Acknowledgements The clindamycin hydrochloride for preparing standards was provided by Upjohn Pty. Ltd. Miss E. Campbell typed the manuscript.
2. PHII.I.IFS. I.. FtwhAsua. R. and WARM& C. (1970): In r i m cnmprison of erythromycin. linmmycin and clindam)rin. Birr. m d . 1. 2. 89. 3. WM;XI:R. J. G.. ~ ~ I N A K 8.. , PATEL.S. C.. Cirirmnr. C. G. a d Luuns. W. 1.11968): Abborptinn. ncncion and half-life of clinimycin h normal adult mdn. Amrr. 1.med. Sri. 256. 25. 4. BI'SMTT. 1. V.. Bmm. J. I... BFNSER.E. J. and Kinnv. W. Y. M. (1%6): RimpliRcd. x c u i d i c n:clhn! Vor antihiotk assay of clinical specimens.
I,,,"' I/,* r.L,..i 14 : 7 1 5 l l ~ l l \ K~ ~X ,I . Y I I I I I ~ .C Y.. Si~riri~ksmnli. I).. V A X ~ Bmr!l. ~S U 1) .m.1 \I%rnm\. E I :IV:i. Pharmarokinniu studies ofclindamycrn :;\':ran~.hivi:du in hiln!cn.. Iw C 7 1 r . 12rrs.ni.rhw. Tariiul. 6. 105. E 1 NII\~LJ I m J l i i t n i ~ I' X I 119591: Ilcrnudiulyrir propcaies ofclindamycin I '-~hlur~i-.-Jcn\?::nuom)cinI. Appr. .Wicroblal. 17, 446.
..
A u t . N.Z. J. Med. (1975). 5,pp. 202-210
A Study of Serum and Myocardial Digoxin Concentrations in Man During Cardiac Arrest G. J. Schapel", M. R. Hawkinst and K.
D.G.
Edwards
F r o m t h e K e i t h K i r k l a n d R e n a l Unit. M e d i c a l Research D e p a r t m e n t , Kanematsu M e m o r i a l I n s t i t u t e . S y d n e y Hospital, Sydney
SUrnmary:
A study of serum and myocardial digoxin concentrations in man during cardiac arrest. G . J. Schapel, M R. H a w k i n s a n d K. D G Edwards, Aust. N.Z.J. Med., 1975, 5, pp. 202-210.
In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 ( & I ,86, range 0.6-8.2) ng/ml, significantly higher ( P < 0.001 ) than the "eudigitalized" concentration (1.3 f0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ngjml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 f 2 . 6 6 v. The research program was supported by a grant from the National Health and Medical Research Council of Australia 'Present address: Clinical Pharmacology Division, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, U S.A tPresent address. Department of Nuclear Medicine and Endocrinology, Royal North Shore Hospital, St. Leonards, N.S.W 2065. Correspondence. Dr G J. Schapel Accepted for publication. 2 December, 1974.
1 f 0 . 2 6 mg/dl for non-toxic subjects, P < O.OOl), partly due to a higher mean daily digoxin dose (0.40 v. 0.31 mg/day, P < 0.05) and frequently associated with potent diuretic therapy (73 v. 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (1 4%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 ( k 6 3 . 3 , range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91 ). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration ( r = 0.8107, P < 0.01) or serum creatinine concentration ( r = 0.4637, P < 0~001). Digitalis intoxication, held to be among the most common adverse drug reactions'. has been estimated to carry more more than twice the mortality rate of the non-toxic state.' No specific cardiac dysrhythmia i s considered pathognomonic of digitalis toxicity', while the correlation between drug dosage and the electrocardiogram i s said to be unsatisfactory3.
JUM
-
1975
CARDIAC AKRkST
20 3
~~
although that between serum digoxin level and electrocardiogram has been rcported to be ~ignificant.~ Since the advent of serum digoxin radioimmunoassay as a more objective. convenient and precise means of assessing the state of digitalization5. 6 , ’. monitoring of the properly standardized or “eudigitalized” serum digoxin level8 has enabled the potential hazards of long-term therapy to become largely avoidable, especially where intoxication is most likely, namely in renal failure and old The present study attempts to examine the relationship of the serum digoxin concentration to cardiac arrest and associated factors considered relevant in both digoxin therapy and cessation of effective spontaneous cardiac function. Previous experimental studies in animals haveattempted to define therelationship between serum and myocardial digoxin levels and the factors influencing this.’ 2-25 Human studies to date have provided rather limited information on the myocardial to serum digoxin ratio during therapeutic circumstances. Initially this was attempted through the estimation of tissue pools and turnover rates of isotopically labelled digoxin2”28 and subsequently by reports on the concentration of digoxin in blood versus atrial and papillary muscle samples removed at the time of cardiac surgery.27*29-31 M ore recently, a brief preliminary study of left ventricular and serum digoxin levels in two fatal cases of digoxin self-poisoning was also reported.32 In the present study, specimens of left-ventricular myocardium were obtained from eight patients Gthin 24 hours of death to enable comparison of their digoxin levels with the concentration of digoxin in the blood sampled during the preceding cardiac arrest. The use of human left-ventricular myocardial tissue obtained in this manner provided information relevant to the situation which existed during long-term digoxin therapy at a time when the inotropic and electropathologic effects of digoxin could be critical factors in human survival. It was also hoped to identify parameters of body size that might correlate with criteria of digitalization, such as serum and myocardial digoxin concentrations, which might enable more precise digoxin dosage to be estimated for individual subjects. Furthermore, confir“ 9
’
mation of a relevant serum to myocardial ratio should help to confirm the clinical usefulness of the serum digoxin concentration with respect to the clinical pharmacology and toxicology of digoxin. Patients and Methods
The 40 patients in this study were selected at random on the basis that because of failure of spontaneous circulation to their vital centres and the periphery they received the attention of the cardiac-arrest team33, one of whose members obtained a venous sample of blood as soon as practicable after arrival at the scene, which varied between casualty, intensive care and regular inpatient care wards, in the ratio of 1 to 2 to 2 respectively, more non-digitalized patients presenting in casualty than in the other two ward areas. Serum obtained from the clotted venous blood sample was then frozen and stored in that condition until radioimmunoassay of its digoxin Concentration could be estimated within a week of obtaining each sample, using the method described by Smith, Butler and Haber’, Johnston et a1.34 and Carroll et The “standard error of the method”. calculated from the differences between duplic a t e and ~ ~ as ~ previously reported by us4*’, was 0.2 ng,/ml, representing a coefficient of variation of 14% for the therapeutic mean serum digoxin concentration of 1.4 ngiml. Serum digoxin levels were estimated without prior knowledge of associated digitalis intake, the history of which was documented in retrospect. Myocardial samples were obtained post mortem from the left ventricular wall within 24 hours of declared death after unsuccessful attempt at cardiac arrest resuscitation, during which the relevant serum digoxin and biochemical values were obtained. The left-ventricular myocardial specimens were obtained from seven subjects during autopsy. Two histologically verified specimens from one patient were obtained by percutaneous needle biopsy of the left ventricle using a disposable “Tru-Cut” (Travenol) needle of Vim Silverman type*, 15 minutes after the patient was declared dead, these myocardial specimens weighing 4 . 2 and 8.4 mg. Left-ventricular myocardial specimens dissected free of fat were blotted dry by compression between layers of paper tissue, weighed (approximate weight of each autopsy specimen 200 mg) and without delay were then stored at -10°C immersed in 100% ethanol until extraction immediately prior to radioimmunoassay. Extraction of each piece of myocardium was performed” by homogenization in the 100% ethanol in which the sample of myocardium was allowed to stand overnight at 4°C. The resultant homogenate was centrifuged at 2000 r.p.m. for 10 minutes and the supernatant was decanted and evaporated under a stream of nitrogen until the amorphous deposit which resulted was just moist. This deposit was then re-dissolved in 1.5 to 20 ml distilled water depending on the already estimated, corresponding serum digoxin concentration and weight of the myocardial aliquot. The digoxin concentration of the resultant solution was determined by radioimmunoassay, using the method to which reference has already been made.5*3 1 * 34 Serum creatinine, urea nitrogen, sodium, potassium and chloride concentrations and carbon dioxide combining
* Code 2N 2702 Travenol Laboratories, Incorporated, Morton Grove, Illinois, 60053, U.S.A.
__
.
power were determined using standard Technicon autoanalvzer methods. Serum calcium and magnesium co11centrations were estimated using standard atomic absorption spectrophotometric methods. with corrections for variation due to scrum specific gravity appiied as follows: serum calcium ~ 0 . 2 and 5 magnesium f 0 . 0 5 rngidl per T0.001 units. adjusted toward a serum specific gravity of 1 .027.4. 3 6 , 3 i
-
~
-
~~~
the latter group of patients were documented to have had no previous digitalis intake. The digitalized arrest patients were significantly heavier ( P < 0.05) than the “eudigitalized” group with therapeutic serum digoxin levels (Table 1). The latter possibly indicated adiposity andior fluid retention in the cardiac arrest group. Furthermore, in the arrest subjects, previous cardiac failure may have been occasioned by the higher incidence of coronary artery disease (7796 versus 41 %. Table 1 ) and it may also have been reflected by the greater use of more potent diuretic therapy (73 ”.;, versus 54‘1”. Table 2), to which less effective response may have occurred because of lowering of cardiac output by excessive digitalization. The digitalized arrest patients had been taking a significantly higher daily dose of digoxin (mean 0.40 mg versus 0.31 mgiday, P < 0.05. Table 2) for a significantly shorter duration (mean 6 months versus 44 months, P < 0.05) than the “eudigitalized” subjects. The very frequent intake of diuretic agents in conjunction with digoxin therapy was documented in 71 ;; and 82 0; of patients, both “eudigitalized” and cardiac arrest groups respectively (Table 2). 73:/: of the latter having received the more potent variety, mainly frusemide. compared
Results
Forty patients were investigated at random when they presented because of cardiac arrest. One patient was subsequently excluded from the study because of interference with the radioiminunoassay of serum digoxin by a radioisotope (renal scan) investigation38 within hours of cardiac arrest. Twenty of the remaining 39 patients were retrospectively documented to haw becn taking digoxin (“Lanoxin”). while two subjects wwe known to have been taking lanatoside C (“Cedilanid”) with which the digoxin antibody crossreacts.’ The post-dose collection interval was more than four hours in all but two arrest patients (mean 28 i 31 hours), compared to the mean “eudigitalized”* post-dose collection interval of 6 I 0.3 hours ( P < 0,001). The second subgroup of 17 cardiac arrest patients were similarly investigated and without knowledge of their pharmacological history at the time, were found to have undetectable digoxin in their serum. Subsequently
TABLE 1 Clinicopathological data for cardiac arrest and “eudigitalized” patients (mean valnzs +_ S D and range) Body hurface area
Sex
Paticnt group ~~
-
No. of L .. patients Male Female
-~*~
,
~
..
