COMPARATIVE STUDIES ON ADRENAL CORTICAL FUNCTION
`AND CORTISOL METABOLISM IN HEALTHY ADULTS AND
`IN PATIENTS WITH SHOCK DUE TO INFECTION
`
`BY JAMES C. MELBY AND WESLEY W. SPINK
`
`(From the University of Minnesota Medical School, Minneapolis, Minn.)
`
`(Submitted for publication April 28, 1958; accepted August 28, 1958)
`
`the adrenal glands has
`Secretory failure of
`continued to be implicated as a factor in the patho-
`genesis of peripheral circulatory collapse due to
`infection since the original
`reports of Water-
`house (1) and of Friderichsen (2). This as-
`sociation of adrenal function and circulatory fail-
`ure has been cited in recent reviews (3-5). How-
`ever, a deficit of adrenal secretory products or
`their urinary metabolites in peripheral collapse
`due to infection has not been reported.
`Investiga-
`tions in our laboratory have shown that shock
`produced in dogs by endotoxins of gram—nega-
`tive bacteria was accompanied by an elevation of
`the concentration of cortisol
`in the plasma, and
`the output of cortisol
`in adrenal venous blood
`rose abruptly immediately after the injection of
`endotoxin (6).
`This report is concerned with the assessment of
`adrenal cortical function in human patients having
`peripheral circulatory failure due to severe in-
`fections.
`Studies with a 21—hemisuccinate ester
`
`of cortisol, which is rapidly hydrolyzed to free
`cortisol in viva, were undertaken in order to de-
`lineate the metabolism of cortisol,
`the principal
`adrenal secretory product in man (7).
`
`M ETH ODS
`
`The subjects in this study included 9 healthy adults and
`22 patients with severe infections complicated by circu-
`latory collapse. Fifteen of these patients had demonstra-
`ble bacteremia at the time the studies were carried out.
`All of the patients were hypotensive with systolic blood
`pressures under 90 mm. of Hg. A summary of the clini-
`cal data on these patients is recorded in Table I.
`Blood samples for the determination of cortisol con-
`centrations in the plasma were analyzed by a modification
`of the method of Silber and Porter (8) as described by
`Peterson, Karrer and Guerra (9). This method is spe-
`cific for steroids with the 17,21-dihydroxy-20-keto con-
`figuration including cortisol, cortisone, Compound S and
`their dihydro- and tetrahydro- derivatives. Of these, only
`cortisol exists in the plasma in significant concentrations;
`therefore, the method may be regarded as highly specific
`for cortisol.
`
`in eight normal
`Adrenal stimulation was carried out
`subjects and in six patients with shock due to infection
`by an intravenous infusion of 25 U.S.P. units of corti-
`cotropin (Upjohn, Sterile Corticotropin Injection) dis-
`solved in 500 ml. of 5 per cent dextrose in water, which
`was given over a period of four hours. Specimens of 15
`ml. of heparinized blood were secured initially and at the
`conclusion of the infusion of corticotropin. The erythro-
`cytes were separated from the plasma within 30 minutes.
`The samples were frozen and plasma cortisol
`levels
`were determined within 72 hours.
`In order to determine the rate of disappearance of
`exogenous cortisol, an intravenous injection of 100 mg. of
`cortisol sodium succinate dissolved in 2 ml. of distilled
`water (Upjohn, Hydrocortisone Sodium Succinate) was
`given to each of 9 normal subjects and to 20 patients with
`shock. Samples of blood were obtained immediately pre-
`ceding the injection of cortisol sodium succinate and at
`30, 90, 150, 210 and 270 minutes thereafter in the patients
`with shock. The blood specimens were treated as above.
`The sodium succinate ester of cortisol was employed be-
`cause it is highly soluble and because it can be adminis-
`tered in a small volume of aqueous diluent in a few sec-
`onds. Hydrolysis of
`the ester
`is
`rapid and complete
`within 15 minutes after injection. The ester is not ex-
`tracted from plasma by methylene chloride which is
`employed as the solvent in the determination of plasma
`cortisol (10). The rate of removal of cortisol from the
`plasma of pregnant women was determined after
`the
`rapid infusion of cortisol sodium succinate by Christy,
`Gordon, Longson, Wallace and Jailer
`(11). The dis-
`posal of
`this cortisol ester did not significantly differ
`from cortisol removal rates following infusions of corti-
`sol free alcohol. Madsen, Done, Ely and Kelley (12)
`found no significant differences in the plasma half—time
`of cortisol whether administered as the free alcohol or
`the 21-hemisuccinate ester.
