Hypocalcemia, Hypomagnesemia and
Hypokalemia during Chemotherapy of Pulmonary
Tuberculosis
Boon Vanasin, Marc Colmer and Paul J. Davis
Chest 1972;61;496-499
DOI 10.1378/chest.61.5.496
The online version of this article, along with updated information and services
can be found online on the World Wide Web at:
http://chestjournal.chestpubs.org/content/61/5/496
Chest is the official journal of the American College of Chest Physicians. It has
been published monthly since 1935. Copyright1972by the American College of
Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights
reserved. No part of this article or PDF may be reproduced or distributed
without the prior written permission of the copyright holder.
(http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians
496 VANASIN, COLMER AND DAVIS
filtration by leukemia, as in our case. Of 119 patients cases in a series of 14,400 necropsies. Arch Intern \led
with leukemia in 500 consecutive autopsies reviewed by 71 :777-792, 1943
Bisel et al/ 44 percent had evidence of cardiac involve- 9 Bisel HF, Wrohlewski F, LaDue JS: Incidlence and clin-
ment. Seven (35 percent) of their 20 patients with ical manifestations of cardiac mnetastases. JAMA 153:712-
715, 1953
chronic granulocytic leukemia had cardiac involve-
10 Wintrobe MM, Mitchell DN1: Atypical manifestations of
ment. Roberts et al’ noted the
slightly more frequent
leukemia. Quart J Mcdl 9:67-90, 1940
presence of hemorrhages (54 percent) than infiltrates in
420 autopsies on patients who died of acute leukemia.
They noted that cardiac abnormalities were probably
being over-shadowed by the clinical manifestations re-
sulting from leukemic involvement in other organs. Hypocalcemia, Hypomagnesemia and
Sometimes the cardiac manifestations may predomi-
nate, leading to errors in diagnosis. Wintrobe and Hypokalemia during Chemotherapy
Mitchell’#{176} describe two such cases, One patientwas
of Pulmonary Tuberculosis*
treated for “heart disease” due to paroxysmal atrial tachy-
cardia for several months before granulocytic leukemia
Boon Vanasin, M.D., Marc Calmer, M.D., and J.
Paul Davis,
was diagnosed. The other was a patient diagnosed as M.D.
having gallbladder and coronary disease. Only at autop-
sy was it realized that he had granulocytic chloroma Marked hypocalcemia hypomagnesemia, tetany, hypo-
with widespread infiltration. Of additional interest is a kalemic alkalosis and hypophosphatemia developed dur-
case reported by Wendkos’ of massive pericardial effu- ing conventional dose viomycin-pyrazinamide treatment
sion in a patient with lymphocytic leukemia which was of pulmonary tuberculosis in a middle-aged man. Recov-
mistaken for tuberculous pericardial effusion. ery of renal potassium conservation required nine weeks,
In other instances, an abnormal electrocardiogram is but serum calcium and magnesium normalized after three
the only indicator of the presence of heart disease. weeks of replacement therapy.
Aronson and Leroy,’ in a study correlating the electro-
cardiogram
patients with
with clinical
leukemia,
and autopsy
noted
findings
several
in eight
electrocardio-
A patient without clinical evidence of liver disease or
malabsorption developed profound hypocalcemia,
graphic abnormalities, including sinus tachycardia, axis hypomagnesemia, tetany and hypokalemia during con-
deviation, premature beats and heart block. ventional dose antituberculosis treatment with viomycin
In the present report, the only evidence of cardiac and pyrazinamide (PZA).
involvement was repeated atrial arrhythmias, progres-
sively worsening with the disease. That these were due
CASE REPORT
to a “sick sinus node” is suggested by the autopsy
findings of a marked infiltration of the sinus node by This 58-year-old man presented with cough and weakness
leukemic cells. This knowledge can be of more than of ten days’ duration. Twenty years prior to admission the
theoretic interest because disturbing symptoms due to patient developed right upper lobe pulmonary tuberculosis
which was treated with right phrenic crush
nerve and a ten-
cardiac arrhythmias may sometimes be amenable to
month course of intramuscular streptomycin. Fifteen years
local treatment such as radiotherapy.”4
prior to admission cavitation was noted in the involved lobe
and the patient underwent right upper lobectomy followed
by a year’s course of isoniazid H)
(IN and para-aminosali-
REFERENCES
cylic acid (PAS). He was followed regularly in a chest
1 Javier By, Yount WJ, Crosby et
DJ, a!: Cardiac metasta- clinic.
sis in lymphoma and leukemia. Dis Chest 52:481-484, One month before admission the patient developed symp-
1967 toms of an upper respiratory infection and ten days before
2 Wendkos MH: Leukemic pericarditis. Amer Heart J 22: admission he noted shortness of breath, weakness, anorexia
417-422, 1941 and some nausea and vomiting.
