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Hypokalaemia with hypotension due to PAS therapy
112
TUBERCLE
allowed of little chance that the primary infections in the children were due to staff with pulmonary tuberculosis. According to my clinic records three members of day nursery staffs were notified as having pulmonary tuberculosis from z946-i95i. One had a minimal lesion (breaking down tuberculoma); another in the same nursery and at the same time had a primary lesion in the lungs; the other had a pleural effusion. It is of interest to note that no primaries or conversions w e r e found in the children of these 2 day nurseries during the six months before or after these findings. T h e more successfnl case finding efforts of Finchley Chest Clinic makes one think that consideration must be given to the tuber-
April 1953
culin testing of children attending child welfare clinics who are also a more representative cross section of children in the pre-school age group.
Summary of Results (z) 2 per cent o f d a y nursery children (aged z-5) were tuberculin positive. (2) 0" 7 per cent of day nursery children converted to tuberculin positive while kept under observation for varying periods during seven years. (3) Case finding resulted in 4 children notified as having Primary P.T. z adult notified as having active P.T.
Hypokalaemia with Hypotension Due to PAS Therapy By G. PENRHYN JONES and P. O. LEGGAT
Aintree Hospital, Liverpool, 9 Introduction The object of this communication is to draw attention again to the condition of low serum potassium occurring as a result of PAS therapy and to the associated feature of cardiovascular hypotension. These sideeffects may have serious consequences with secondary myocardial and thrombotic complications as a result of prolonged PAS therapy for middle-aged and elderly patients. Hypokalaemia due to this cause has been recognized since Cayley (195o) first drew attention to it. All his patients had received liquorice-flavoured PAS in a mixture and both Strong (i95i) and Roussak (I952) described similar complications with tetany and hypokalaemic alkalosis as a result of administering PAS with liquorice. Roussak held the liquorice responsible since it had been shown by Borst (195o) that liquorice has a deoxycortone-like action. Sodium retention following D.C.A. administration produces potassium diuresis (Seldin, i95i ) and hypokalaemia, is a recognized feature of D.C.A. over-dosage (Thorn and Firor, 194o). The following report of hypokalaemia
following PAS therapy may, therefore, be of interest in that the patient received sodium PAS with no liquorice. Since previous reports suggest deoxycortonc-action as a cause of hypokalaemia, the significant hypotension with no sodium and chloride retention is a notable feature.
Case Report A man, aged 60, received dihydrostreptomycin, I gramme thrice weekly with sodium PAS, I8 grammes daily from 25.8.52. Chronic bilateral fibrocaseous tuberculosis had been diagnosed following a routine Mass Radiography film, the sputum having been found positive for acid-fast bacilli. Domiciliary chemotherapy was continued until 2o.Io.52 when, following two days' severe vomiting and diarrhoea, ttle patient developed gradual muscle weakness. He had received 27 grammes of streptomycin and t,oo8 grammes of sodium PAS. Diagnosis was presumed to be hypokalaemia following PAS therapy and he was admitted to hospital. He was a stocky, muscular individual, showing no evidence of cerebral impairment. He gave no history of previous limb weakness and apart from periodic attacks of so-called bronchitis, he had been well and working until the institution of chemotherapy for tuberculosis. There were numerous moist sounds audible
TUBERCLE
April 1953
over both lungs. Chest films showed bilateral nodular disease with gross cavitation in the left upper lobe. He was afebrile with a pulse rate of 7o/8o per minute. Blood pressure was x4o/8o. No abnormal murmurs or changes in heart sounds were detected, but an occasional premature beat was heard. The fundi showed no significant atherosclerosis. Apart from the flabbiness of the anterior abdominal wall, no abdominal abnormality could be detected clinically. Abdominal reflexes could not be elicited. Objective weakness was most obvious in the proximal muscle masses. Abduction of the shoulders, extension of the elbows, flexion at knee and hip were all very weak. T h e patient could not sit up in bed owing to the considerable weakness of the spinal muscles and flexion of the head by the sternomastoids was particularly weak. The left side of the body was perceptibly weaker than the right and the patient volunteered the information that the left arm weakness was the first symptom noted. Finger movements were within normal limits, although the supinators of the wrists were paretic. Tendon reflexes in the arms were not elicited, leg reflexes were weak and plantar responses flexor. There were no sensor), changes, superficial or deep. The organic reflexes were normal. Serum potassium was" Io rag. per cent. Electrocardiogram showed a Q . T . interval of 0. 5 second. C.S.F. pressure was normal, the CI.S.F. potassium being I2 mg. per cent. Since potassium intoxication is a real danger and rapid rise of serum potassium is especially to be avoided, and since the patient could tolerate a fitll diet, no additional potassium therapy was given (Lancet, I951). Serial serum potassium estimations showed a gradual rise and in two days power was obviously returning to the paretic muscles. Blood pressure remained a t I 4 O / 8 5 . Five days foUowing admission there was no objective sign of paresis, apart from a slight weakness of elbow extension. On 3.11.52 full power was present in the
!13
trunk and limbs. Blood pressure was 2 I o / I I o , serum potassium 20 mg. per cent, E.CI.G. normal. The patient's blood pressure has since remained about this level.