`In patients with shock these procedures were carried
`out within a few hours after the recognition of peripheral
`circulatory failure.
`
`RESULTS
`
`A. Relationship of the clinical status to the out-
`come
`
`The data recorded in Table I reveal that demon-
`strable bacteremia was associated with shock in
`
`70 per cent of the cases. Gram-negative bacteria
`
`1791
`
`Amerigen Exhibit 1163
`Amerigen Exhibit 1163
`Amerigen v. Janssen IPR2016-00286
`Amerigen V. Janssen IPR2016-00286
`
`

`
`JAMES C. MELBY AND WESLEY W. SPINK
`
`TABLE I
`
`Clinical data on 22 patients with peripheral circulatory failure due to infection
`
`Diagnosis
`
`Bacteriology
`
`Source of
`bacteria
`
`Blood
`DIESSIIYC
`
`Duration
`of hypo-
`tension
`
`Temp.
`in F.
`
`Skin
`appearance
`
`Lobar pneumonia
`
`D. pneumo-
`coccus
`
`Sputum
`
`80/55
`
`Diabetes, urinary
`tract infection
`
`Prostatic hypertrophy,
`cystoscopy
`
`Postoperative
`ovarian cystectomy
`
`Urethral stricture,
`cystoscopy
`
`Pseudomembranous
`enteritis
`
`E. coli
`
`E. ooh’
`
`E. colt"
`
`Proteus
`
`Staph.
`
`Blood
`Urine
`
`Blood
`Urine
`
`Urine
`
`Blood
`Urine
`
`Feces
`Blood
`
`60/30
`
`84/50
`
`50/30
`
`72/50
`
`64/36
`
`24 hrs.
`
`105.0
`
`24 hrs.
`
`103.0
`
`16 hrs.
`
`104.4
`
`24 hrs.
`
`105.0
`
`12 hrs.
`
`103.2
`
`Warm,
`suffused
`
`Warm,
`suflused
`
`Warm,
`suffused
`
`Warm,
`suffused
`
`Warm,
`sufiused
`
`Outcome
`
`Recovered
`
`Recovered
`
`Recovered
`
`Recovered
`
`Recovered
`
`M. tuberculosis
`
`24 hrs.
`
`36 hrs.
`
`104.0
`
`Cold, moist
`
`Recovered
`
`Recovered
`
`Recovered
`
`Died
`
`Died
`
`Miliary tuberculosis
`
`Sputum
`
`74/44
`
`104.0
`
`24 hrs.
`
`102.2
`
`Warm,
`suffused
`
`Warm,
`suffused
`
`TUR, metastases from
`cancer of renal pelvis
`
`E. coli
`
`. Osteomyelitis,
`pyelonephritis
`
`Chronic lymphatic
`leukemia, peritonitis,
`cirrhosis
`
`Peritoneal abscess,
`metastatic adeno-
`carcinoma of colon
`
`Massive pneumonia,
`renal abscess
`
`Cancer of prostate,
`pneumonia
`
`Perforated ulcer
`with peritonitis
`
`Postoperative bowel
`obstruction, staph.
`septicemia with
`metastatic abscesses
`
`Pyelonephritis,
`cholangitis,
`purpura, hepatic
`abscesses
`
`Suppurative
`peritonitis,
`postoperative
`gastrectomy
`
`Pulmonary emboli
`
`Total gastrectomy for
`cancer of stomach,
`post-gastrectomy
`
`Staph.
`
`Staph .
`
`Proteus
`E. coli
`
`Staph.
`
`Pseudomonas
`E. coli
`
`Pseudomonas
`
`E. ooh’
`Strep. viridans
`Proteus
`Staph.
`Pseudomonas
`
`30/50
`
`86/56
`
`50/0
`
`Blood
`Urine
`
`Blood
`Wound
`
`Blood
`Peri-
`toneal
`fluid
`
`Blood
`
`Blood
`Sputum
`
`Sputum
`Urine
`
`Peri-
`toneal
`fluid
`
`Blood
`Urine
`
`Blood
`Peri-
`toneal
`fluid
`
`Urine
`Blood
`
`Sub-
`phrenic
`abscess
`Empyema.