3 Roberts BodeyWB, CP, Wertlake PT: he
T heart in acute The patient had a 15-year history of rheumatoid arthritis
leukemia. Amer J Cardiol 21:388-412, 1968 which had required joint surgery. He admitted consuming a
4 Blotner H, Sosman MC: X-ray therapy of the in a
heart half-pint of vodka weekly.
patient with leukemia, heart block and hypertension. New On physical examination the patient was
a thin white man
Eng J Med 230:793-796, 1944 who appeared chronically ill. His blood pressure was 100/70
5 Aronson SF, Leroy E: Electrocardiographic findings in mm Hg, heart rate 100 per minute and regular, respiratory
leukemia. Blood 2:356-362, 1947 rate 20 per minute and oral temperature 99.6#{176}F. Skin turgor
6 Amronin CD: Pathology of leukemia (section chap
III, * From the Divisions of Castroenterology and Endocrinology,
8). Heart, Lungs and Urinary Tract. New York, Hoeber, Department of Medicine, Baltimore City Hospitals and! the
Harper and Row, 1968 Department of Medicine, Johns Hopkins University School
7 Dresdale DT, Spain D, Perez-Pina F: Heart block and of Medicine, Baltimore.
leukemic cell infiltration of interventricular septum of This work was supported in part by NIH AM 07862,
Grant
National Institute of Arthritis andl Metabolic Diseases, and
heart. Amer J Med 6:530-533, 1949
by an Institutional Research Support Grant.
8 Kirshbaum JD, Preuss FS: Leukemia: a clinical and Reprint requests: Dr. Davis, Baltimore City Hospitals,
pathologic study of one hundred and twenty-three fatal Baltimore 21224
CHEST, VOL. 61, NO. 5, MAY 1972
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians
HYPOCALCEMIA, HYPOMAGNESEMIA AND HYPOKALEMIA IN TUBERCULOSIS 497
was poor and there wa.s no edema. Conjunctival pallor was The sputum smear was positive for acid-fast bacilli. Be-
present. There was a surgical scar over the right upper cause of the possibility that an INH-resistant organism might
postenor chest and dullness, decreased tactile and
fremitus be present, the patient was treated with viomycin (15 mg/kg
diminished breath sounds the
at right base. Heart sounds body weight) and pyrazinamide.
were normal. The abdomen was normal, including liver size. Forty days the patient
after admission developed a two-
Changes consistent with rheumatoid arthritis were present inweek of intermittent
period watery stools (up to three stools
wrists and hands. There was no cyanosis. The neurologic per day) which responded to paregoric administration. On
examination gave normal results. the 53rd hospital day he complained of profound weakness
Laboratory data included: hematocrit 26 percent, WBC and showed postural hypotension, confusion and a positive
3,800/iniii: with a normal differential, normal platelet count Chvostek’s sign. His hematocrit was now 14 percent, serum
and a peripheral blood smear showing hypochromic red blood Na 137 mEq/L, K 1.6 mEq/L, Cl 86 mEq/L and HCO3 34
cells. The results of urinalysis were normal, including a urine mEq/L. He developed grand
a mal seizure which was
pH of 5 and a specific gravity of 1.024. Chest film
x-ray treated with anticonvulsants as well as empirically with
showed an elevated right hemidiaphragm and blunted costo- parenteral calcium gluconate. Intravenous KC1 was begun,
phrenic angle, together with lingular cavitation. two of whole blood raised his hematocrit
units to 28 percent
The serum urea nitrogen was 5 mg/100 ml, fasting blood and viomycin and PZA were withheld. His serum calcium at
sugar 106 mg/10() ml, serum Na 130 mEq/L, K 3.9 mEq/L, the time of his seizure was subsequently reported as 4.3
Cl 94 mEq/L and HCO: 24 mEq/L. Serum creatinine was mg/100 ml. Grand mal seizures recurred on the 54th day and
0.7 mg/10() iiil, uric acid 2.9 mg/100 ml, calcium 8.0 mg/100 were terminated with intravenous calcium glticonate. Hypo-
ml, phosphorus 3.9 mg/ m
100 l, alkaline phosphatase 14.1 magnesemia (0.6 mEq/L; normal = 1.5 to 2.4 mEq/L) was
King-Armstrong units. protein was 6.5 gm/100
Serum total documented and the patient was begun on parenteral mag-
ml, with 2.9 gm/100 Liver function ml tests gave
albumin. nesium sulfate.
