal metabolic rate.

Landau (1933) agrees with the ~ther investigators

by stating that diabetes is always accompanied by normal microsedimentation in uncomplicatad cases. Cutler confirms the above results. - 88 -

ALLERGY A ND .SKIN

Scbulhof {1933) reports 610 non-selected cases of allergy and finds that the.retarded sedimentation rate is prevalent in all allergic individuals unless there is some underlying infection which may accelerate the ra ta. He adds· that there is a frequency of slow sedimentation rates among non-allergic relatives of al~ lergi c patients, and that this has not. been thoroug1:1ly • investigated. Galford, (1933) however, found the rate rema·ins normal before and during the season in which· the al­ lergic individual is sensitive.· Uffe (1932) found that out of .150 cases i4,per cent bad high fever and all of .these showed retarded sedimentation rates; 108 patients had asthma; and the majority showed normal rates. He is in accord with Schulhof that an allergic individual may show a de­ creas~d rate in the presence of some complicating in­ fection of short duration, such as acute gangrenous appendicitis and that all allergic patients with ac­ celerated sedimentation rates should be carefully studied for accompanying conditions. Westcott and Spain { 1932) concluded .that in- un­ complicated non-infect'ious asthma, bay fever or aller- ,....--

- 89 -

gic non-seasonal coryza all have sedimentation rates within the normal range. There has not been a great deal written on the affect of the various dermatological conditions on the sedimentation rate. Tulipe.n and Director ( 1933) stud­ ied 115 patients by the westergren method, and found the sedimentation rate usually normal in lupus ery­ thematosus and erythema multiformi, including the bul­ lous variety, and the generalized group of vesicular dermatoses, including dermatophytids. The sedimenta­ tion rate was found to be accelerated in tubercular lesions of the skin, erytbema nodosum, and markedly increased in eruptions due to phenolphthalein, derma­ titis herpetiformis. The sedimentation rate varied as to the extent of the lesion in epitheliomas and many border-line readings in mycosis, fungoids and erythroderma.

NEUROPSYCHIATRY

Up until 1928 the sedimentation reaction had been studied very little in the field of neuropsychiatry. In that year Goldwyn (1928) investigated over 200 cases in the Worcester State Hospital at Worcester, Massachusetts, and came to the following conclusions: The velocity of settling blood .was d:J..rectly related - 90 -

to the amount of mental deterioration, the amount or organic destruction, and the amount of toxicity present. The sedimentation rates were found to be normal in cases of manic depressive psychosis, psychopathic per­ sonalities; psychoneurosis, and paranoia. The rates were increased in senile psychosis, psychoses witb cerebral arteriosclerosis, paresis, neurosyphilis, psychosis with mental deficiency, psychoses with so­ matic disease, acute types of alcohol! c psychoses, in many cases of epileptic psychoses and involutional melancholia. Normal readings were found in the simple and paranoid types of dementia praecox, and slightly accelerated readings were found in hebephrenic and catatonic types. Unless there were complications, no cases of schizophrenia gave a noticeable acceleration. Freeman (1933) substantiates- the work of Goldwyn in a study of 50 normal and 47 schizophrenia male sub­ jects, whom he selected because of the absence of any discernible infective processes, and found no expres­ sive variations in the sedimentation rate in the var­ ious subclasses of the disorder. The results were all found to be within normal range. Gregory's (1936) observations also coincide with those of Goldwyn, and he goes further to state that the high rates seen in senile psychosis and arterio- - 91 -

sclerotic psychoses can, in most cases, be explained by the diseases common to persons of advanced age, such as cardio-renal respiratory diseases. Hoverson {1934) made tests on the blood of male paretics. He believed the daily variations in red cell sedimentation rate might be explained by changes which are produced 1 n normal or a bnorma 1 individuals by mete­ orological conditions, rather than by an encroachment . of disease. He found wide daily variations in the sed­ imentation rate, as mu~h as 100 per can~. The rate was found to be normal in paretics. It was concluded that a correlation existed between daily variations of sedimentation rate and the meteorological changes. Wes·tergren ( 1928) expresses harmony of opinion in that most organic nerve diseases show only slightly accelerated or normal rates. Border-line rates were i'ound in tabes and paresis. Increased rates were i'ound in multiple sclerosis during the exacerbations oi' the disease process; and in epilepsy and neurosis the sed­ imentation rates were normal. Some investigators (Stainsby 1934, Westergren 1928, Roche, 1932) used the test in determining whether a patient's complaints are on a functional basis or due to some organic dis­ ease. However, the test has only a limited value in solving this problem. If a patient shows a normal - 92 -