i,i;;ti;i[iiiiliiill
|. nt M!li Fro. I. - S t a n d a r d L e a d s I a n d I I . Q . T . i n t e r v a l 0. 5 see. S l i g h t S.T. s e g m e n t deviation. ~2.Io.52.
l:Io. 2. - S t a n d a r d Leads I and II. Normal. 3.II.52.
Blood count (4-Ir.5@ - H b . 99 per cent; ~V.B.C. 1o,2oo per c.mm.; Polys. 60 per cent, lymphos. 39 per cent, monos, t per cent. Blood urea 28 mg. per cent. Wassermann reaction negative. Renal function test. = Normal response to concentration and dilution test (Rosenberg's modification of Volhard's). Specific gravity range
Io25/roo2. Discussion H y p o k a l a e m i a is a recognized complication o f gastro-intestinal disturbances involving loss o f fluid a n d electrolyte. I t has been described in pyloric stenosis (Hawkins, I 9 5 I ) , idiopathic steatorrhoea ( L u b r a n and McAllen, I95Ia), infantile d i a r r h o e a (Darrow, i946 ) . L o w serum potassium has also been p r o d u c e d experimentally in m a n by
INVESTIGATIONS
.Date
22.Io.52
Sfrum K
..
Serum aVa
Serum Cl
Urine
(C.S.F.) 23.Io.52 25.10.52 27.xo.52 29.Io.5 ° 3I.IO.52 3. I 1.52
Io mg.% 15 mg.% ~3 rag.% I4 mg.% i6 mg.% 2o mg.%
Blood pressure
660 mg.%
xo mg.% 33 ° mg.% 35 ° mg.%
14o/8o Acid: alb. 60 mg.% Alk: alb. trace
57 ° mg.% Acid: alb. neg.
x4o/85 I6O/IOO 2Io/IIO
!14
April
TUBERCLE
oral administration of ion-exchange resins (Fourman, i952 ). Lubran and McAllen (i 951 b) in a detailed study of 4 cases ofhypokalaemia in ulcerative colitis showed that the deficiency was due to an excess loss of potassium in the faeces and that this was closely related to the fluid volume of the faeces. Diarrhoea and vomiting are ,frequent accompaniments of PAS therapy and with the administration of the sodium salt this might of itself be sufficient cause for the electrolyte imbalance, the disturbance of acid-base equilibrium, and their secondary effects. The patient here described had severe diarrhoea and vomiting for two days before the occurrence of limb weakness and at his age such a resultant body fluid imbalance would be more readily produced. The transient albuminuria of 60 rag. per cent may be evidence o f a prcrenal deviation of fluid with glomerular shunt. The secretion of an acid urine at this time, in spite of the alkalosis usually produced by PAS administration may be secondary to loss of base in the bowel. Even when the serum potassium was 13-15 mg. per cent, the serum sodium and chloride were within normal limits, the C.S.F. chloride also being normal. This suggests that the hypotension was not secondary to sodium loss such as occurs in Addison's disease. The non-specific reaction to injury or allergy which may be an underlying factor in some cases of PAS reaction is due to an increase ofadreno-cortical activity. Although such stress reaction m a y lead to hypokalaemia, it is very unlikely to be a real entity in this patient in view of the absence of any generalized reaction to PAS and such a considerable falling of serum potassium level being unaccompanied by any real change in the serum sodium and chloride levels. It is suggested that since D.C.A. overaction from any cause be an uncommon factor in toxic hypokalaemia produced by sodium PAS therapy, a significant hypotension may occur in such patients. Attention has already been drawn to the electro-cardiographic
1953
changes accompanying low serum potassium (McAllen, I95I , Frenkel, I947; Gass, i948 ) and particular notice has been attached to conduction defects and premature beats. The presence of associated hypotension is now emphasized. Gass could find no relation between the blood pressure and the serum potassium level in a closely studied case of familial periodic paralysis. On the other hand Freed and Friedman (I95o) found in the experimental animal a close relation between the level of serum potassium and the blood pressure level: They suggested that the hypotension observed was due to a specific deficiency of potassium. Since numerous patients are treated in domiciliary practice with PAS, both sodium salt and with liquorice flavour, often without close supervision, particular attention should be kept for this toxic complication. Thrombotic and other cardiovascular side-effects are a real danger, especially for the patient with manifest arteriosclerosis.