normal results. Evaluation of the patient’s anemia showed With continuing parenteral calcium, magnesium and potas-
normal haptoglobin and a normal m
bone arrow with stainable sium replacement, the patient showed gradually improved
iron; serum folate and iron levels were decreased. Stool guaiac mental status over the ensuing seven days. The course of the
tests were negative. Barium enema was normal and upper serum calcium, magnesium and potassium recovery is shown
gastrointestinal series showed a deformed duodenal bulb. in Figure 1. The recovery period was marked by excessive
SERUM
Mg 1.0
mEq/L 0.5
1-2gm/day
7.5
SERUM
Ca 5.0
mg/lOOmI 2.5 :::::::::::::::]CaCI2 3-6gm/day
// I I I I
4.0
FIGTJRE 1. Serum and urine electro-
SERUM 3.0
lytes after recognition of magnesium,
calcium and potassium abnormalities K
which developed after seven weeks of mEq/L 2.0
viomycin-PZA
sion serum
administration.
electrolyte values
Admis-
are listed
1.0
in the text. Serum calcium and mag-
nesium normalized concurrently by day
75 and required no further supplemen-
tation (amounts of magnesium sulfate 300 INTAKE
and calcium chloride cited in the Fig- OUTPUT
ure represent nondietary supplementa-
tion; calcium gluconate was also ad- URINE
ministered on clays 53 and 54). Senim K 15
K stabilized at 3.5 mEq/L by day 110
when supplementary KC1 was discon- mEq/24 hr
tinued. The intake of potassium (bot-
tom panel) includes supplemental and
estimated dietary K. Urinary potassium
excretion shows inability to conserve K 60 70 80 90 100 110 120
appropriately until day 80, and signifi-
cant K retention only after day 100. HOSPITAL DAY
CHEST, VOL. 61, NO. 5, MAY 1972
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians
498 VANASIN, COLMER AND DAVIS
urinary potassium loss (Fig ) and
I a requirement for large agents led to increased aldosterone production. Because
potassium supplements to maintain serum K until the ninth the patient had a period of diarrhea concomitant with
week after hypokalemia developed. Senim calcium and mag-
the development of serum potassium, calcium and mag-
nesium returned to normal within 20 days of his seizures and
nesium abnormalities, we considered the possibility that
remained normal when supplemental calcium and magne-
malabsorption was responsible for the appearance of
sium were stopped at that time.
There was no diarrhea during the period of acute illness
these abnormalities. Clearly, however, conservation,
and recovery. A betazole test evoked normal gastric acid rather than wasting (Fig 1), of urinary potassium should
response. Subsequent antituberculosis management was with have been observed if the gastrointestinal tract dis-
INH and ethambutol. Norecurrence of electrolyte abnormal- turbance was primarily responsible for hypokalemia. In
ity was observed in subsequent follow-up (nine months). addition, urinary potassium wasting and low serum cal-
cium and potassium persisted long after diarrhea had
COMMENTS ceased. Thus, diarrhea could have hastened the clinical
Viomycin in large doses (30 to 75 body
mg/kg deterioration which was observed but did not appear to
weight) is known to depress serum potassium and cal- be primarily responsible for the electrolyte abnormalities.
cium levels in certain patients,1’2 as early asweeks
six There was no evidence that the patient had renal disease
after initiation of therapy. The patient described here which antedated the administration of viomycin-PZA.
received acceptably low viomycin dosage but developed We have cited the work of Holmes and colleagues’ to
profound electrolyte abnormalities which culminated in indicate that the disordered renal tubular function in
confusion and seizures. Clarke and McCarthy re- this patient may have a complex origin involving renal
ported a patient who developed hypocalcemia, mag- juxtaglomerular apparatus, renin production and exces-
nesium deficiency, hypokalemia and hypophosphatemia sive aldosterone production. Finally, the anemia which
during viomycin-PZA administration in what we believe was noted on admission in our patient was thought to be
is the only previous instance of viomycin-related serum related to longstanding rheumatoid arthritis.’#{176} The sub-
electrolyte disturbance comparable to that observed insequent decline in hematocrit, unaccompanied by reticu-
our patient. Clarke postulated renal electrolyte loss tolocytosis, which occurred during viomycin-PZA therapy
account for the syndrome. However, an insight into the was not associated with gastrointestinal tract bleeding.
mechanism of these abnormalities has been provided by and was possibly related to PZA administration.h1 His
Holmes and co-workers’ who have shown that ad- hematocrit was stable after transfusion and rose slowly
ministration of certain antituberculosis drugs may be with discontinuation of viomycin and PZA.