sedimentation rate one should not be too hasty in ruling out all organic diseases, as this reaction may be due to some pathological process which does not affect the rate. ·On the other hand, however, if the sedimentation rate is markedly accelerated, a search must be made for the underlying cause. The usual causes of error, such as pregnancy and minor upper-respiratory infections, should be taken into consideration. Westergren (1928) finds that polyneurotics show a markedly accelerated rate, sciatica a slight ac­ celeration, and myalgias and neuralgias show no ac­ celeration. / It has been the writer's experience that all I types of psychoses usually show no acceleration of sedimentation rate unless, however, the patient bas some complicating infection or serious mental dete­ rioration. In syphilis of the nervous system the re­ sults were found to be variable, depending upon the activity of the disease. Although there are no graphs to illustrate this, the material is easily obtainable, as all sedimentation tests which a re done at the Hastings State Hospital are kept as permanent records. - 93 -

CONCLUSION

This pa.per does not maintain that the sedimentation test can diagnose any one disease condition; it cannot do this, as it is non-specific. The sedimentation reaction of blood merely indicates the degree of activity and severity of tissue destruction, the products of which are absorbed in the blood. - 94 -

BIBLIOGRAPHY

Ashhurst, John: Principles and practice of surgery. Page 36, Lea Bros. & Co., Philadelphia, 1893 Bach, Francis, and Hill, N .G. s Erythrocyte sedimenta­ tion rate in rheumatic fever. Lancet, Jan. 9, 1932, PP• 75-77 Baer, J .L., and Reis, ReA..: The sedimentation test in gynecology. Surgery, Gynecology and Obstetrics, 11 :691-695, 1925 Bannick, E.G., Gregg, R.O. and Guernsey, C.M.: The erythrocyte sedimentation rate; the adequacy of a simple test and its practical application in clinical medicine. J .A.M.A., · 10911257-1262, 1937 Banyai, A ·L., and Anderson, Sylvia: The erythrocyte sedimentation test in tuberculosis. Arch. Int. Med., 46:787-796, 1930 Beaumont, G.E. and. Maycock, J .w.: The erythrocyte sedimentation rate. Lancet, 19:229, July 6, 1935

Biern, O.B.: Value of the sedimentation ra~e in medi­ cine. The West Virginia Medical Journal, 33:289-295, 1937 Blacklock, E.: Percentage and fractional dilution. Lancet, 1:377, 1921 Boots, R.H.s (See Dawson, 1929) Bouton, S.M.: Personal communication, 1937 Bouton, s.M.: Erythrocyte sedimentation and anemia. J. Lab. and Clin. Med., 23:519-525, 1938· Buchanan, A,.J.: Is the sedimentation test a reliable indicator of disease. Medical Record, 142 :464-465, 1935 Cecil, R.L.: Text-book of Medicine, Third Edition, PP• 80, 1120, 1168, w. B. Saunders Company, Philadel­ phia, 1933 - 95 -

Cutler, Jacob: The graphic method for the blood sedi­ mentation test; presents. ti on of a 1-cc. technique and other important modifications and suggestions. Am. Rev. Tuberc., 19:544-558, 1929 Cutler, Jacob: The graphic presentation of blood sedi­ mentation test:. Study in pulmonary tuberculosis. Am. J. Med. Sci., 171:882-901, 1926 Cutler, Jacob, and Cohen, Louis: The blood sedimenta­ tion test as a routine procedure in the tuberculosis dispensary. Am. Rev. Tuberc,, 21:347-~53, 1930 Cutler, Jacob: The practical application of the blood sedimentation test in general medicine. Am. J. Med. Sci., 183:643-649, 1932 Dawson, M.H. Sia, R.H.P., and Bootsi R.H.: The differ­ ential diagnosis of rheumatoid and osteoarthritis: The sedimentation reaction and its value. J. Lab. and Olin. Med., 15s1065-1071, 1929-30 Dunn, F.L., and Sharpe, J.c.: The use of calculation charts for Wintrobe hematocrit and sedimentation rates. Am. J. Olin. Path., 6:497-499, 1936 Ellenberg, s.L.: Sedimentation reaction in the newborn. J. Lab. and Olin. Med., 19f944-947, 1933-34 Fabraeus, Robin: The suspension stability of the blood. Physiological Reviews, 9:241-274, 1929 Falta, B.: The use of corpuscle sedimentttion in ob­ stetrics and gynecology. Zentralblat fur Gpiakologie, 47:1478, 1924, Dep't. of Rev. and Abs., Am. J. Ob. and Gyn., 13:270, 1927 Fischl, K.: Suspenslon·stability rate of erythrocytes in pulmonary tuberculosis, and its significance in artificial pneumotborax. Am. Rev. Tuberc., 10s606- 629, 1924 . Fo$ter, D.P., and Whipple, E.: Blood fibrin studies; fibrin values influenced by cell injury, inflammation, into xi ca ti on, liver injury and· the Eck fistula. Am. J. Physiol., 58:407-431, 1921 ,-- -