Agz
(years)
-- ... .
(m2)
.+-.-
Digitalixd cardiac arre\t pa ti en Ii
22
17
9
6 0 x 1 2 1 7 4 k 0 20 123-83) 1 1 26-1 951
Cardiac arrest pa!ients wit!iout eiidence of difitaliration
17
12
5
59+14 (25 X2\
“Eudigitalized“ patienti
41
22
19
’
Body wight
(kg) .~
67**-14 (37 831
.
Height (cm) ~~
,
Heart weight fr)* ~~
~
Cardiac pathology: ”i, of group with diagnosis
____~
-
~.
Coronary artery disease -77;,” Hyperrensive heart disease -14 O D Cor pulmonale-4.5 ”,: Rheumatic heart disease-4.5 yo
1 7 2 k 5 6 436: k 8 7 . 7 (161- 1781 (305-580)
Coronary artery disease-59 %; Hypertensive heart diseaie 29:,: Cardiomyopathy-6 a& Traumatic head injury 6 uo,
6 3 f 1 1 1 6 3 ~ 024 59**+12.7 1 6 7 f 9 . 1 (30 78) 11 24-2 17) 131-96) (142-188)
Coronary artery disease-41 :: Rheumatic heart disease-17 1: Hypertensive heart disease- -10% Cardiomyopathy-7 ”/, Pulmonary thromboemholism -5 ?(J Pericardial neoplasm 2 “j0 Undiagnosed I7 O,;f ~
* Determined after rcmoval at autopsy and included portions of pericardium and roots of great vessels + n o = 15.
i:n o = 9. ** Significantly different by Student‘s t-test (P < 0.05)
~
I67 i- 9 . 5 4 8 8 t k 1 3 4 . 5 (146- 182) (290-770)
JUNE
1975
’
20 5
DIGOXIK LEVELS IN CARDIAC ARREST
-~
-~
TABLE 2 Pharmacological data : Drug intake pre-cardiac arrest or during life (mean dosage i SD and range, or percent of group on drug)
1 Patient group
1
Frusemide or 1 ethacrynic i Diuretic acid ’ Thiazide
Digoxin dosage (mg) Daily
5 day
-L
~~
Digitalized cardiacarrest patients “Eudigitalized” patients
I I
i
I
1.5k0.76
o.4+0.16* (0.125-0.75)
(0.5-2.5)
i s ( 8 2 ~ ) 16(73%)
I
,
to 54% in the former, although the difference did not achieve significance by the chi-square test. No significant differences were apparent between the two groups of cardiac arrest patients (those on and those not on digoxin) with regard to other significant factors affecting the management of a patient requiring urgent resuscitation for cardiac arrest (Table 3). Assessment of any difference in successful response to cardiac arrest resuscitation was difficult here because of the relatively small numbers involved. Fewer digitalized than non-digitalized patients recovered immediately (27 versus 35 %) and fewer were alive at two weeks post-arrest or on discharge from hospital (Table 3), although the differences did not achieve significance (by the chi-square test). The mean serum digoxin concentration in digitalized patients studied during cardiac arrest (2.6k1.86, range 0.6-8.2 ng/ml) and plotted in Figure 1 was significantly higher ( P -=z 0.001) than the mean therapeutic, or “eudigitalized” serum digoxin concentration (1.3 0.52, range 0.5 -2.6 ng/ml), studied under carefully stan-
+
~~
Antikaliuretic Potassium (spironolactone) supplementation Antidysrhythmic
__
~-
j z(9:/;)
2 (9 %)
11 (50%)
4 (10%)
24 (59
nil
I
~
1.5f0.71 29(71%)1 22(54%) (0,3125-3.75) 1 I
0.31f0.15* (0.0625-0.75)
-1
7(17%)
I
m
4(10%)
dardized circumstances and reported elsewhere.4* Eleven of the 22 patients (50%)had serum digoxin levels in the toxic range (2.4ng/ml, or above). The serum creatinine and urea nitrogen of both the arrest groups (on and off‘ digoxin) were significantly higher than those of the “eudigitalized” group (means 2.9 versus 1 .O and 52 and 33 versus 18 mg/dl, respectively, P < 0.001). Thus, as might be expected, the glomerular filtration rate, on which excretion of digoxin depends, was grossly inferior in the critically ill, cardiac arrest population, accounting for the relative digoxin overdosage and toxic serum digoxin levels in these patients. Significant differences in serum carbon dioxide combining power, chloride, calcium and magnesium concentrations (the latter corrected for serum specific gravity, as previously indicated in methods) and in serum specific gravity (Table 4) probably reflected the combined influence of more potent diuretic therapy (Table 2), administration of relatively large amounts of intravenous electrolyte fluids and multiple other therapeutic agents during arrest resusci-
TABLE 3 Cardiac arrest data (mean values 2 SD and range)
Electrocardiogram at onset (percent of group)
1
Patient group Digitalized patients
Duration of Delay in resuscitation (min) 2
($20) Patients without evidence of digitalization
(10-100)
Defibrillation
Resuscitation success Number of (number and percent therapeutic of group agents administered Aliveon 1 discharge during
1
.
~~~~~~
~~
~
~
tation (Table 3) and the more severe renal failure (Table 4) in the cardiac arrest compared to the "eudigitalized" patients. The mean myocardial digoxin concentration for eight patients, documented to have been taking digoxin before cardiac arrest, was 150 ng,(g (SDk63.3, range 52--252ngig) (Table 4), determined on 48 samples of left ventricular wall removed post mortem. The average myocardial to serum digoxin concentration ratio was 62.5 (range 38-91) to one. There was a significant, positive, linear correlation between the serum and myocardial digoxin concentrations ( ( n o = 8, r = 0.8107, P < 0.01, Fig. 2), the regression equation being as follows : myocardial digoxin concentration (ngig) = 30.7 x serum digoxin concentration (nglml) + 67.0. There was also a significant. positive, linear correlation between serum creatinine and serum digoxin concentration in both groups of digitalized patients (Fig. 3) with the following regression equation : serum digoxin concentration (ngiml) = 0.34 x serum creatinineconcentration (mg,'dl)+l.2 ( n = 63, T = 0.4637, P < 0.001). There was no significant correlation between any of the following and the myocardia1:serum digoxin concentration ratio : serum urea nitrogen and creatinine concentrations: daily or five-day digoxin dose, heart weight or body surface area. Nor was there any significant correlation between serum digoxin concentration and either body surface area or heart weight.
... .. .. .
a
---I
I FIGURE I Serum digoxin concentration in 22 patients during cardiac arrest and 41 "eudigitalized" patients, siqnificantly different by Student's t test ( P < 0 001)
Cardiac enlargement3' was observed at autopsy in both the digitalized and nondigitalized arrest sub-groups whose mean cardiac weights were 488 and 436 g respectively. Unlike findings previously reported39,40, in the
TABLE 4 Relevant laboratory data for cardiac arrcst and "rudigitalired" patients (mran values
I V)d,go\r ingd ~
+ SD and range,
Lleilllnlne
(mg!dl)
._. ..
*
-
2 6 ? I .86+ 150-63 3 2 - 9 + 2 6 6 t 10.4 8 21 152-2521 . (0 5-11) Cardiac arrest patient\ , < 0.3 t i ",I++ 2 9_12 94 Digitalired cardiac arrest patients without evidence or digitalization
np:ml
"Eudlgitalired" patients
1 .1+0-52+ 10.5. 2-61
S o m a 1 range for this laboratory
10.5-7.31
* Serum calcium and magncsiurn
,
significant
(0.94-10.4)
-
I i0 26t (0 6-1 6)
-
,
0-7 1 2 j
8 22
136-145
3 . 5 ~ 5 I 97 105
concentrations corrected to SG 1.027 (text: Patients and Methods) Significantly different by Student's t-test ( P < 0.001 I Signiiicantl) different by Student's t-test ( P < 0.05) ** Significantly different by Student's t-test ( P < 0.01) tt Below the range of 5encitkity for digoxin radioimrnunoasray +
:
21-29
'
9.2-10
'
1.5-2.1
'
1 - 0 2 5 1.029
’OI
X
x Cordioc orrest values Eudigitalised volues
X
’
FIGURE 2 Left ventricular myocardial and serum dlgoxin concentrations in eight patients presenting wlth cardiac arrest r = 0 8107 P < O 01
X
present study there was no significant difference in heart weight between the sexes and no significant correlation between heart weight and body weight, weight or surface area. although the correlation with the latter two parameters did approach significance.