associated with the development of hyperaldosteronism Awareness of the rare syndrome of hypocalcemia,
and consequent serum potassium and magnesium dis- hypomagnesemia and hypokalemia complicating treat-
turbances due to renal loss of these electrolytes. One ofment of tuberculosis may permit more prompt detection
the patients described by them had asymptomatic hypo- of subtler alterations in serum electrolytes than are pre-
calcemia as well, but serum calcium was normal in the sented here. Because the syndrome seems to be a feature
other patients studied. The manner in which elevated of so-called second-line antituberculosis drug therapy,
plasma renin and aldosterone have been induced by the retreatment patients are the population at risk.
administration to such patients of gentamycin and
ethambutol or capreomycin5 is not clear. ACKNOWLEDGMENT: Mrs. Marlene Butler (Gerontology
Research Center, NICHD, NIH) estimated diet potassium
Development of low serum calcium after viomycin
content. Mr. Rowland Schnick and Mr. William Fisher as-
therapy may represent, as has been postulated, primary
a sisted in the preparation of the manuscript.
renal tubular effect of the drug with resultant hypercal-
ciuria, but also possible is an effect of the agent on bone, REFERENCES
as in the case of mithramycin,6 an antibiotic with anti-
tumor and hypocalcemic properties. In addition, some 1 Werner CA, Tompsett R, Muschenheim E, et al: The
hypomagnesemic patients may be relatively parathyroid toxicity of viomycin humans.
in Amer Rev Tuberc 63:49,
1951
hormone-resistant and develop hypocalcemia which is
2 Schaffeld HG, Carthwaite B, Amberson JR: Viomycin
responsive to magnesium administration, alone.
therapy in human tuberculosis. Amer Rev Tuberc 69:520,
The patient had several other clinical problems which 1954
deserve comment. A borderline low serum
Clarke M, sodium
McCarthy CF: was Electrolyte
3 changes due to
recorded on admission and normalized during
viomycin. Tubercle the period
42:358, 1961
when hypocalcemia and hypokalemia developed. His 4 Holmes AM, Hesling CM, Wilson TM: Druginduced
serum cortisol level was normal; dietary factors and prior secondary aldosteronism in patients with pulmonary
drug administration (such as thiazide) could not be tuberculosis. Quart J Med 39:299, 1970
5 Holmes AM, Hesling CM, Wilson TM: Capreomycin
implicated in the genesis of hyponatremia. It was specu-
induced serum electrolyte abnormalities. Thorax 25:608,
lated that the transiently low serum sodium may have
1970
been due to impaired water load tolerance,8 related to
6 Parsons V, Baum M, Self M: Effect of mithramycin on
increased circulating levels of antidiuretic hormone ob- calcium and hydroxyproline metabolism in patients with
served in certain patients with active pulmonary tuber- malignant disease. Brit Med J 1:474, 1967
culosis. Normalization of the serum sodium could be 7 Estep H, Shaw WA, Watlington C,et a!: Hypocalcemia
expected during viomycin-PZA administration if these due to hypomagnesemia and reversible parathyroid unre-
CHEST, VOL. 61, NO. 5, MAY 1972
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians
ALTERNATE PATTERNS OF PREMATURE VENTRICULAR EXCITATION 499
sponsiveness. J Clin Endocrinol 29:842, 1969 CASE 2
8 Shalhoub RJ, Antoniu M
LD: echanism of hyponatremia
patient was a 69-year-old woman
The whowas referred as
in pulmonary tuberculosis. Ann Intern Med 70:943, 1969
ambulatory patient because an of palpitation two
of weeks’
9 Vocherr H, Massry SG, Fallet R, et al: Antidiuretic
duration. She had a prolonged episode of rapid heart action
principle in tuherculous lung tissue of a patient with
one year before which responded to mild sedation. brief A
pulmonary tuberculosis and hyponatremia. Ann Intern
syncopal episode occurred six months ago which was pre-
Med 72:383, 1970
ceded by palpitation and dizziness. She
was being treated
10 Ziff M, Baum J: Laboratory findings in rheumatoid ar-
with hydrochlorthiazide, 50 mg a day, for hypertension.
thritis. in Arthritis and Allied Conditions (Hollander JL
Physical examination revealed blood pressure of 170/100
ed), 7th ed, Philadelphia, Lea Febiger,
& 1966, pp 236-
and an irregular pulse. The arrhythmia was diagnosed as
237
intermittent atrial bigeminy with alternate patterns of prema-
11 Verwilghen R, Reybrouck G, CallensL, et al: Antituber-
ture ventricular excitation (Fig 3). Serum electrolytes were
culous drugs and sideroblastic anaemia. Brit J Haemat
normal. Oral administration of quinidine gluconate, 330 mg
11:92. 1965
every eight hours, resulted in normal sinus rhythm within two
days.