Summary A case of hypotension in association with hypokalaemia, secondary to sodium PAS therapy is described. It is suggested that the low serum potassium was due to diarrhoea and vomiting and the hypotension resulted from the primary myocardial effect of the low serum potassium. We arc grateful to Dr O. F. Thomas, Physician Superintendent, Aiutree Hospital, for permission to publish this case.
References Borst,J. G. G., et al. (I95o) Lancet, u, 38i. Cayley, F. E. de W. (195o) Lancet, I, 447Darrow, D. C. 0946) 07. Pediat., xXVnl,515. Fourman, P. (i952) Lancet, I, 1o4.o. Freed, S. C., and Friedman, M. (195o)Science, cxu, 788. Frenkel, M., et al. (i947) Arch. hit. ,lied., Lx~x, 7-°8. Gass, It., et al. 0948) Medicbze, xxvu, 1o5. Hawkins, C. F., et al. (1951) Lancet, 1, 318. Lancet (I951) Editorial, I, 393. Lubran, M., and McAllen, P. M. 09511) Lancet, I, 3o.I. Lubran, M., and McAllen, P. M. (195Ib) Quart. J . . t i e d . ,
XX~ 221. McAllen, P. M. (I951) Brit. Heart 07., xxn, I59. Roussak, N.J. (1952) Brit. Med..7,., z, 360. Seldin, D. W., et al. 0951) 07. Clin. lnrest., xxx, 673. Strong, J. A. (1951) Brit. Med. 07, u, 998. Thorn, G. W., and Firor, W. M. (I94o) o7. Amer. Med. Ass., cxIv, 2517.
TUBERCLE
allowed of little chance that the primary infections in the children were due to staff with pulmonary tuberculosis. According to my clinic records three members of day nursery staffs were notified as having pulmonary tuberculosis from z946-i95i. One had a minimal lesion (breaking down tuberculoma); another in the same nursery and at the same time had a primary lesion in the lungs; the other had a pleural effusion. It is of interest to note that no primaries or conversions w e r e found in the children of these 2 day nurseries during the six months before or after these findings. T h e more successfnl case finding efforts of Finchley Chest Clinic makes one think that consideration must be given to the tuber-
April 1953
culin testing of children attending child welfare clinics who are also a more representative cross section of children in the pre-school age group.
Summary of Results (z) 2 per cent o f d a y nursery children (aged z-5) were tuberculin positive. (2) 0" 7 per cent of day nursery children converted to tuberculin positive while kept under observation for varying periods during seven years. (3) Case finding resulted in 4 children notified as having Primary P.T. z adult notified as having active P.T.
Hypokalaemia with Hypotension Due to PAS Therapy By G. PENRHYN JONES and P. O. LEGGAT
Aintree Hospital, Liverpool, 9 Introduction The object of this communication is to draw attention again to the condition of low serum potassium occurring as a result of PAS therapy and to the associated feature of cardiovascular hypotension. These sideeffects may have serious consequences with secondary myocardial and thrombotic complications as a result of prolonged PAS therapy for middle-aged and elderly patients. Hypokalaemia due to this cause has been recognized since Cayley (195o) first drew attention to it. All his patients had received liquorice-flavoured PAS in a mixture and both Strong (i95i) and Roussak (I952) described similar complications with tetany and hypokalaemic alkalosis as a result of administering PAS with liquorice. Roussak held the liquorice responsible since it had been shown by Borst (195o) that liquorice has a deoxycortone-like action. Sodium retention following D.C.A. administration produces potassium diuresis (Seldin, i95i ) and hypokalaemia, is a recognized feature of D.C.A. over-dosage (Thorn and Firor, 194o). The following report of hypokalaemia
following PAS therapy may, therefore, be of interest in that the patient received sodium PAS with no liquorice. Since previous reports suggest deoxycortonc-action as a cause of hypokalaemia, the significant hypotension with no sodium and chloride retention is a notable feature.