X
X X
In the present study, highly significant serum digoxin toxicity was demonstrated during cardiac arrest in digitalized patients, whose mean serum digoxin concentration of 2.6 ng,ml was twice that (1.3 ngjml. P < 0.001) of “eudigitalized” subjects studied concurrently under carefully standardi~edcircumstances in a stabilized, non-toxic state during A previous study of digitalis intoxication (23 to 29 % incidence) in hospitalized patients in Boston drew atten_tion to the ominous prognosis in toxic patients, whose mortality was more than twice as high and whose serum drug levels were significantly higher than in non-toxic patients.2 Because glomerular filtration. as assessed by creatinine clearance and reflected by the serum creatinine concentration4, 4 1, is the major pathway of digoxln elimination from the bodyt0. 42-44 ,renal failure is the most frequently associated cause of digoxin intoxication2. 3 4 although hyperkalaemia may tend to counteract this effect.45 The significantly poorer renal function in the cardiac arrest patients largely accounted for their toxic serum digoxin levels (Table 4 and Fig. 3), although the daily digoxin
’
‘ 7
X
X
0 Discussion
N
1 5 10 SERUM CREATININE CONCENTRATION ( mg /dl)
FIGURE 3 Serum digoxin and creatinine concentration in 22 cardiac arrest and 41 ”eudigitalized” patients r = 0 4637, P < O 001
dosage was also significantly (P < 0.05) higher in this group than in the “eudigitalized” subjects (Table 4). The shorter duration of digoxin therapy in cardiac arrest compared to “eudigitalized” patients probably reflected more rapid deterioration of health in the former group associated with more pronounced and more rapid decompensation of renal function than was the situation in the “eudigitalized“ group, many of whom had been stabilized on an appropriate dose of digoxin for years (instead of weeks to months, as in the cardiac arrest subjects). The influence of many often independent variables. including drug intake. on the occurrence. course and outcome of a sudden unexpected critical event like cardiac arrest is, to say the least, difficult to assess. One factor likely to influence the outcome of this issue is the functional state of the myocardium. varying with the type and degree of cardiac
208
W H A P F L I T AL. ~
pathology2, 46. 47. which in the present study revealed the great prevalence of coronary artery disease, especially in the digitalized cardiac arrest group (77’1/, incidence, Table 1). The significantly higher daily digoxin dosage in sero-toxic cardiac arrest compared to ”eudigitalized” patients agrees with the observations 4 7 , who found sigof other workers’. 6, nificant differences between serum digoxin concentrations of patients on differing daily doses. The intefactions between the absolute. and more significant relative digoxin overdosage. renal failure (both acute and chronic). the very high rate of exposure of these patients to diuretic therapy preceding cardiac arrest. and intravenous fluid and electrolyte administration during resuscitation may well be relevant to the biochemical abnormalities of serum carbon dioxide combining power, chloride, calcium and magnesium concentrations and serum specific gravity previously mentioned (results, Table 4). Moreover, it is worth noting that biochemical imbalance, due to rapid diuresis, was considered the major factor precipitating digitalis intoxication in a previous study of 88 patients exhibiting 92 separate episodes of electrocardiographic digitalis cardiotoxicity in a hospital population in Miami.46 The influence of all these factors on the course and outcome of cardiac arrest could not be analyzed precisely in the present study, but there certainly did not appear to be any significant difference between cardiac arrest sub-groups in factors considered relevant to survival, such as: location, duration and hour of day of the arrest: delay in the duration of resuscitation ; frequency or amount of electrical countershock and number of therapeutic agents used during the event.33 Interestingly the long-term survival rate for arrest patients not receiving digoxin u7as identical with that of 50 consecutive cases of cardiac arrest studied over six months in the same hospital seven years p r e v i ~ u s l y .It~ ~is worth noting that the long-term survival in the digitalized subjects (14 was barely over half that of the control group (26%) (Table 3). The immediate success rate (27% versus 35);,” also tended to be less in the digoxin sero-toxic group. If the number of subjects had been larger this increased mortality may have achieved 9 9
97
x)
~
. ..
-
\OL ~~~~
5 , \o. 3 ~~~
statistical significance. The findings in the present study provide support for the increased cardiac irritability reported previously in association with digitalis i n t o ~ i c a t i o n . ~ ~ The value for left-ventricular digoxin concentration (mean 150k63.3 ng/g) found in the present study agrees with that reported elsewhere.32 Moreover, the demonstration of a significant, positive, linear correlation between the serum and myocardial digoxin concentrations (r = 0.8107. P < 0.01, Fig. 2) in 8 of these digitalized arrest patients supports the relativcly constant relationship between concentrations of digoxin in the blood and myocardium established by several previous studies13.2 0 , ’*, but refuted by other^.'^-^' Previous studies have provided evidence that the distribution of digoxin does vary appreciably between ventricle and atrium in the dog, with maximum uptake of glycoside in the left ~entric1e.l~. 23, 25 Variability in digoxin binding to atrial. in contrast to ventricular, receptors has also been implied by the greater per cent reduction in atrial compared to ventricular digoxin produced by reserpine ~re-treatrnent.’~ The use of atrial and papillary muscle tissue obtained during cardiac surgery may thus have led to an erroneous conclusion that the serum level is unrelated to the myocardial digoxin concent r a t i ~ n . ” It ~ ~was ~ therefore considered that determination of left ventricular myocardial digoxin concentrations more truly reflected the drug’s pharmacology and possibly its toxicology, during a critical stage of illness in the patients in the present study. Serum digoxin levels have been found to be related to their maximal left-ventricular function, under conditions of blood-tissue equilibration in man, at four hours following intravenous49 and six hours after oral” digoxin administration. Furthermore, stable serum and myocardial digoxin concentrations have been found six hours post-dose26, while the onset of the plateau for the post-dose, blood level response curve has been documented to occur between four and eight hours after the oral intake of digoxin.’. 52p54 Failure to determine serum digoxin concentrations at constant appropriate post-dose time intervals (such as six hours) may account for the failure
’’,’’
‘‘3
~ t i 1975 i ~ ~
I>I(;OXIN LF.VF1.S IN CARDIAC ARREST
of certain studies to have demonstrated a correlation between serum digoxin le\els and other parameters of into~ication.~'. 56 Lack of significant relationship between parameters of body size and criteria of digitalization in the present study may well have been due to the excessively prolonged post-dose collection interval in most of the subjects from whom both serum and left-ventricular samples were obtained. Also the effect of independent variables. such as the pathophysiology of hypertensive cardiovascular disease have been shown to affect4' the significant correlation between heart weight and body length. previously established for the "normal" heart.39 Thus, because of the relationship of myocardial to serum digoxin levels and the correlation of serum drug levels with other evidence of intoxication in carefully controlled studies', 5 7 , it is concluded here, as elsewhere58, 59. that estimation of the serum drug level should be used to monitor digoxin therapy and avoid intoxication. Furthermore, digoxin therapy should be administered in accordance with renal function, sex, body weight and age4. *. 5 7 and. when practicable, digitalization should precede diuretic therapy6' especially when the principal cause of cardiac failure is diminished ventricular contractility rather than salt and water overload.
-
I
1
5 6 ?
8
9 10.
I? 1.5 14 15 I6 17
I8
19
20.
21 22
23. 24
Acknowledgements
26
The authors thank Dr. M. F. O'Rourke, Senior Lecturer in Medicine, Medical Professorial Unit, St. Vincent's Hospital, Sydney, for valuable advice and supply of rabbit anti-digoxin antibody; Drs A. A. Palmer, E. Hirst, F. C. Neale, A. S. Mitchell, M. Swinbum and R. D. Hull, Messrs. E. Hung and G. Ferguson and other members of the Resident Medical and Clinical Pathology Staffs of Sydney Hospital, for their assistance and co-operation during this study ; Messrs. R. Money and J. Collins, for assistance with illustrations. The research programme was supported by a grant from the National Health and Medical Research Council of Australia.
27
28. 29. 30 31
32 33.
References 1. MASOI, D T , ZFILIS,R., LEI, G , Ht:ctifs. J L , SPA\T, J F and AMSTLRDAX, E A. (1971): Current concept, and treatment ui digitalis toxicity, Amrr. J Cnrdiol 27. 546 2 B t - ~ i t . Ci. ~ , A , SWIH, T. W., ABEI.MA\N,W I i . , HAnFn. E and Hooll. W. B. (1971): Digitalii i n t o ~ ~ ~ a t i o A r . . prvrpectiue cliiiical study with serum correlatiims, Nea Enxi. J. Med. 284, YR9. 3 S L K A ~ I CBZ .and LAsatTm, K C. 11970): EITcct 01 drug? on thc elecfrocardiogram, Progr. rardiurusc. Dis. 13, 26. 4. STHAPt.L, Ci 1 , McGRArH, B P.. EDWART)$, K D G.. HAWKIU.M R. and MIICHELI..A S . (1973) Therapeutic serum digoxin concentration: Relation to age, weight. sex and serum creatinine level. Aurr ,V Z J M < d 3, 606
34. 35. 36.
37.
38 39 40.