`
`80/50
`
`80/0
`
`2 wks.
`
`104.0
`
`Cold, moist
`
`48 hrs.
`
`101.0
`
`Cold, moist
`
`Cold, moist
`
`Cold, moist
`
`Cold, moist
`
`Cold,
`cyanotic
`
`Cold,
`cyanotic
`
`Cold, moist
`
`Cold, moist
`
`

`
`ADRENAL FUNCTION IN SHOCK DUE TO INFECTION
`
`TABLE I—Cant1'nued
`
`Diagnosis
`
`Bacteriology
`
`Source of
`bacteria
`
`Blood
`pressure
`
`Duration
`of hypo-
`tension
`
`Temp.
`in F.
`
`Skin
`appearance
`
`Outcome
`
`Postoperative
`cholecystectomy,
`diabetes mellitus
`
`E. colt’
`
`Blood
`
`66/30
`
`24 hrs.
`
`102.0
`
`Cold, moist
`
`Died
`
`Urethral stricture
`
`E. coli
`
`Postoperative
`cancer of stomach
`
`Pseudomonas
`aeruginosa
`
`Urine
`Blood
`
`ne
`
`Uri
`Sputum
`
`78/50
`
`24 hrs.
`
`101.0 Warm,
`sufl'used
`
`Recovered
`
`80/54
`
`24 hrs.
`
`103.0 Warm,
`sufiused
`
`Recovered
`
`tensive for an average of 23 hours, the patients
`who succumbed were hypotensive for an average
`of six to seven days. Pressor substances were
`used to maintain blood pressure during the hy-
`potensive period and all patients were considered
`to be hypotensive until they no longer required
`pressor substances for the maintenance of blood
`pressure.
`
`were most frequently isolated. The severity of
`the underlying infectious process is emphasized
`by the fact that staphylococci were isolated from
`the blood in 50 per cent of those who died. Nine
`autopsies were performed in the series and no
`adrenal pathological change could be demon-
`strated, except in one patient, who had a hema-
`toma of a single adrenal. A characteristic dif-
`ference in the appearance of those who died from
`those who recovered was
`recorded frequently
`enough to note. The patients who succumbed
`The results of this study are given in Table II.
`displayed more often an ashen gray, cold, moist
`In the healthy subjects the concentrations of
`skin with mottling and cyanosis such as is en-
`plasma cortisol averaged 13 pg. per 100 ml., with
`countered in severe hemorrhagic shock.
`The
`a range of from 7 to 22 pg. per 100 ml.
`In this
`survivors had suffused, warm skin and a full pulse
`control group, all samples were obtained at 8:00
`in the presence of hypotension. The dichotomy
`am. The mean plasma cortisol concentrations of
`in the clinical picture of shock has been re-
`patients with shock due to infection was 63 pg.
`ported by Waisbren (13)
`and by Hall and
`per 100 ml., ranging from 30 to 160 pg. per 100
`Gold (14). The two groups differed significantly
`ml.
`The mean plasma cortisol concentration
`in the period of time they remained hypotensive.
`for the patients in shock was initially higher than
`Whereas the patients who recovered were hypo-
`TABLE II
`
`B. Concentration of cortisol in the plasma
`
`Concentration of cortisol in the plasma
`
`Patients with shock due to infection
`
`Survivors
`
`29
`
`Age
`
`Sex
`
`pg./100 ml.
`
`Fatalities
`
`No.
`
`Age
`
`Sex pg./I00 ml.
`
`28
`70
`64
`54
`60
`38
`S2
`79
`
`0O\lO\UInk<»N_r-
`
`47
`40
`49
`S3
`41
`43
`40
`78
`
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`58
`72
`60
`84
`73
`48
`85
`62
`53
`62
`67
`72
`
`30
`82
`69
`120
`61
`160
`72
`45
`68 -
`36
`54
`74
`
`Mean = 50 :1: 12
`Range = 40-78
`
`Mean = 73 :l: 34
`Range = 30-160
`
`2.°
`
`Normal subjects
`Age
`Sex
`pg./I00 ml.
`
`24
`23
`23
`19
`37
`22
`23
`31
`42
`
`§§E§""""§EE
`
`\OOO\lO\UlI5C»Is.)r-
`
`11
`12
`9
`22
`10
`16
`7
`17
`11
`
`Mean = 13 :l: 4-‘
`Range = 7-22
`
`* Standard deviation.