Case Report A man, aged 60, received dihydrostreptomycin, I gramme thrice weekly with sodium PAS, I8 grammes daily from 25.8.52. Chronic bilateral fibrocaseous tuberculosis had been diagnosed following a routine Mass Radiography film, the sputum having been found positive for acid-fast bacilli. Domiciliary chemotherapy was continued until 2o.Io.52 when, following two days' severe vomiting and diarrhoea, ttle patient developed gradual muscle weakness. He had received 27 grammes of streptomycin and t,oo8 grammes of sodium PAS. Diagnosis was presumed to be hypokalaemia following PAS therapy and he was admitted to hospital. He was a stocky, muscular individual, showing no evidence of cerebral impairment. He gave no history of previous limb weakness and apart from periodic attacks of so-called bronchitis, he had been well and working until the institution of chemotherapy for tuberculosis. There were numerous moist sounds audible
TUBERCLE
April 1953
over both lungs. Chest films showed bilateral nodular disease with gross cavitation in the left upper lobe. He was afebrile with a pulse rate of 7o/8o per minute. Blood pressure was x4o/8o. No abnormal murmurs or changes in heart sounds were detected, but an occasional premature beat was heard. The fundi showed no significant atherosclerosis. Apart from the flabbiness of the anterior abdominal wall, no abdominal abnormality could be detected clinically. Abdominal reflexes could not be elicited. Objective weakness was most obvious in the proximal muscle masses. Abduction of the shoulders, extension of the elbows, flexion at knee and hip were all very weak. T h e patient could not sit up in bed owing to the considerable weakness of the spinal muscles and flexion of the head by the sternomastoids was particularly weak. The left side of the body was perceptibly weaker than the right and the patient volunteered the information that the left arm weakness was the first symptom noted. Finger movements were within normal limits, although the supinators of the wrists were paretic. Tendon reflexes in the arms were not elicited, leg reflexes were weak and plantar responses flexor. There were no sensor), changes, superficial or deep. The organic reflexes were normal. Serum potassium was" Io rag. per cent. Electrocardiogram showed a Q . T . interval of 0. 5 second. C.S.F. pressure was normal, the CI.S.F. potassium being I2 mg. per cent. Since potassium intoxication is a real danger and rapid rise of serum potassium is especially to be avoided, and since the patient could tolerate a fitll diet, no additional potassium therapy was given (Lancet, I951). Serial serum potassium estimations showed a gradual rise and in two days power was obviously returning to the paretic muscles. Blood pressure remained a t I 4 O / 8 5 . Five days foUowing admission there was no objective sign of paresis, apart from a slight weakness of elbow extension. On 3.11.52 full power was present in the
!13
trunk and limbs. Blood pressure was 2 I o / I I o , serum potassium 20 mg. per cent, E.CI.G. normal. The patient's blood pressure has since remained about this level.
i,i;;ti;i[iiiiliiill
|. nt M!li Fro. I. - S t a n d a r d L e a d s I a n d I I . Q . T . i n t e r v a l 0. 5 see. S l i g h t S.T. s e g m e n t deviation. ~2.Io.52.
l:Io. 2. - S t a n d a r d Leads I and II. Normal. 3.II.52.
Blood count (4-Ir.5@ - H b . 99 per cent; ~V.B.C. 1o,2oo per c.mm.; Polys. 60 per cent, lymphos. 39 per cent, monos, t per cent. Blood urea 28 mg. per cent. Wassermann reaction negative. Renal function test. = Normal response to concentration and dilution test (Rosenberg's modification of Volhard's). Specific gravity range
Io25/roo2. Discussion H y p o k a l a e m i a is a recognized complication o f gastro-intestinal disturbances involving loss o f fluid a n d electrolyte. I t has been described in pyloric stenosis (Hawkins, I 9 5 I ) , idiopathic steatorrhoea ( L u b r a n and McAllen, I95Ia), infantile d i a r r h o e a (Darrow, i946 ) . L o w serum potassium has also been p r o d u c e d experimentally in m a n by
INVESTIGATIONS
.Date
22.Io.52
Sfrum K
..