209
S w t u , ?' W . BLTIFX.V P. I r and k i n s i n . F. I 19691 Determination of therapeutic and toxic scruin d i g o m cunccntrations by radioimmonoassay. .VEH Di,cl J . Mcd. 281. 1212 S M I I HT. W. and H A K I RE. (19701. Dlgorin mtohicatim the relationship of clinical prcsentatmn to seriim digohm concmiration. .I i b n l , > ! c > r 49.2377 SuIiH. 7 W Il9:l) Measurement of serum d i p t a l h plycoridc. Clinical ~ n i p l ~ a t i o n Circulorinn s. 43, 179 S < I I A P IG I , J , M < GKATII. B P.. EUW4Rt>5.K D. G . HAWKIN?.'4 R and M i r r n r i i , A S. (1973) Therapeuric serum dipoxin ConcL'ntrdLion. rrlatlon to ape. w e ~ r h t WI . and serum rreatmine level. 4iirr S Z.J . M d 3.606 BI'TIfm. V. P Jr 1 19721: Assays o f d i D i S . 14, 57: E v a . G. A . KAPADIA.G G . YAO. L LI II IY. v!T and M ~ n c . \. 1 t I (19691: Digoxin metahohm in the elderly. CirLiilorion 39. 449. . C ( 1 9 7 l i ' Plasnia digoxin concentralions I patient,. Brrr t l r a r : .I 33. 540. COYRAI),L 1. and B4YT€n. D. J (19b3). Prchminan obscrvaiiona on the in1raccllul;ir l o c a l i ~ a t i o n of d i g o x w H 3 in the dng myocardium as determined by rddloauiugrdphy. ('/in. Re.$ 2, 53 D o r 1 1 : ~ ~ uJ . F and PrRKtTs. W' H (1966) Tissue concentration and turnover of tritiated digoxin i n dog\. Anicr. J. Curilrol 17, 47 Cncntn, I. W , L C ~ H IR. J. and TURBIII. J S 11967): Cardiac dimihulion of H'-dipoxin and its alteration by reserpine. C'rrcrrlufion (suppl to POIS 35 and 36) 2, 127 ~ ~ A R R I S I C. J ~ E. , Jr and BKOWS.A . L. Jr 11967): Myocardial digoxin-H3 uptake m experimental hypokalemic cardiomyopathy. Cirrrilarion (suppl tu vols 35 and 3 6 ) 2, 114. U I s s i O s , P. t . and Mon(;4u L M. (1968): Plasma leYels and tissue distribution of H'-digosin. Brit. Hriiri J 30. X i 1 H A R R I ~ IC. N ,E. JT and W ~ K I UK. G 11969): Inhibition of binding of tntiated digoxin to myocaidium by sodium depletion in dog.;, Ctrculnr. Rus. 24, 263. Gr,i.i)wirri. C.. KAPAIIIA. G. G , rVIInO. L.. MlRPIIY. C . M(lR4\, €1 and MARCLA,F. I (1969): Currebation of digitalis intuxication with inyocardm1 concentration of tntiated digoxin in hypokalcmic and normokalemic dogs, Ctrrulariou (ruppl to bols 39 and 40) 3, 92. MOMGAY. I.. M.and UI\\IO\. P F (1970). The distribu in normal and acutely hypeikalcmic dosa, Cardrour,< R O H ~ R GQ.. I . M4nr1:\, F I . K41~,\oia.G Ci. and D~gmlizdtionof the myocardium in ihe intact amma1 arterial drug administration. Reiation of the rate of myocard!al cnncentralion arid l n h ~ c i t y .Amrr. J . Cordrol 26, q65 PRiNr>i.i. K k1. 11.SKCI TO\. C. L.. E P ~ T I .SI ~E., and MARI.Is, I:. I. 119711: Influence of extracellular potassium concentration on myocardtal uptake and inntropic eficct of tritiatcd digoxrn. Cirridor Rrc 28, 337 G O L U M AR. ~ . ti., Ki FiGIK. K E , S c l i u t IZER, E and H.&RKIx)~, I) C. (1971)' The effect on myocardial H'-dipoxm of magnesium deficiency. Proc. Soc e . ~ p Biol. . Mcd. (N.Y.) 136, 747 HARRISOS. C. E JI. WAKIM,K G. and BROW>,A. L. Jr (1971). Effect of hemodynamic slatus on myocardml dlgorin binding In hypomagncsemia. J . Pharntacoi. cxp Thcr 176, 361 MARVL'S. F . I , NIMMil. L.. KAPAIIIA.G Ci. and Ciotusnirii. C 119711 The effect of acute hbpokalemia o n the myocardial concentration and bodv dis~iibiitionof tnt~a~talsd digoxin in the dog. J . Pha,marol P I P 7 h r r 17i, 27 I H t R . R N.. H A K R I S OD. ~ . C . and GOI.UMAS.R. ti. 11972) 'The relation bclween myocardial '11-digoxin concentration and Its hemudynamic effects. Am?,. J . Cordiol. 29, 47. DOIll.Rl>. J E , PI.RKIh5. W. H. and M!TCIItI[, G K (IYhl) Trmaied diFinin studies in human SUhJects, Arch. mlcm M r d 108, 531. BI A1 L, A. C.. JUlihSljh. P. C , DRtSCOl L , T , A1 F X & \ I > I R. I. K , Di >\I$. E. W.. M ~ N A M A R A D. , G , CUOr EY. D A and DIUKEY, M. E. (19631: EFIect of total cardiopulmonary bypass on m)ocardtal and blood digoun coiicenlration in man, Amer. .I. Cordrol. 11, 194 Dotibnrv. 1. F-.. PI'RKINC, W H and F i ~ h i m h W . J. 11967): The distnhution and concentration of lritiated digoxin In human t m u e , Ann. Inirrrr. Mrd. 66, 116. Blh\lOh. P. F , M(IRGA\. L. M , STE\.?>SON. H. M and FLErC1rl.R. E. (1969) Plasnia and myocardial digoxin concentration in patients on oral therap), Br??.Hear! J . 31, 636 COLT4HT. J , HOWARD. M. and CIIAMBIRLAIN. D (19721: Myocardial and skeletal m u d e concentrations of dlgoxln in patients on long-lenn therapy, Brit. mcd. J . 2, 318. C A R R O L l , P. R., GI.LB4RT. A.. O ' R O l ' R K l ~ , h4. F. and SHORTt 5 , J (1972): Relationship between serum and myocardial digoxin levels in man. Pro'. Airst ?/!.I Fin/. Pharmoiol. S u c . 3, 147. IISALU, E. and Nt 1 ~ ~ A.1 1M (1973). Myocardlal digoxm concentrations in fatal ~ n t o x ~ c a t ~Lancer ~ n s . 1, 25:. NI.A\EKSOS.M. A. and SI IIAPFI..G. .I (1967) Sudden unexpected death. Mud. J . Ausr. 2. 667 Jl)imsTou, C I . , P l h l K ~ s .N B. and D o w i . M. ( 1 9 7 2 J : Plasma digoxin levels 111 dieitalired and toxic Datienrs. M s d . J . Au.rr I . 863 E I ) w A R ~ I ~ .D - KG . , Cunrir, E. A. and S I O K F R , L.M. I 19711. A one-week introductoi) course in clinical biochemt~tryand research based on renal iunction testing in man. .I. d i n Purh. 24, 870. U t h ~ C. . E (1962): Some prohlems of hyperparathyroldisln. Brzr mud 1. 2, 1419. POSES,S Personal communication. Cr ncro. E and El.ioso. C A 11972): Factors affecting the radiolmmunaassay of digoxin, Ciiii. C'hem. 18. 539. ZEt.K. P. M (1942)' Heart weight. 1. The weight of the normal human heart. Arch Prrrh 34, 820. BI.I.L,E . T and HAKTZItl, T B (19241: Studies un hypertension: the relalion of age to the s ~ ofe the heart. J mcd Rcs. 44, 473.
?I Et)NAnix. K D G. and W w r r . H M 119591: Plasmli creatimne level and creatinine clearance as tests olrendl function. Aus:. Amr. W e d (1. 218 4:. DOI~IRT J YE. , PrnKizs. W H and W i i s o y , 51. C. 11964): Stodirs n i t h mtiated digoxin in renal failure. dmer. 1. .+fed 37, 526 4.7 M A K ( L S . F 1 . PlIFRSl)>. A . S A l l l . A . S c i ' i l Y . I and K A P A t i l & . , K and J (1971) Serum digorin after dosage regimen hased body-waghi and rcnal function. Lanirr 2, 326. 5 8 SVITH. T W and HAHER, E (1971) rhe cliiucal value of >erum digitalic plycoridc conccntrdtions in the evaluation of drug f o ~ i c i t yAnn. . N Y Acod Sci 179. 322 59 B A Y I I S E . M..HAII. M S , L I W K F and M A K K \ V. . (1972) Effects of renal Sunctmn on p l a m a digoxin Icvels in cldcrly ambulant patient\ in domiciliary practice, Hrrr. mcd. 3 I. 33R. 60. B C K ~ HG. . E 11972) Elegant dipitahration ror CongC51lve hc;m failure. dmcr Hwrt .I 83. 541
on
Aust. N.Z. J. Med. (1975),5, pp. 210-219
Type V Hyperlipoproteinaemia Re-visited : Findings in a Sydney Population* L. A. Simonst, P.
F. Williams:
and J. R. Turtle**
From the Department of Medicine, University of Sydney
Summary: Type V hyperlipoproteinaemia re-visited: Findings in a Sydney population. L. A. Simons, P. F. Williams and J. R. T u r t l e , Aust N.Z. J. Med., 1975, 5, pp. 21 0-21 9.
The clinical and biochemical features of eleven patients with Type V hyperlipoproteinaemia have been reviewed. All patients were male, and there was a high incidence in the group of obesity, vascular disease, acute abdominal pain, gout, diabetes mellitus and alcoholism. Plasma cholesterol concentrations ranged from 21 2 to 1512 mg/ ~~
~
~
~~~~
~
~
-
"This w o r k w a s s u p p o r t e d b y a grant f r o m the N a t i o n a l Heart F o u n d a t i o n o f Australia. t l e c t u r e r , S c h o o l o f Medicine, University o f N.S.W. a n d Physician-in-Charge, L i p i d Clinic, S t Vincent's Hospital, Sydney. :Scientific Officer, D e p a r t m e n t o f Endocrinology. Royal Prince A l f r e d Hospital, S y d n e y **Associate Professor o f Medicine, University of S y d n e y Correspondence: Dr. L. A. Simons, M e d i c a l Professorial U n i t , S t Vlncent's Hospital. Darlinghurst, N.S.W. 201 0. A c c e p t e d f o r p u b l i c a t i o n : 21 November. 1974
100 ml and triglycerides from 708 t o 7670 m g / l 0 0 ml. Lipaemia was associated with significant hyponatraemia, and also interfered with the determination of plasma glucose and serum amylase. Chylomicronaemia and hyperprebetalipoproteinaemia were accompanied by reduction in the pools of beta and alpha lipoproteins. All lipoprotein classes were relatively depleted of cholesterol compared to triglyceride. There was a variable pattern of treatment response. In some patients alcohol withdrawal produced a rapid improvement in plasma lipids. In diabetes mellitus there were t w o types of response: a rapid one in chronic insulin deficiency, and secondly, a more gradual one in mild diabetes associated with hyperinsulinaemia. In other patients there was a rapid response to carbohydratecalorie restriction but the respective contributions of each of the steps remained unclear.