`
`

`
`1794
`
`JAMES C. MELBY AND WESLEY W. SPINK
`
`the mean plasma cortisol concentration in normals
`after a four hour infusion of corticotropin.
`In
`only one patient with shock was
`the plasma
`cortisol
`level within the normal
`range as ob-
`tained in this laboratory. The highest concentra-
`tions were found in the moribund patients.
`
`C. Effect of an intravenous infusion of cortico-
`tropin on plasma cortisol concentrations
`
`The results for normal subjects and for pa-
`tients are summarized in Tables III and IV.
`
`Four hour intravenous corticotropin tests were
`performed in eight normal
`individuals.
`The
`mean control value for cortisol was 15 pg. per 100
`ml. of plasma, with a range of 5 to 24 pg. per
`cent. Following the infusion of corticotropin, the
`concentrations rose to a range of 32 to 63 pg. per
`cent with a mean of 46 pg. per cent. Rarely
`have values exceeded 65 pg. per cent in normal
`subjects after corticotropin. Four hour cortico-
`tropin tests were carried out in six patients with
`shock. The initial plasma cortisol levels averaged
`53 pg. per 100 ml. and ranged from 36 to 76
`pg. per 100 ml. After a four hour infusion of
`corticotropin the cortisol
`levels rose to an aver-
`age level of 100 pg. per 100 ml. of plasma, with
`a range of 81 to 119 pg. per 100 ml. Three of
`the patients given corticotropin, all of whom died
`(Nos. 18, 19 and 20), had average postcortico-
`tropin infusion levels of 112 pg. per 100 ml. of
`plasma, whereas the mean value in three patients
`who recovered was 88 pg. per 100 ml. Sand-
`
`TABLE III
`
`Eflecl of corticotropin (25 U.S.P. units intravenously over a
`four hour period) on plasma cortisol concen-
`trations in normal subjects
`
`Plasma cortisol (pg./100 ml.)
`After
`Before
`cortico-
`cortico-
`tropin
`tropin
`
`16
`5
`19
`15
`10
`24
`14
`21
`
`52
`32
`40
`63
`33
`44
`51
`52
`
`O0\lO\<IIn-FOJIQI-d
`
`Mean = lS:I:6* Mean = 46:l:10
`Range = 5-24
`Range = 32-63
`
`* Standard deviation.
`
`TABLE IV
`
`Efiect of corticotropin (25 U.S.P. units intravenously over a
`four hour period) on plasma cortisol concentrations
`in patients with shock due to infection
`
`Patient
`no.
`
`Age Sex
`
`Outcome
`
`18
`20
`19
`3
`21
`22
`
`62 F
`72
`67 M
`64 M
`86 M
`75 M
`
`Died
`Died
`Died
`Recovered
`Recovered
`Recovered
`
`Plasma cortisol (pg./I00 ml.)
`Before
`After
`conica-
`cortico-
`tropin
`tropin
`
`36
`76
`5 1
`57
`45
`57
`
`1 19
`104
`l 14
`81
`96
`86
`
`Mean = 53 Mean = 100
`Range = 36- Range = 81-
`76
`119
`
`berg, Eik-Nes, Migeon and Samuels (15) have
`reported similar values in agonal patients.
`In
`their study the injection of cortisol—4—C“ into
`dying patients resulted in a reduced urinary ex-
`cretion of radioactive metabolites when compared
`with the normal. They concluded that the high
`levels of plasma cortisol that they obtained were
`due to impaired metabolism in the presence of
`normally functioning adrenals. Urinary 17-hy-
`droxycorticosteroid determinations were not made
`in the patients reported in this study because
`nearly all of the patients were oliguric and some
`rapidly developed azotemia. Under usual circum-
`stances the excretion of urinary l7-hydroxycorti—
`costeroids is a valuable index of cortisol produc-
`tion. But in shock, where there exists a reduc-
`
`tion in urinary output coupled with retention of
`conjugated cortisol metabolites
`in the plasma,
`the results would be unreliable (16).
`
`D. The rate of disappearance of infused cortisol
`sodium succinate from the plasma
`
`Levels of plasma cortisol following the rapid
`infusion of 100 mg. of cortisol sodium succinate
`are shown in Figure 1.