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Freeman, H.: Sedimentation rate of the blood in Schizo­ phrenia. Arch. of Neurology and Psychiatry, 30:1298- 1308, 1933 Fremming, K. H., and Madsen, J.: Investigations on sedi­ mentation reaction in dementia paralytics. Hospital­ stidende, Co»enhagen, 79:1137-1148, 19361 abs. J.A.M.A., 108, 1937 Friedlander, B.: Blood sedimentation test as an aid in diagnosis in surgical infee-tions. Am. J. Ob. and Gyn., 2sl25~144, 1924 Gallagher, J.R.s The value of the blood sedimentation test in the routine medical examination of adolescents and in certain of their diseases. Am. J. Med. Sci., 188:450-455, 1934 Galford, H.H., and Victor, George: The sedimentation rate in hay fever. Journal of Allergy, 5:583-291, 1933-34

Gold, A.E., and Bel~f H.o.: Improvement in the diagnosis of whooping cough. Am. J. Dis. Child., 52:25-40, 1936. Goldbloom, A.A., and Libin, Isaiah: Clinical studies in circulatory adjustments. Arch. Int. Med., 55:485-511, 1935. Goldwyn, J.: The sedimentation test; its use as routine procedure in psychiatric institutions. Am. J. Psychiat., 8: 59-74, 192_8 Gordon, M.D., and Cohn, D.J.: Effect of external temper­ ature on sedimentation r~te of red blood corpuscles. Am. J. Med. Sci., 176:211-214, 1928 Gram, H.c.: On causes of variation in the sedimentation of the corpuscles and the forms. ti.on of the crusta phlogistica ("buffy coat") on the blood. Arch. Int. Med., 38:312-319, 1921 Gregg, R.o.: The sedimentation rate in experimental anemia (rabbit). J. Lab & Olin. Med., 22:786-795, 1937 Gregory, H.s.: The value of the erythrocyte sedimentation rate determination in psychiatric cases. New York State Journal of Medicine, 36:391-394, 1936 - 97 -

Greisheimer, E.M., Hodapp,A., and Goldsworthy, Edith: Effect of anti coagulants on s edimen ta ti on rate. A:m. J. Med. Sci., 190:775-779, '1935 Greisheimer, E. M., Treloar, A·E., Ryan, Mary: Inter­ relationship of Cut1er, Linzenmeier and Westergren sedimentation tests. Am. J. Med. Sci., 187:213-221, 1934 Greisheimer, E.B., Johnson, O.H., and Ryan, Mary: The relationship between sedimentation index and fibrin content in relatively normal individuals. Am. J. Med. Sci., 177: 816-827, 192:> Grodinsky, Manuel: The blood sedimentation test in the differentiated diagnosis of lower right quadrant dis­ ease. The Nebraska State Medical Journal, 18:47-52, 1933 He.kansson,. E.G.: Clinical notes, experi encas with the blood sedimentation tests. U. s. Naval Medical Bulle­ tin, 26:607-637, 19~ Harvey, W.F., and Hami 1 ton, T .n. : Blood s edimen ta ti on test. Edinburgh Med. J., 43:29-46, 1936 Haskins, H.o., Trotman, F.E., Osgood, E.E., and Mathieu, Albert: A rapid method for. determination of the sedi­ mentation rate of the red cells with results in health and disease. J. Lab. Clin. Med., 16:487-494, 1930-31 Hench, P.s., Bauer, Walter, Fletcher, A·A·, Ghrist, David, Hall, Francis, White, P.T.: The present status of the problem of rheumatism and arthritis; review of American and English literature for 1934. Ann. Int. Med., 9:883-982, 1936 Hirsh, J.E.: The value of the sedimentation test as a diagnostic aid. Ann. Int. Med., 10:495-504, 1936 Hoffmann, M.B.: The clinical significance of the sedi­ mentation rate in coronary occlusion. Minn. Med., 19 '512-519, 1936

Hoverson, E.T., and Petersen, W.F.: Met.orologic effects on the sedimentation rate of erythrocytes. Am. J. Med. Sci., 188:455-461, 1934 - 98 -