2. PHII.I.IFS. I.. FtwhAsua. R. and WARM& C. (1970): In r i m cnmprison of erythromycin. linmmycin and clindam)rin. Birr. m d . 1. 2. 89. 3. WM;XI:R. J. G.. ~ ~ I N A K 8.. , PATEL.S. C.. Cirirmnr. C. G. a d Luuns. W. 1.11968): Abborptinn. ncncion and half-life of clinimycin h normal adult mdn. Amrr. 1.med. Sri. 256. 25. 4. BI'SMTT. 1. V.. Bmm. J. I... BFNSER.E. J. and Kinnv. W. Y. M. (1%6): RimpliRcd. x c u i d i c n:clhn! Vor antihiotk assay of clinical specimens.
I,,,"' I/,* r.L,..i 14 : 7 1 5 l l ~ l l \ K~ ~X ,I . Y I I I I I ~ .C Y.. Si~riri~ksmnli. I).. V A X ~ Bmr!l. ~S U 1) .m.1 \I%rnm\. E I :IV:i. Pharmarokinniu studies ofclindamycrn :;\':ran~.hivi:du in hiln!cn.. Iw C 7 1 r . 12rrs.ni.rhw. Tariiul. 6. 105. E 1 NII\~LJ I m J l i i t n i ~ I' X I 119591: Ilcrnudiulyrir propcaies ofclindamycin I '-~hlur~i-.-Jcn\?::nuom)cinI. Appr. .Wicroblal. 17, 446.
..
A u t . N.Z. J. Med. (1975). 5,pp. 202-210
A Study of Serum and Myocardial Digoxin Concentrations in Man During Cardiac Arrest G. J. Schapel", M. R. Hawkinst and K.
D.G.
Edwards
F r o m t h e K e i t h K i r k l a n d R e n a l Unit. M e d i c a l Research D e p a r t m e n t , Kanematsu M e m o r i a l I n s t i t u t e . S y d n e y Hospital, Sydney
SUrnmary:
A study of serum and myocardial digoxin concentrations in man during cardiac arrest. G . J. Schapel, M R. H a w k i n s a n d K. D G Edwards, Aust. N.Z.J. Med., 1975, 5, pp. 202-210.
In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 ( & I ,86, range 0.6-8.2) ng/ml, significantly higher ( P < 0.001 ) than the "eudigitalized" concentration (1.3 f0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ngjml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 f 2 . 6 6 v. The research program was supported by a grant from the National Health and Medical Research Council of Australia 'Present address: Clinical Pharmacology Division, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, U S.A tPresent address. Department of Nuclear Medicine and Endocrinology, Royal North Shore Hospital, St. Leonards, N.S.W 2065. Correspondence. Dr G J. Schapel Accepted for publication. 2 December, 1974.
1 f 0 . 2 6 mg/dl for non-toxic subjects, P < O.OOl), partly due to a higher mean daily digoxin dose (0.40 v. 0.31 mg/day, P < 0.05) and frequently associated with potent diuretic therapy (73 v. 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (1 4%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 ( k 6 3 . 3 , range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91 ). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration ( r = 0.8107, P < 0.01) or serum creatinine concentration ( r = 0.4637, P < 0~001). Digitalis intoxication, held to be among the most common adverse drug reactions'. has been estimated to carry more more than twice the mortality rate of the non-toxic state.' No specific cardiac dysrhythmia i s considered pathognomonic of digitalis toxicity', while the correlation between drug dosage and the electrocardiogram i s said to be unsatisfactory3.
JUM
-
1975
CARDIAC AKRkST
20 3
~~
although that between serum digoxin level and electrocardiogram has been rcported to be ~ignificant.~ Since the advent of serum digoxin radioimmunoassay as a more objective. convenient and precise means of assessing the state of digitalization5. 6 , ’. monitoring of the properly standardized or “eudigitalized” serum digoxin level8 has enabled the potential hazards of long-term therapy to become largely avoidable, especially where intoxication is most likely, namely in renal failure and old The present study attempts to examine the relationship of the serum digoxin concentration to cardiac arrest and associated factors considered relevant in both digoxin therapy and cessation of effective spontaneous cardiac function. Previous experimental studies in animals haveattempted to define therelationship between serum and myocardial digoxin levels and the factors influencing this.’ 2-25 Human studies to date have provided rather limited information on the myocardial to serum digoxin ratio during therapeutic circumstances. Initially this was attempted through the estimation of tissue pools and turnover rates of isotopically labelled digoxin2”28 and subsequently by reports on the concentration of digoxin in blood versus atrial and papillary muscle samples removed at the time of cardiac surgery.27*29-31 M ore recently, a brief preliminary study of left ventricular and serum digoxin levels in two fatal cases of digoxin self-poisoning was also reported.32 In the present study, specimens of left-ventricular myocardium were obtained from eight patients Gthin 24 hours of death to enable comparison of their digoxin levels with the concentration of digoxin in the blood sampled during the preceding cardiac arrest. The use of human left-ventricular myocardial tissue obtained in this manner provided information relevant to the situation which existed during long-term digoxin therapy at a time when the inotropic and electropathologic effects of digoxin could be critical factors in human survival. It was also hoped to identify parameters of body size that might correlate with criteria of digitalization, such as serum and myocardial digoxin concentrations, which might enable more precise digoxin dosage to be estimated for individual subjects. Furthermore, confir“ 9
’
mation of a relevant serum to myocardial ratio should help to confirm the clinical usefulness of the serum digoxin concentration with respect to the clinical pharmacology and toxicology of digoxin. Patients and Methods
The 40 patients in this study were selected at random on the basis that because of failure of spontaneous circulation to their vital centres and the periphery they received the attention of the cardiac-arrest team33, one of whose members obtained a venous sample of blood as soon as practicable after arrival at the scene, which varied between casualty, intensive care and regular inpatient care wards, in the ratio of 1 to 2 to 2 respectively, more non-digitalized patients presenting in casualty than in the other two ward areas. Serum obtained from the clotted venous blood sample was then frozen and stored in that condition until radioimmunoassay of its digoxin Concentration could be estimated within a week of obtaining each sample, using the method described by Smith, Butler and Haber’, Johnston et a1.34 and Carroll et The “standard error of the method”. calculated from the differences between duplic a t e and ~ ~ as ~ previously reported by us4*’, was 0.2 ng,/ml, representing a coefficient of variation of 14% for the therapeutic mean serum digoxin concentration of 1.4 ngiml. Serum digoxin levels were estimated without prior knowledge of associated digitalis intake, the history of which was documented in retrospect. Myocardial samples were obtained post mortem from the left ventricular wall within 24 hours of declared death after unsuccessful attempt at cardiac arrest resuscitation, during which the relevant serum digoxin and biochemical values were obtained. The left-ventricular myocardial specimens were obtained from seven subjects during autopsy. Two histologically verified specimens from one patient were obtained by percutaneous needle biopsy of the left ventricle using a disposable “Tru-Cut” (Travenol) needle of Vim Silverman type*, 15 minutes after the patient was declared dead, these myocardial specimens weighing 4 . 2 and 8.4 mg. Left-ventricular myocardial specimens dissected free of fat were blotted dry by compression between layers of paper tissue, weighed (approximate weight of each autopsy specimen 200 mg) and without delay were then stored at -10°C immersed in 100% ethanol until extraction immediately prior to radioimmunoassay. Extraction of each piece of myocardium was performed” by homogenization in the 100% ethanol in which the sample of myocardium was allowed to stand overnight at 4°C. The resultant homogenate was centrifuged at 2000 r.p.m. for 10 minutes and the supernatant was decanted and evaporated under a stream of nitrogen until the amorphous deposit which resulted was just moist. This deposit was then re-dissolved in 1.5 to 20 ml distilled water depending on the already estimated, corresponding serum digoxin concentration and weight of the myocardial aliquot. The digoxin concentration of the resultant solution was determined by radioimmunoassay, using the method to which reference has already been made.5*3 1 * 34 Serum creatinine, urea nitrogen, sodium, potassium and chloride concentrations and carbon dioxide combining
* Code 2N 2702 Travenol Laboratories, Incorporated, Morton Grove, Illinois, 60053, U.S.A.
__
.
power were determined using standard Technicon autoanalvzer methods. Serum calcium and magnesium co11centrations were estimated using standard atomic absorption spectrophotometric methods. with corrections for variation due to scrum specific gravity appiied as follows: serum calcium ~ 0 . 2 and 5 magnesium f 0 . 0 5 rngidl per T0.001 units. adjusted toward a serum specific gravity of 1 .027.4. 3 6 , 3 i
-
~
-
~~~
the latter group of patients were documented to have had no previous digitalis intake. The digitalized arrest patients were significantly heavier ( P < 0.05) than the “eudigitalized” group with therapeutic serum digoxin levels (Table 1). The latter possibly indicated adiposity andior fluid retention in the cardiac arrest group. Furthermore, in the arrest subjects, previous cardiac failure may have been occasioned by the higher incidence of coronary artery disease (7796 versus 41 %. Table 1 ) and it may also have been reflected by the greater use of more potent diuretic therapy (73 ”.;, versus 54‘1”. Table 2), to which less effective response may have occurred because of lowering of cardiac output by excessive digitalization. The digitalized arrest patients had been taking a significantly higher daily dose of digoxin (mean 0.40 mg versus 0.31 mgiday, P < 0.05. Table 2) for a significantly shorter duration (mean 6 months versus 44 months, P < 0.05) than the “eudigitalized” subjects. The very frequent intake of diuretic agents in conjunction with digoxin therapy was documented in 71 ;; and 82 0; of patients, both “eudigitalized” and cardiac arrest groups respectively (Table 2). 73:/: of the latter having received the more potent variety, mainly frusemide. compared
Results
Forty patients were investigated at random when they presented because of cardiac arrest. One patient was subsequently excluded from the study because of interference with the radioiminunoassay of serum digoxin by a radioisotope (renal scan) investigation38 within hours of cardiac arrest. Twenty of the remaining 39 patients were retrospectively documented to haw becn taking digoxin (“Lanoxin”). while two subjects wwe known to have been taking lanatoside C (“Cedilanid”) with which the digoxin antibody crossreacts.’ The post-dose collection interval was more than four hours in all but two arrest patients (mean 28 i 31 hours), compared to the mean “eudigitalized”* post-dose collection interval of 6 I 0.3 hours ( P < 0,001). The second subgroup of 17 cardiac arrest patients were similarly investigated and without knowledge of their pharmacological history at the time, were found to have undetectable digoxin in their serum. Subsequently
TABLE 1 Clinicopathological data for cardiac arrest and “eudigitalized” patients (mean valnzs +_ S D and range) Body hurface area
Sex
Paticnt group ~~
-
No. of L .. patients Male Female
-~*~
,
~
..