`It is to be recalled that
`the mean initial plasma concentrations of cortisol
`in the patients who recovered and in those who
`died were significantly elevated compared to the
`values found in the normal subjects. However,
`in the patients who died,
`the initial levels were
`higher than those in the patients who survived.
`Levels of cortisol in the plasma after the infusion
`of cortisol sodium succinate are plotted on semi-
`logarithmic paper at various time intervals. The
`
`

`
`ADRENAL FUNCTION IN SHOCK DUE TO INFECTION
`
`0 Control (8)
`0 Died (12)
`e Recovered (8)
`
`initial preinfusion or endogenous values are not
`subtracted from the
`subsequent
`postinfusion
`levels.
`It should be noted that in the patients
`who survived most of
`the postinfusion plasma
`cortisol concentrations were less than the initial
`
`Scheuer
`concentration of endogenous cortisol.
`and Bondy (17) demonstrated in healthy sub-
`jects that plasma cortisol concentrations were
`lower
`than endogenous preinjection concentra-
`tions at five to seven hours after the injection of
`100 mg. of cortisol-free alcohol.
`It cannot be
`assumed that the basal plasma levels of cortisol
`remain constant after an infusion of cortisol
`in
`
`in the light of consider-
`the “stressed” subject
`able experimental evidence.
`Sydnor
`(18) has
`shown that
`the intravenous administration of
`
`cortisol to bilaterally adrenalectomized “stressed”
`rats efiectively inhibits corticotropin secretion.
`Brodish and Long (19)
`in similar experiments
`found that complete inhibition of corticotropin
`release is accomplished within 5 to 20 minutes fol-
`lowing the infusion of cortisol. Richards and
`Pruitt (20), using permanent adrenal vein can-
`nulas in dogs, suppressed maximal adrenal secre-
`tory acivity after the induction of respiratory aci-
`dosis and operative trauma by infusions of corti-
`sol. Thus, it would seem unjustified to subtract
`initial plasma cortisol values from postinfusion
`values in patients with shock.
`In Table V,
`the individual plasma biological
`TABLE V
`
`Biological half-time of plasma cortisol after the intravenous
`injection of 100 mg. of cortisol as the
`21-hemisuccinate
`
`Healthy adults
`Subject
`Ti
`no.
`(min.)
`
`110.0
`102.1
`78.9
`65.7
`112.5
`131.2
`70.0
`142.8
`
`®\IO\UIb§CNI\JI-
`
`Patients with shock due to infection
`Survivors
`Fatalities
`
`Patient
`no.
`
`T}
`(min.)
`
`Patient
`no.
`
`T}
`(min.)
`
`106.2
`79.5
`85.9
`87.1
`105.8
`80.6
`95.4
`120.0
`
`0O\IO\UIrkoaI\)I—A
`
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`169.1
`332.3
`566.1
`661.5
`300.0
`592.1
`360.8
`578.8
`1,020.3
`444.3
`420.0
`173.0
`
`Mean = 101.6
`Range = 65.7—
`142.8
`
`Mean = 95.1
`Range = 79.5——
`120.0
`
`Mean =468.2
`Range = 169.1-
`1,020.3
`
`
`
`
`
`
`
`(N O
`
`PLASMACORTISOL(pg./I00ml.) N0
`
`A O
`
`I00 mg. of cortisol (as the
`/ hernisuccinate)
`I.V.
`2|O
`90
`I50
`TIME IN MINUTES
`
`270
`
`FIG. 1. RATE or DISAPPEARANCE or CORTISOL (IN-
`JECTED As THE 21—HEMISUCCINATE)
`‘I-‘ROM PLASMA or
`PATIENTS WITH SHOCK DUE TO INFECTION
`
`half-times for cortisol were compared in healthy
`subjects, in patients who survived and in patients
`who died from shock due to severe infection.
`
`The mean biological half-time of cortisol in the
`normal subjects was found to be 101.6 minutes.
`In patients who recovered,
`this value was 95.1
`minutes and in those. who died, 468.2 minutes.
`The biological half-time of cortisol in the plasma
`is determined to a large extent by the functional
`integrity of the liver (16). Liver function tests
`were performed in six of the moribund patients.
`These were abnormal
`in all six patients tested.