Hubba.rd, R.s., and Gieger, B.,A..s Anemia as a factor in the sedimentation time of erythrocytes. J. Lab. and Clin. Med., 12 :322-326, 1928 Hunt, H.F.: Studies of the sedimentation of erythrocyte. J. Lab.and Olin. Med., 13:327-332, 1928 Hunt, H.F.: Studies of sedimentation of erythrocytes. J. Lab. and Clin. Med.,14:1061-1077, 1929 Hunter, J .H.: A Treatise on the Blood, Inflammation and Gun Shot Wounds. PP• 9-91, Thomas Bradford, Philadelphia, 1796 Keefer, C.S., and Myers, W.D.: Gonococcal arthritis# e1in1ca1 study of 69 cases. Ann. Int. Med., 8:581- 594, 1934 Kling, D.H.: Sedimentation rate of blood corpuscles in synovial fluid and in plasma. Arch. Int .• Med., 50 :419- 434, 1932 Kramer, W.D.: Blood sedimentation rate in diabetes mellitus. J. Lab. and Olin. Med., 21:37-43, 1935-36 Kunz, Hubert: The value of the sedimentation rate in surgery. Medizinische Klinik, 32:1394-1397, 1936. Abstract, Prior and Company, Hagerstown, Md•, 1937 Landau~ A.: Micro-sedimentation. Am. J. Dis. Child., 45:691-734, 1933 Lattes, Leon: History of blood sedimentation. Policlin­ ico (sez prat), 32:1151-1152, 1925. Abstract, Prior and Company, Hagerstown, Md., 1937 La.utmann, M.F.: The sedimentation test in chronic arth­ ritis; its value as an aid to differential diagnosis and treatment. J. Ark. Med. Soc., 33:187-188, 1937 Lesser, Albert and Goldberger, H.A.: The blood sedi- mentation test and its value in the differential diag­ nosis. of acute appendicitis. Surgery, Gynecology and Obstetrics, 60 :157-166, 1935 Lintz, R.M.: The red blood cell sedimentation rate in chronic sinusitis, chronic tonsillitis and dental periapical infections. J. Lab. and Olin. Med., 21:1259-1263, 1935-36 - 99 -

Lyon, J.A.s Rheumatic heart dlsease in children. Med. Rec., 141:239-242, 1935 Mathieu, Albert, Trotman, F.E., Baskins, H.D., Osgood, E.E., and Albert, Joyce: The sedimentation rate in gynecology and obstetrics. Am. J. Obst. and Gynec., 21:197-204, 1931 Meeker, Olan: Theoretical explanation of erythrocyte sedimentation. Clifton Medical Bulletin, Vol. 11, No. 2, June 1925 Merritt, W.A.: The sedimentation rate in general prac­ tice. Minn. Med., 20:99-101, 1937 Miller, Isidore: Blood sedimentation rates in middle­ aged and old people. J. Lab. and Olin. Med.,. 21: 1227-1230, 1935-36 Mora, J.M., and Gault, J.T.s The sedimentation veloc­ ity of erythrocytes in thyrotoxicosis. J. Lab. and Clin. Med., 15:590-592, 1929-30 Morris, W.H.: The value of erythrocyte sedimentation determination in pulmonary.tuberculosis. Am. Rev. Tuberc., 10:431-437, 1924 Morris, W.H., and Rubin, E.li.: · The sedimentation reac­ tion of erythrocytes. J. Lab. and Olin. Med., 11: 1045-1052, 1926 Mos sell, B.F., and Duckett, J.: Evaluation of signs of active rbeuma tic fever; With especial reference to the erythrocyte sedimentation rate and leucocyte count. New England Journal of .Medicine, 215:1269-1276, . 1936 Murphy, F .D.: Disease of the kidney. 6 :549-691, 1937. Tice, F.: Practice of .Medicine, Prior and Company, Hagerstown, Md., 1937 Newham, H.B.: The sedimentation rate of erythrocytes in certain tropical diseases. Quart. J • .Me.d., 20: 371-382, 1926-27 . Nitschmann, w.: Our experience with the erythrocyte sedimentation test.. Deutscbe Mediziniscbe Wocken­ schrift, 51:393, 1925. Dep 1 t. Rev. and Abts., Am. J. Obst. and Gynec., 13:271, 1927 - 100 -

Nungester, W.J., and Klein, Louise K.: Effect of pneu­ mococcus type III specific polysacharide on sedimen­ tation of blood cells. Proc. Soc. Exper. Biol. and Med., 36:315-317, 1937 Oppel, T.W., Myers, W.K., and Keefer, C.S.:. The sedi­ mentation rate of the red blood cells in various types of arthritis. J. Olin. Invest., 12:291-296, 1933 Ostendorf, L.: .Theory and clinical importance of the blood sedimentation. Monatsschrift f~r Beburtscb~fe und Gynakologie, 77:359, 1927. Abstract, Prior and Company, Hagerstown, Md. 1937 Payne, W.W.: Acute rheumatism and the sedimentation rate. Lancet, pp. 74-75, Jan. 9, 1932