Agz
(years)
-- ... .
(m2)
.+-.-
Digitalixd cardiac arre\t pa ti en Ii
22
17
9
6 0 x 1 2 1 7 4 k 0 20 123-83) 1 1 26-1 951
Cardiac arrest pa!ients wit!iout eiidence of difitaliration
17
12
5
59+14 (25 X2\
“Eudigitalized“ patienti
41
22
19
’
Body wight
(kg) .~
67**-14 (37 831
.
Height (cm) ~~
,
Heart weight fr)* ~~
~
Cardiac pathology: ”i, of group with diagnosis
____~
-
~.
Coronary artery disease -77;,” Hyperrensive heart disease -14 O D Cor pulmonale-4.5 ”,: Rheumatic heart disease-4.5 yo
1 7 2 k 5 6 436: k 8 7 . 7 (161- 1781 (305-580)
Coronary artery disease-59 %; Hypertensive heart diseaie 29:,: Cardiomyopathy-6 a& Traumatic head injury 6 uo,
6 3 f 1 1 1 6 3 ~ 024 59**+12.7 1 6 7 f 9 . 1 (30 78) 11 24-2 17) 131-96) (142-188)
Coronary artery disease-41 :: Rheumatic heart disease-17 1: Hypertensive heart disease- -10% Cardiomyopathy-7 ”/, Pulmonary thromboemholism -5 ?(J Pericardial neoplasm 2 “j0 Undiagnosed I7 O,;f ~
* Determined after rcmoval at autopsy and included portions of pericardium and roots of great vessels + n o = 15.
i:n o = 9. ** Significantly different by Student‘s t-test (P < 0.05)
~
I67 i- 9 . 5 4 8 8 t k 1 3 4 . 5 (146- 182) (290-770)
JUNE
1975
’
20 5
DIGOXIK LEVELS IN CARDIAC ARREST
-~
-~
TABLE 2 Pharmacological data : Drug intake pre-cardiac arrest or during life (mean dosage i SD and range, or percent of group on drug)
1 Patient group
1
Frusemide or 1 ethacrynic i Diuretic acid ’ Thiazide
Digoxin dosage (mg) Daily
5 day
-L
~~
Digitalized cardiacarrest patients “Eudigitalized” patients
I I
i
I
1.5k0.76
o.4+0.16* (0.125-0.75)
(0.5-2.5)
i s ( 8 2 ~ ) 16(73%)
I
,
to 54% in the former, although the difference did not achieve significance by the chi-square test. No significant differences were apparent between the two groups of cardiac arrest patients (those on and those not on digoxin) with regard to other significant factors affecting the management of a patient requiring urgent resuscitation for cardiac arrest (Table 3). Assessment of any difference in successful response to cardiac arrest resuscitation was difficult here because of the relatively small numbers involved. Fewer digitalized than non-digitalized patients recovered immediately (27 versus 35 %) and fewer were alive at two weeks post-arrest or on discharge from hospital (Table 3), although the differences did not achieve significance (by the chi-square test). The mean serum digoxin concentration in digitalized patients studied during cardiac arrest (2.6k1.86, range 0.6-8.2 ng/ml) and plotted in Figure 1 was significantly higher ( P -=z 0.001) than the mean therapeutic, or “eudigitalized” serum digoxin concentration (1.3 0.52, range 0.5 -2.6 ng/ml), studied under carefully stan-
+
~~
Antikaliuretic Potassium (spironolactone) supplementation Antidysrhythmic
__
~-
j z(9:/;)
2 (9 %)
11 (50%)
4 (10%)
24 (59
nil
I
~
1.5f0.71 29(71%)1 22(54%) (0,3125-3.75) 1 I
0.31f0.15* (0.0625-0.75)
-1
7(17%)
I
m
4(10%)
dardized circumstances and reported elsewhere.4* Eleven of the 22 patients (50%)had serum digoxin levels in the toxic range (2.4ng/ml, or above). The serum creatinine and urea nitrogen of both the arrest groups (on and off‘ digoxin) were significantly higher than those of the “eudigitalized” group (means 2.9 versus 1 .O and 52 and 33 versus 18 mg/dl, respectively, P < 0.001). Thus, as might be expected, the glomerular filtration rate, on which excretion of digoxin depends, was grossly inferior in the critically ill, cardiac arrest population, accounting for the relative digoxin overdosage and toxic serum digoxin levels in these patients. Significant differences in serum carbon dioxide combining power, chloride, calcium and magnesium concentrations (the latter corrected for serum specific gravity, as previously indicated in methods) and in serum specific gravity (Table 4) probably reflected the combined influence of more potent diuretic therapy (Table 2), administration of relatively large amounts of intravenous electrolyte fluids and multiple other therapeutic agents during arrest resusci-
TABLE 3 Cardiac arrest data (mean values 2 SD and range)
Electrocardiogram at onset (percent of group)
1
Patient group Digitalized patients
Duration of Delay in resuscitation (min) 2
($20) Patients without evidence of digitalization
(10-100)
Defibrillation
Resuscitation success Number of (number and percent therapeutic of group agents administered Aliveon 1 discharge during
1
.
~~~~~~
~~
~
~
tation (Table 3) and the more severe renal failure (Table 4) in the cardiac arrest compared to the "eudigitalized" patients. The mean myocardial digoxin concentration for eight patients, documented to have been taking digoxin before cardiac arrest, was 150 ng,(g (SDk63.3, range 52--252ngig) (Table 4), determined on 48 samples of left ventricular wall removed post mortem. The average myocardial to serum digoxin concentration ratio was 62.5 (range 38-91) to one. There was a significant, positive, linear correlation between the serum and myocardial digoxin concentrations ( ( n o = 8, r = 0.8107, P < 0.01, Fig. 2), the regression equation being as follows : myocardial digoxin concentration (ngig) = 30.7 x serum digoxin concentration (nglml) + 67.0. There was also a significant. positive, linear correlation between serum creatinine and serum digoxin concentration in both groups of digitalized patients (Fig. 3) with the following regression equation : serum digoxin concentration (ngiml) = 0.34 x serum creatinineconcentration (mg,'dl)+l.2 ( n = 63, T = 0.4637, P < 0.001). There was no significant correlation between any of the following and the myocardia1:serum digoxin concentration ratio : serum urea nitrogen and creatinine concentrations: daily or five-day digoxin dose, heart weight or body surface area. Nor was there any significant correlation between serum digoxin concentration and either body surface area or heart weight.
... .. .. .
a
---I
I FIGURE I Serum digoxin concentration in 22 patients during cardiac arrest and 41 "eudigitalized" patients, siqnificantly different by Student's t test ( P < 0 001)
Cardiac enlargement3' was observed at autopsy in both the digitalized and nondigitalized arrest sub-groups whose mean cardiac weights were 488 and 436 g respectively. Unlike findings previously reported39,40, in the
TABLE 4 Relevant laboratory data for cardiac arrcst and "rudigitalired" patients (mran values
I V)d,go\r ingd ~
+ SD and range,
Lleilllnlne
(mg!dl)
._. ..
*
-
2 6 ? I .86+ 150-63 3 2 - 9 + 2 6 6 t 10.4 8 21 152-2521 . (0 5-11) Cardiac arrest patient\ , < 0.3 t i ",I++ 2 9_12 94 Digitalired cardiac arrest patients without evidence or digitalization
np:ml
"Eudlgitalired" patients
1 .1+0-52+ 10.5. 2-61
S o m a 1 range for this laboratory
10.5-7.31
* Serum calcium and magncsiurn
,
significant
(0.94-10.4)
-
I i0 26t (0 6-1 6)
-
,
0-7 1 2 j
8 22
136-145
3 . 5 ~ 5 I 97 105
concentrations corrected to SG 1.027 (text: Patients and Methods) Significantly different by Student's t-test ( P < 0.001 I Signiiicantl) different by Student's t-test ( P < 0.05) ** Significantly different by Student's t-test ( P < 0.01) tt Below the range of 5encitkity for digoxin radioimrnunoasray +
:
21-29
'
9.2-10
'
1.5-2.1
'
1 - 0 2 5 1.029
’OI
X
x Cordioc orrest values Eudigitalised volues
X
’
FIGURE 2 Left ventricular myocardial and serum dlgoxin concentrations in eight patients presenting wlth cardiac arrest r = 0 8107 P < O 01
X
present study there was no significant difference in heart weight between the sexes and no significant correlation between heart weight and body weight, weight or surface area. although the correlation with the latter two parameters did approach significance.