`Liverfunction was assessed in four of the pa-
`tients who survived and was found to be normal
`
`four patients. The half-time values of
`in all
`plasma cortisol
`in the healthy subjects and in
`the patients who survived are not significantly
`difierent.
`
`DISCUSSION
`
`The most significant feature in this study is that
`patients with shock due to an infection did not
`exhibit evidence of adrenal
`insufficiency. High
`concentrations of cortisol were present
`in the
`plasma in all patients studied. Furthermore, even
`in agonal patients there was a continued response
`of the adrenals to stimulation with corticotropin.
`
`

`
`1796
`
`JAMES C. MELBY AND WESLEY W. SPINK
`
`in the plasma of
`The high levels of cortisol
`the patients who recovered would appear to be
`solely due to an acceleration of the rate of produc-
`tion of endogenous cortisol because the admin-
`istered cortisol disappeared from the plasma at a
`normal rate. On the other hand, the greater con-
`centration of cortisol in the plasma of moribund
`patients may be accounted for, in part, by factors
`retarding the removal of cortisol from the blood
`and by increased cortisol production. The rela-
`tive contribution of adrenal secretory activity to
`the high blood levels of cortisol could not be de-
`termined in the presence of impeded removal of
`injected cortisol from the plasma in the moribund
`patients. However, documented clinical and ex-
`perimental evidence indicates that adrenal secre-
`tion of cortisol may be supranormal under similar
`conditions, in that the blood cortisol and urinary
`17-hydroxycorticosteroid excretion were markedly
`elevated in patients dying of severe burns (21).
`Dogs subjected to hemorrhagic shock demon-
`strated a maximal secretion of cortisol (22). The
`shock induced in dogs by lethal
`injections of
`bacterial endotoxin is associated with high blood
`levels of cortisol and maximal secretion of corti-
`
`sol in the adrenal venous efiiuent (23).
`Factors influencing the slope of
`the plasma
`cortisol removal curves have been reviewed by
`Samuels, Brown, Eik-Nes, Tyler and Dominguez
`(16).
`If the curves plotted in Figure 1 are ex-
`trapolated to zero time it will be seen that the
`values obtained-for the survivors and fatalities are
`not
`significantly different.
`Samuels and co-
`workers (16) refer to this value as the “apparent
`distribution volume” of cortisol. Thus, it appears
`unlikely that changes in the volume distribution
`of cortisol account for the difference observed.
`
`function, hepatic
`Impairment of hepatocellular
`blood flow, renal function and thyroid function
`all operate to reduce the rate of metabolic disposal
`of cortisol. All patients studied who were mori-
`bund were either markedly oliguric or anuric.
`The patients who survived demonstrated less
`significant abnormalities of
`renal
`function,
`:'.e.,
`mild azotemia and transient oliguria.
`Among the patients who died of bacterial
`shock, significant abnormalities of liver function
`were demonstrated.
`In none of
`the survivors
`
`studied was hepatic function significantly dis-
`turbed.
`In human patients major surgical pro-
`
`cedures (24), agonal states (15), certain acute
`infectious diseases in childhood (25), myxedema
`(26) and liver disease (27) have been associated
`with reduced plasma
`cortisol
`removal
`rates.
`Tourniquet shock (28)
`retards the turnover of
`cortisol—4—C1‘ in the rat.
`In the dog lethal doses
`of endotoxin induce shock and slow the removal
`
`of injected cortisol from the plasma (23).
`Eik-Nes and Samuels (29) have roughly cor-
`related the severity of “stress” with the degree
`of impairment of cortisol removal from the plasma
`of the dog—the more severe or lethal the “stress,”
`the greater the reduction of the rate of removal of
`cortisol from the plasma. Our own studies con-
`firm this view (30).
`It should be pointed out
`that small doses of bacterial polysaccharide (0.1
`to 2.0 pg.) injected into the dog accelerate the
`removal of exogenous cortisol from the plasma,
`whereas larger doses have the opposite effect.
`These observations
`supplement
`the results of
`McDonald, Weise and Peterson (31) who in-
`jected a bacterial pyrogen (Piromen@)
`into hu-
`mans and noted a rise in plasma cortisol and an
`acceleration of the removal of exogenous cortisol
`from the plasma.