Plass, E.D., an(i Rourke, .M.D.: Effect of venous stasis on proteins of blood plasma and in rate of sedimenta­ tion of red blood corpuscles. J. Lab. and Clin. Med., 12 :735-782, 1927 Polak, J.o., and Tollefson, D.G.: The clinical signif­ icance of the sedimentation test. J.A.M.A., 90:168- 172, 1928 Ponder, ·E.: Ori sedimentation and rouleaux formation. Quart. J. Exper. Physiol., 15:236-252, 1925 Reichel, Hans: Blood sedimentation in malignant disease. Medizinische Klinik, 32:1769-1770, 1936. Abstract J.A.M.A., 1937 Reyner, c.E.: The sedimentation of red blood cells. J. Lab. and Clin. M~~., 12:630-635, 1929 Ringer, P.H., and Roach, Mary: The blood sedimentation test; its use as a routine, especially in pulmonary tuberculosis. Ann. Int. Med., 8:258-267, 1934 Riseman, E.F., and Brown, M.G.: The sedimentation rate in angina pectoris and coronary thrombosis. Am. J. Med. Sci., 194:392-3.99, 1937 Roche, Hilary: The blood sedimentation rate in pulmonary tuberculosis; its value in the management of the patient.· British Med. J ., pp. 466-468, Jan.-June, 1932 - 101 -

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Short, C.L., Dienes, Louis and Bauer, Walter: Rheuma­ toid arthritis. J.A.M.A., 108:2087-2091, 1937 Smith, C.T., Harper, Thelma and Watson, Anna: Sedi­ mentation time as an aid in differentiating acute appendicitis and acute salpingitis. Am. J. Med. Sci., 189:383-387, 1935 Stainsby, Wendell J.: The practical value of the er·ythrocytic sedimentaticn test. Med. Olin. No. Am., 18:911-915, 1934 Stainsby, W.J-., and Nicholls, E.E.: The clinical sig­ nificance of 'the erythrocyte sedimentation test in rheumatoid arthritis. J. Olin. Invest., 12:1041. 1049, 1933 Tulipan, L., and Director, w.: The sedimentation test in dermatology. Arch. Darm. and Syph., 27:759-765, 1933 Uffe, Alexander: Blood sedimentation rate in allergic disease. J. of Allergy, 4:379-384, 1932-33 Walton, A.C.R.: Erythrocyte sedimentation test; clin­ ical and experimental study. Quart. J. Med., 2:79- 115, 1933 Walton, A.c.R.: The corrected erythrocyte sedimenta­ tion test. J. Lab. and Clin. Med., 18:711-723, 1933 (same article as above reference) Waugh, T.R.; Blood sedimentation test; its history, technique, nature and clinical application. Can. Med. Assn. J., 13:604-609, 1923 Weiss, A.: Blood sedimentation: Prognostic value in arthritis; a modification of technique. Am. J. Med. Sci., 1811379-392, 1931 Westcott, H.F., and Spain, w.c.: Sedimentation of red blood cells in allergic dis eases. J. of Allergy, 4s370-378, 1932-33 Westergren, A.: Technique of red cell sedimentation reaction. Am. Rev. Tuberc., 14:94-101, 1926 Westergren, A.: The red cell sedimentation reaction in some a cute infectious conditions and in diseases of the jo:i,.nts. Int. Olin., 1:70-77, 1928 - 103 -

White, P.D.: Heart Diseases, Second Edition, pp. 243, The Macmillan Co., New York City, 1937 Williams, P .F.: Is the sedimentation test of practical value in gynecology. Am. J. Obst. and Gynec., 13: 22 8-233, 1927 Wintrobe, M.M., and Landsberg, J.w.: Standardized tech­ nique for sedimentation test. Am. J. Med. Sci., 189: 102-115, 1935 Wood, Paul: The erythrocyte sedimentation rate in dis­ eases of the heart. Quart. J. Med., 5:1-19, 1936 Yardum.ian, K.: Physicochemical factors influencing the red cell sedimentation rate. Am. J. Olin. Path., 7:105-119, 1937 Zwecker, O.T ., and Goodall, H.: Sedimentation rate or erythrocytes. Am. J. Med. Sci., 169:209-216, 1925,

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