X
X X
In the present study, highly significant serum digoxin toxicity was demonstrated during cardiac arrest in digitalized patients, whose mean serum digoxin concentration of 2.6 ng,ml was twice that (1.3 ngjml. P < 0.001) of “eudigitalized” subjects studied concurrently under carefully standardi~edcircumstances in a stabilized, non-toxic state during A previous study of digitalis intoxication (23 to 29 % incidence) in hospitalized patients in Boston drew atten_tion to the ominous prognosis in toxic patients, whose mortality was more than twice as high and whose serum drug levels were significantly higher than in non-toxic patients.2 Because glomerular filtration. as assessed by creatinine clearance and reflected by the serum creatinine concentration4, 4 1, is the major pathway of digoxln elimination from the bodyt0. 42-44 ,renal failure is the most frequently associated cause of digoxin intoxication2. 3 4 although hyperkalaemia may tend to counteract this effect.45 The significantly poorer renal function in the cardiac arrest patients largely accounted for their toxic serum digoxin levels (Table 4 and Fig. 3), although the daily digoxin
’
‘ 7
X
X
0 Discussion
N
1 5 10 SERUM CREATININE CONCENTRATION ( mg /dl)
FIGURE 3 Serum digoxin and creatinine concentration in 22 cardiac arrest and 41 ”eudigitalized” patients r = 0 4637, P < O 001
dosage was also significantly (P < 0.05) higher in this group than in the “eudigitalized” subjects (Table 4). The shorter duration of digoxin therapy in cardiac arrest compared to “eudigitalized” patients probably reflected more rapid deterioration of health in the former group associated with more pronounced and more rapid decompensation of renal function than was the situation in the “eudigitalized“ group, many of whom had been stabilized on an appropriate dose of digoxin for years (instead of weeks to months, as in the cardiac arrest subjects). The influence of many often independent variables. including drug intake. on the occurrence. course and outcome of a sudden unexpected critical event like cardiac arrest is, to say the least, difficult to assess. One factor likely to influence the outcome of this issue is the functional state of the myocardium. varying with the type and degree of cardiac
208
W H A P F L I T AL. ~
pathology2, 46. 47. which in the present study revealed the great prevalence of coronary artery disease, especially in the digitalized cardiac arrest group (77’1/, incidence, Table 1). The significantly higher daily digoxin dosage in sero-toxic cardiac arrest compared to ”eudigitalized” patients agrees with the observations 4 7 , who found sigof other workers’. 6, nificant differences between serum digoxin concentrations of patients on differing daily doses. The intefactions between the absolute. and more significant relative digoxin overdosage. renal failure (both acute and chronic). the very high rate of exposure of these patients to diuretic therapy preceding cardiac arrest. and intravenous fluid and electrolyte administration during resuscitation may well be relevant to the biochemical abnormalities of serum carbon dioxide combining power, chloride, calcium and magnesium concentrations and serum specific gravity previously mentioned (results, Table 4). Moreover, it is worth noting that biochemical imbalance, due to rapid diuresis, was considered the major factor precipitating digitalis intoxication in a previous study of 88 patients exhibiting 92 separate episodes of electrocardiographic digitalis cardiotoxicity in a hospital population in Miami.46 The influence of all these factors on the course and outcome of cardiac arrest could not be analyzed precisely in the present study, but there certainly did not appear to be any significant difference between cardiac arrest sub-groups in factors considered relevant to survival, such as: location, duration and hour of day of the arrest: delay in the duration of resuscitation ; frequency or amount of electrical countershock and number of therapeutic agents used during the event.33 Interestingly the long-term survival rate for arrest patients not receiving digoxin u7as identical with that of 50 consecutive cases of cardiac arrest studied over six months in the same hospital seven years p r e v i ~ u s l y .It~ ~is worth noting that the long-term survival in the digitalized subjects (14 was barely over half that of the control group (26%) (Table 3). The immediate success rate (27% versus 35);,” also tended to be less in the digoxin sero-toxic group. If the number of subjects had been larger this increased mortality may have achieved 9 9
97
x)
~
. ..
-
\OL ~~~~
5 , \o. 3 ~~~
statistical significance. The findings in the present study provide support for the increased cardiac irritability reported previously in association with digitalis i n t o ~ i c a t i o n . ~ ~ The value for left-ventricular digoxin concentration (mean 150k63.3 ng/g) found in the present study agrees with that reported elsewhere.32 Moreover, the demonstration of a significant, positive, linear correlation between the serum and myocardial digoxin concentrations (r = 0.8107. P < 0.01, Fig. 2) in 8 of these digitalized arrest patients supports the relativcly constant relationship between concentrations of digoxin in the blood and myocardium established by several previous studies13.2 0 , ’*, but refuted by other^.'^-^' Previous studies have provided evidence that the distribution of digoxin does vary appreciably between ventricle and atrium in the dog, with maximum uptake of glycoside in the left ~entric1e.l~. 23, 25 Variability in digoxin binding to atrial. in contrast to ventricular, receptors has also been implied by the greater per cent reduction in atrial compared to ventricular digoxin produced by reserpine ~re-treatrnent.’~ The use of atrial and papillary muscle tissue obtained during cardiac surgery may thus have led to an erroneous conclusion that the serum level is unrelated to the myocardial digoxin concent r a t i ~ n . ” It ~ ~was ~ therefore considered that determination of left ventricular myocardial digoxin concentrations more truly reflected the drug’s pharmacology and possibly its toxicology, during a critical stage of illness in the patients in the present study. Serum digoxin levels have been found to be related to their maximal left-ventricular function, under conditions of blood-tissue equilibration in man, at four hours following intravenous49 and six hours after oral” digoxin administration. Furthermore, stable serum and myocardial digoxin concentrations have been found six hours post-dose26, while the onset of the plateau for the post-dose, blood level response curve has been documented to occur between four and eight hours after the oral intake of digoxin.’. 52p54 Failure to determine serum digoxin concentrations at constant appropriate post-dose time intervals (such as six hours) may account for the failure
’’,’’
‘‘3
~ t i 1975 i ~ ~
I>I(;OXIN LF.VF1.S IN CARDIAC ARREST
of certain studies to have demonstrated a correlation between serum digoxin le\els and other parameters of into~ication.~'. 56 Lack of significant relationship between parameters of body size and criteria of digitalization in the present study may well have been due to the excessively prolonged post-dose collection interval in most of the subjects from whom both serum and left-ventricular samples were obtained. Also the effect of independent variables. such as the pathophysiology of hypertensive cardiovascular disease have been shown to affect4' the significant correlation between heart weight and body length. previously established for the "normal" heart.39 Thus, because of the relationship of myocardial to serum digoxin levels and the correlation of serum drug levels with other evidence of intoxication in carefully controlled studies', 5 7 , it is concluded here, as elsewhere58, 59. that estimation of the serum drug level should be used to monitor digoxin therapy and avoid intoxication. Furthermore, digoxin therapy should be administered in accordance with renal function, sex, body weight and age4. *. 5 7 and. when practicable, digitalization should precede diuretic therapy6' especially when the principal cause of cardiac failure is diminished ventricular contractility rather than salt and water overload.
-
I
1
5 6 ?
8
9 10.
I? 1.5 14 15 I6 17
I8
19
20.
21 22
23. 24
Acknowledgements
26
The authors thank Dr. M. F. O'Rourke, Senior Lecturer in Medicine, Medical Professorial Unit, St. Vincent's Hospital, Sydney, for valuable advice and supply of rabbit anti-digoxin antibody; Drs A. A. Palmer, E. Hirst, F. C. Neale, A. S. Mitchell, M. Swinbum and R. D. Hull, Messrs. E. Hung and G. Ferguson and other members of the Resident Medical and Clinical Pathology Staffs of Sydney Hospital, for their assistance and co-operation during this study ; Messrs. R. Money and J. Collins, for assistance with illustrations. The research programme was supported by a grant from the National Health and Medical Research Council of Australia.
27
28. 29. 30 31
32 33.
References 1. MASOI, D T , ZFILIS,R., LEI, G , Ht:ctifs. J L , SPA\T, J F and AMSTLRDAX, E A. (1971): Current concept, and treatment ui digitalis toxicity, Amrr. J Cnrdiol 27. 546 2 B t - ~ i t . Ci. ~ , A , SWIH, T. W., ABEI.MA\N,W I i . , HAnFn. E and Hooll. W. B. (1971): Digitalii i n t o ~ ~ ~ a t i o A r . . prvrpectiue cliiiical study with serum correlatiims, Nea Enxi. J. Med. 284, YR9. 3 S L K A ~ I CBZ .and LAsatTm, K C. 11970): EITcct 01 drug? on thc elecfrocardiogram, Progr. rardiurusc. Dis. 13, 26. 4. STHAPt.L, Ci 1 , McGRArH, B P.. EDWART)$, K D G.. HAWKIU.M R. and MIICHELI..A S . (1973) Therapeutic serum digoxin concentration: Relation to age, weight. sex and serum creatinine level. Aurr ,V Z J M < d 3, 606
34. 35. 36.
37.
38 39 40.