`Although several factors probably influence the
`removal
`rate of exogenous cortisol
`from the
`plasma,
`it is conceivable that one of the most
`important
`independent variables
`in this study
`was the size of the bacterial
`inoculum and the
`amount of endotoxin made available.
`
`Peterson, Pierce, Wyngaarden, Bunim and
`Brodie (32) have been unable to correlate the
`rate of disposal of cortisol or its analogs with
`its biological activity. Neither does cortisol ex-
`ert
`its biological effects as a by-product of its
`catabolism. Any speculation as to rate of “utili-
`zation” of cortisol
`is not
`relevant. The term
`
`“relative adrenal insufficiency” in vascular collapse
`due to infection is misleading because the con-
`centration of biologically active cortisol
`in the
`plasma is
`supraphysiologic. Daughaday (33)
`has demonstrated two protein binding systems
`for cortisol in the plasma. The first, a globulin,
`is saturated at plasma levels of between 15 and
`30 pg. per 100 ml. The second, albumin, binds
`cortisol more loosely and can accomodate high
`plasma concentrations of cortisol. This system
`is easily reversible and readily allows dissociation
`of cortisol so that it may traverse the capillary
`
`

`
`ADRENAL FUNCTION
`
`IN SHOCK DUE TO INFECTION
`
`1797
`
`measured in terms of change in plasma cortisol
`concentration. Third, the biological half—time of
`exogenous cortisol injected as thesuccinate ester
`in plasma was evaluated.
`2. All of the patients with shock had consider-
`ably higher basal concentrations of cortisol in the
`plasma than did the healthy subjects.
`.In six pa-
`tients with shock who were studied there was a
`
`response to corticotropin similar to that' obtained
`in the healthy adults. The biological half—time
`of exogenous cortisol was not different
`from
`healthy subjects in those patients with shock who
`survived, but in those patients having fatal shock
`the biological half—time was considerably more
`prolonged than that observed in healthy subjects.
`The significance of these differences is discussed.
`3. Accelerated adrenal secretory activity was
`demonstrated in those patients who survived.
`In
`moribund patients unequivocal proof for increased
`adrenal secretory activity could not be obtained.
`
`ACKNOWLEDGMENT
`
`We deeply appreciate the technical assistance of Mrs.
`Harriet A. Aaker.
`
`REFERENCES
`
`membranes and become directly available to the
`tissues. Thus, it is likely that when the globulin
`system is exceeded the excess of plasma cortisol
`is freely diffusible.
`In the present study it would
`appear
`that under normal conditions adequate
`amounts of diflusible cortisol were available to
`
`the tissues in all of the patients studied. But
`under the unphysiologic conditions of shock these
`hormonal concentrations are insufficient. Obser-
`
`vations on patients in shock and investigations in
`animals with endotoxin shock make it apparent
`that the necessary amount of exogenous cortisol
`or its synthetic analogs far exceeds that which
`can be produced by maximal endogenous secre-
`tory activity (5).
`The importance of the relationship between the
`plasma concentration of readily diffusible corti-
`sol and the degree of tissue injury has been demon-
`strated experimentally.
`These studies will be
`reported in detail elsewhere (34), but
`the es-
`sential data can be cited here. After dogs had
`been injected intravenously with endotoxin pre-
`pared from E. coli, there was a prompt rise in
`the plasma concentration of cortisol, and a rise
`in the level of serum glutamic oxaloacetic trans-
`aminase.
`It is generally assumed that elevations
`in serum transaminase are associated with cellular
`
`It was apparent that maximal endogen-
`injury.
`ous secretion of cortisol did not ‘prevent the rise
`in transaminase levels. However, when large
`doses of cortisol were administered to the dogs
`along with the endotoxin there was only a small
`rise in the levels of transaminase. These observa-
`
`tions suggest that the level of cortisol concentra-
`tions found within the physiological range are
`inadequate for protection against
`tissue injury.
`These observations support
`the concept
`that
`if
`cortisol
`is to be used as a therapeutic agent in
`fulminant sepsis with vascular collapse, its action
`and therefore its dose should be pharmacologic.
`In this context
`it does not represent “replace-
`ment” therapy.
`'
`
`SUM MARY
`
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`adults and in 22 adult patients having shock due
`to infection. Three quantitative studies were
`employed. First, the basal plasma cortisol level
`was determined.
`Second,
`the response of
`the
`adrenal
`to stimulation with corticotropin was
`
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