DISCUSSION
Alternate Patterns of Premature
Atrial premature beats commonly excite the ventricles
Ventricular Excitation during abnormally through an altered pathway.2 During such
aberrant conduction, normal intraventricular impulse
Spontaneous Atrial Bigeminy*
propagation is altered because of a refractory state in
Stafford I. Cohen, M.D. part of the usual conduction pathway. Thus, aberrant
conduction occurs whenever an atrial premature beat
This report documents two instances of spontaneous traverses the atrioventricular node and spreads to a
alternate patterns of premature ventricular excitation portion of refractory distal specialized conduction tissue.
During any given cycle, the length of the refractory
during atrial bigeminy (alternating premature ventricular
excitation). Previous reports of “alternating premature period of the branches of the specialized conducting
ventricular excitation” have required control of electro- system is directly related to the length of the preceding
physiologic parameters by atrial pacing methods. Illus- cycle;14-6 a longer preceding cycle results in a longer
refractory period than does a shorter cycle. Accordingly,
tration of this arrhythmia and a discussion of its mecha-
nism constitute the substance of this report.
atrial premature beats which follow a long cycle are
more likely to excite the ventricles abnormally than do
T he clinical presentation of
two instances of spontane-
those
ture beat
which follow
in Figure
a shorter
1 followed
cycle. The first atrial
a short cycle and
prema-
was
ously occurring alternate patterns of premature ven-
conducted normally; it was followed by a pause which
tricular excitation during atrial bigeminy (alternating
prolonged the refractory period after the next regular
premature ventricular excitation) and a discussion its of
beat so that the subsequent atrial premature heat was
mechanism constitute the substance of this report. The
conducted aberrantly.
previously reported instances of such “alternating pre-
The alternate patterns of ventricular excitation may
mature ventricular excitation” have required the con-
take several forms.’ The premature beats may alternate
trolled conditions provided by atrial pacing methods.’
between a normal and an abnormal configuration (Fig
3C) or between two abnormal configurations (Fig 2).
CASE REPORTS
Alternating patterns of right and left bundle branch
CASE 1 block may result from differences in refractoriness of the
right and left bundle branches due to changes in preced-
The patient was a 58-year-old white man
with of
a history
arteriosclerotic heart disease and angina pectoris com-who
plained of prolonged chest pain. Physical examination re-
vealed an irregular pulse. The patient was referred the to
Beth Israel Hospital with a diagnosis of possible myocardial
infarction. The arrhythmia was diagnosed as atrial bigeminy
with alternate patterns of premature ventricular excitation
(Fig 1 and 2). Administration of oral quinidine sulfate 400
mg each six hours eliminated the ectopia. The patient was
discharged from the hospital on the fourth day without
evidence of myocardial damage.
0From the Cardiac Unit and Department of Medicine, Beth FIc.uRE 1 (top). After four consecutive sinus heats, there is a
Israel Hospital and Harvard Medical School, Boston.
normally conducted atrial premature beat whichs followed
i
This work was supported in part by Grants HL-11414 and
HLTIHC 05909-03 from the National Institutes of Health, by a pause before the next sinus beat. The following atrial
United States Public Health Service. premature beat is aberrantly conducted through the ventricles.
Reprint requests: Dr. Cohen, Department of Medicine, Beth The bottom panel demonstiates an alternating pattern of
israel Hospital, Boston 02215 premature ventricular excitation for theatrial premature beats.
CHEST, VOL. 61, NO. 5, MAY 1972
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians
Hypocalcemia, Hypomagnesemia and Hypokalemia during Chemotherapy of
Pulmonary Tuberculosis
Boon Vanasin, Marc Colmer and Paul J. Davis
Chest 1972;61; 496-499
DOI 10.1378/chest.61.5.496
This information is current as of October 23, 2011
Updated Information & Services
Updated Information and services can be found at:
http://chestjournal.chestpubs.org/content/61/5/496
Cited Bys
This article has been cited by 1 HighWire-hosted articles:
http://chestjournal.chestpubs.org/content/61/5/496#related-urls
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found
online at:
http://www.chestpubs.org/site/misc/reprints.xhtml
Reprints
Information about ordering reprints can be found online:
http://www.chestpubs.org/site/misc/reprints.xhtml
Citation Alerts
Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to
the right of the online article.
Images in PowerPoint format
Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint
slide format. See any online figure for directions.
Downloaded from chestjournal.chestpubs.org by guest on October 23, 2011
1972, by the American College of Chest Physicians