209
S w t u , ?' W . BLTIFX.V P. I r and k i n s i n . F. I 19691 Determination of therapeutic and toxic scruin d i g o m cunccntrations by radioimmonoassay. .VEH Di,cl J . Mcd. 281. 1212 S M I I HT. W. and H A K I RE. (19701. Dlgorin mtohicatim the relationship of clinical prcsentatmn to seriim digohm concmiration. .I i b n l , > ! c > r 49.2377 SuIiH. 7 W Il9:l) Measurement of serum d i p t a l h plycoridc. Clinical ~ n i p l ~ a t i o n Circulorinn s. 43, 179 S < I I A P IG I , J , M < GKATII. B P.. EUW4Rt>5.K D. G . HAWKIN?.'4 R and M i r r n r i i , A S. (1973) Therapeuric serum dipoxin ConcL'ntrdLion. rrlatlon to ape. w e ~ r h t WI . and serum rreatmine level. 4iirr S Z.J . M d 3.606 BI'TIfm. V. P Jr 1 19721: Assays o f d i D i S . 14, 57: E v a . G. A . KAPADIA.G G . YAO. L LI II IY. v!T and M ~ n c . \. 1 t I (19691: Digoxin metahohm in the elderly. CirLiilorion 39. 449. . C ( 1 9 7 l i ' Plasnia digoxin concentralions I patient,. Brrr t l r a r : .I 33. 540. COYRAI),L 1. and B4YT€n. D. J (19b3). Prchminan obscrvaiiona on the in1raccllul;ir l o c a l i ~ a t i o n of d i g o x w H 3 in the dng myocardium as determined by rddloauiugrdphy. ('/in. Re.$ 2, 53 D o r 1 1 : ~ ~ uJ . F and PrRKtTs. W' H (1966) Tissue concentration and turnover of tritiated digoxin i n dog\. Anicr. J. Curilrol 17, 47 Cncntn, I. W , L C ~ H IR. J. and TURBIII. J S 11967): Cardiac dimihulion of H'-dipoxin and its alteration by reserpine. C'rrcrrlufion (suppl to POIS 35 and 36) 2, 127 ~ ~ A R R I S I C. J ~ E. , Jr and BKOWS.A . L. Jr 11967): Myocardial digoxin-H3 uptake m experimental hypokalemic cardiomyopathy. Cirrrilarion (suppl tu vols 35 and 3 6 ) 2, 114. U I s s i O s , P. t . and Mon(;4u L M. (1968): Plasma leYels and tissue distribution of H'-digosin. Brit. Hriiri J 30. X i 1 H A R R I ~ IC. N ,E. JT and W ~ K I UK. G 11969): Inhibition of binding of tntiated digoxin to myocaidium by sodium depletion in dog.;, Ctrculnr. Rus. 24, 263. Gr,i.i)wirri. C.. KAPAIIIA. G. G , rVIInO. L.. MlRPIIY. C . M(lR4\, €1 and MARCLA,F. I (1969): Currebation of digitalis intuxication with inyocardm1 concentration of tntiated digoxin in hypokalcmic and normokalemic dogs, Ctrrulariou (ruppl to bols 39 and 40) 3, 92. MOMGAY. I.. M.and UI\\IO\. P F (1970). The distribu in normal and acutely hypeikalcmic dosa, Cardrour,< R O H ~ R GQ.. I . M4nr1:\, F I . K41~,\oia.G Ci. and D~gmlizdtionof the myocardium in ihe intact amma1 arterial drug administration. Reiation of the rate of myocard!al cnncentralion arid l n h ~ c i t y .Amrr. J . Cordrol 26, q65 PRiNr>i.i. K k1. 11.SKCI TO\. C. L.. E P ~ T I .SI ~E., and MARI.Is, I:. I. 119711: Influence of extracellular potassium concentration on myocardtal uptake and inntropic eficct of tritiatcd digoxrn. Cirridor Rrc 28, 337 G O L U M AR. ~ . ti., Ki FiGIK. K E , S c l i u t IZER, E and H.&RKIx)~, I) C. (1971)' The effect on myocardial H'-dipoxm of magnesium deficiency. Proc. Soc e . ~ p Biol. . Mcd. (N.Y.) 136, 747 HARRISOS. C. E JI. WAKIM,K G. and BROW>,A. L. Jr (1971). Effect of hemodynamic slatus on myocardml dlgorin binding In hypomagncsemia. J . Pharntacoi. cxp Thcr 176, 361 MARVL'S. F . I , NIMMil. L.. KAPAIIIA.G Ci. and Ciotusnirii. C 119711 The effect of acute hbpokalemia o n the myocardial concentration and bodv dis~iibiitionof tnt~a~talsd digoxin in the dog. J . Pha,marol P I P 7 h r r 17i, 27 I H t R . R N.. H A K R I S OD. ~ . C . and GOI.UMAS.R. ti. 11972) 'The relation bclween myocardial '11-digoxin concentration and Its hemudynamic effects. Am?,. J . Cordiol. 29, 47. DOIll.Rl>. J E , PI.RKIh5. W. H. and M!TCIItI[, G K (IYhl) Trmaied diFinin studies in human SUhJects, Arch. mlcm M r d 108, 531. BI A1 L, A. C.. JUlihSljh. P. C , DRtSCOl L , T , A1 F X & \ I > I R. I. K , Di >\I$. E. W.. M ~ N A M A R A D. , G , CUOr EY. D A and DIUKEY, M. E. (19631: EFIect of total cardiopulmonary bypass on m)ocardtal and blood digoun coiicenlration in man, Amer. .I. Cordrol. 11, 194 Dotibnrv. 1. F-.. PI'RKINC, W H and F i ~ h i m h W . J. 11967): The distnhution and concentration of lritiated digoxin In human t m u e , Ann. Inirrrr. Mrd. 66, 116. Blh\lOh. P. F , M(IRGA\. L. M , STE\.?>SON. H. M and FLErC1rl.R. E. (1969) Plasnia and myocardial digoxin concentration in patients on oral therap), Br??.Hear! J . 31, 636 COLT4HT. J , HOWARD. M. and CIIAMBIRLAIN. D (19721: Myocardial and skeletal m u d e concentrations of dlgoxln in patients on long-lenn therapy, Brit. mcd. J . 2, 318. C A R R O L l , P. R., GI.LB4RT. A.. O ' R O l ' R K l ~ , h4. F. and SHORTt 5 , J (1972): Relationship between serum and myocardial digoxin levels in man. Pro'. Airst ?/!.I Fin/. Pharmoiol. S u c . 3, 147. IISALU, E. and Nt 1 ~ ~ A.1 1M (1973). Myocardlal digoxm concentrations in fatal ~ n t o x ~ c a t ~Lancer ~ n s . 1, 25:. NI.A\EKSOS.M. A. and SI IIAPFI..G. .I (1967) Sudden unexpected death. Mud. J . Ausr. 2. 667 Jl)imsTou, C I . , P l h l K ~ s .N B. and D o w i . M. ( 1 9 7 2 J : Plasma digoxin levels 111 dieitalired and toxic Datienrs. M s d . J . Au.rr I . 863 E I ) w A R ~ I ~ .D - KG . , Cunrir, E. A. and S I O K F R , L.M. I 19711. A one-week introductoi) course in clinical biochemt~tryand research based on renal iunction testing in man. .I. d i n Purh. 24, 870. U t h ~ C. . E (1962): Some prohlems of hyperparathyroldisln. Brzr mud 1. 2, 1419. POSES,S Personal communication. Cr ncro. E and El.ioso. C A 11972): Factors affecting the radiolmmunaassay of digoxin, Ciiii. C'hem. 18. 539. ZEt.K. P. M (1942)' Heart weight. 1. The weight of the normal human heart. Arch Prrrh 34, 820. BI.I.L,E . T and HAKTZItl, T B (19241: Studies un hypertension: the relalion of age to the s ~ ofe the heart. J mcd Rcs. 44, 473.
?I Et)NAnix. K D G. and W w r r . H M 119591: Plasmli creatimne level and creatinine clearance as tests olrendl function. Aus:. Amr. W e d (1. 218 4:. DOI~IRT J YE. , PrnKizs. W H and W i i s o y , 51. C. 11964): Stodirs n i t h mtiated digoxin in renal failure. dmer. 1. .+fed 37, 526 4.7 M A K ( L S . F 1 . PlIFRSl)>. A . S A l l l . A . S c i ' i l Y . I and K A P A t i l & . , K and J (1971) Serum digorin after dosage regimen hased body-waghi and rcnal function. Lanirr 2, 326. 5 8 SVITH. T W and HAHER, E (1971) rhe cliiucal value of >erum digitalic plycoridc conccntrdtions in the evaluation of drug f o ~ i c i t yAnn. . N Y Acod Sci 179. 322 59 B A Y I I S E . M..HAII. M S , L I W K F and M A K K \ V. . (1972) Effects of renal Sunctmn on p l a m a digoxin Icvels in cldcrly ambulant patient\ in domiciliary practice, Hrrr. mcd. 3 I. 33R. 60. B C K ~ HG. . E 11972) Elegant dipitahration ror CongC51lve hc;m failure. dmcr Hwrt .I 83. 541
on
Aust. N.Z. J. Med. (1975),5, pp. 210-219
Type V Hyperlipoproteinaemia Re-visited : Findings in a Sydney Population* L. A. Simonst, P.
F. Williams:
and J. R. Turtle**
From the Department of Medicine, University of Sydney
Summary: Type V hyperlipoproteinaemia re-visited: Findings in a Sydney population. L. A. Simons, P. F. Williams and J. R. T u r t l e , Aust N.Z. J. Med., 1975, 5, pp. 21 0-21 9.
The clinical and biochemical features of eleven patients with Type V hyperlipoproteinaemia have been reviewed. All patients were male, and there was a high incidence in the group of obesity, vascular disease, acute abdominal pain, gout, diabetes mellitus and alcoholism. Plasma cholesterol concentrations ranged from 21 2 to 1512 mg/ ~~
~
~
~~~~
~
~
-
"This w o r k w a s s u p p o r t e d b y a grant f r o m the N a t i o n a l Heart F o u n d a t i o n o f Australia. t l e c t u r e r , S c h o o l o f Medicine, University o f N.S.W. a n d Physician-in-Charge, L i p i d Clinic, S t Vincent's Hospital, Sydney. :Scientific Officer, D e p a r t m e n t o f Endocrinology. Royal Prince A l f r e d Hospital, S y d n e y **Associate Professor o f Medicine, University of S y d n e y Correspondence: Dr. L. A. Simons, M e d i c a l Professorial U n i t , S t Vlncent's Hospital. Darlinghurst, N.S.W. 201 0. A c c e p t e d f o r p u b l i c a t i o n : 21 November. 1974
100 ml and triglycerides from 708 t o 7670 m g / l 0 0 ml. Lipaemia was associated with significant hyponatraemia, and also interfered with the determination of plasma glucose and serum amylase. Chylomicronaemia and hyperprebetalipoproteinaemia were accompanied by reduction in the pools of beta and alpha lipoproteins. All lipoprotein classes were relatively depleted of cholesterol compared to triglyceride. There was a variable pattern of treatment response. In some patients alcohol withdrawal produced a rapid improvement in plasma lipids. In diabetes mellitus there were t w o types of response: a rapid one in chronic insulin deficiency, and secondly, a more gradual one in mild diabetes associated with hyperinsulinaemia. In other patients there was a rapid response to carbohydratecalorie restriction but the respective contributions of each of the steps remained unclear.