Serum aVa
Serum Cl
Urine
(C.S.F.) 23.Io.52 25.10.52 27.xo.52 29.Io.5 ° 3I.IO.52 3. I 1.52
Io mg.% 15 mg.% ~3 rag.% I4 mg.% i6 mg.% 2o mg.%
Blood pressure
660 mg.%
xo mg.% 33 ° mg.% 35 ° mg.%
14o/8o Acid: alb. 60 mg.% Alk: alb. trace
57 ° mg.% Acid: alb. neg.
x4o/85 I6O/IOO 2Io/IIO
!14
April
TUBERCLE
oral administration of ion-exchange resins (Fourman, i952 ). Lubran and McAllen (i 951 b) in a detailed study of 4 cases ofhypokalaemia in ulcerative colitis showed that the deficiency was due to an excess loss of potassium in the faeces and that this was closely related to the fluid volume of the faeces. Diarrhoea and vomiting are ,frequent accompaniments of PAS therapy and with the administration of the sodium salt this might of itself be sufficient cause for the electrolyte imbalance, the disturbance of acid-base equilibrium, and their secondary effects. The patient here described had severe diarrhoea and vomiting for two days before the occurrence of limb weakness and at his age such a resultant body fluid imbalance would be more readily produced. The transient albuminuria of 60 rag. per cent may be evidence o f a prcrenal deviation of fluid with glomerular shunt. The secretion of an acid urine at this time, in spite of the alkalosis usually produced by PAS administration may be secondary to loss of base in the bowel. Even when the serum potassium was 13-15 mg. per cent, the serum sodium and chloride were within normal limits, the C.S.F. chloride also being normal. This suggests that the hypotension was not secondary to sodium loss such as occurs in Addison's disease. The non-specific reaction to injury or allergy which may be an underlying factor in some cases of PAS reaction is due to an increase ofadreno-cortical activity. Although such stress reaction m a y lead to hypokalaemia, it is very unlikely to be a real entity in this patient in view of the absence of any generalized reaction to PAS and such a considerable falling of serum potassium level being unaccompanied by any real change in the serum sodium and chloride levels. It is suggested that since D.C.A. overaction from any cause be an uncommon factor in toxic hypokalaemia produced by sodium PAS therapy, a significant hypotension may occur in such patients. Attention has already been drawn to the electro-cardiographic
1953
changes accompanying low serum potassium (McAllen, I95I , Frenkel, I947; Gass, i948 ) and particular notice has been attached to conduction defects and premature beats. The presence of associated hypotension is now emphasized. Gass could find no relation between the blood pressure and the serum potassium level in a closely studied case of familial periodic paralysis. On the other hand Freed and Friedman (I95o) found in the experimental animal a close relation between the level of serum potassium and the blood pressure level: They suggested that the hypotension observed was due to a specific deficiency of potassium. Since numerous patients are treated in domiciliary practice with PAS, both sodium salt and with liquorice flavour, often without close supervision, particular attention should be kept for this toxic complication. Thrombotic and other cardiovascular side-effects are a real danger, especially for the patient with manifest arteriosclerosis.
Summary A case of hypotension in association with hypokalaemia, secondary to sodium PAS therapy is described. It is suggested that the low serum potassium was due to diarrhoea and vomiting and the hypotension resulted from the primary myocardial effect of the low serum potassium. We arc grateful to Dr O. F. Thomas, Physician Superintendent, Aiutree Hospital, for permission to publish this case.
References Borst,J. G. G., et al. (I95o) Lancet, u, 38i. Cayley, F. E. de W. (195o) Lancet, I, 447Darrow, D. C. 0946) 07. Pediat., xXVnl,515. Fourman, P. (i952) Lancet, I, 1o4.o. Freed, S. C., and Friedman, M. (195o)Science, cxu, 788. Frenkel, M., et al. (i947) Arch. hit. ,lied., Lx~x, 7-°8. Gass, It., et al. 0948) Medicbze, xxvu, 1o5. Hawkins, C. F., et al. (1951) Lancet, 1, 318. Lancet (I951) Editorial, I, 393. Lubran, M., and McAllen, P. M. 09511) Lancet, I, 3o.I. Lubran, M., and McAllen, P. M. (195Ib) Quart. J . . t i e d . ,
XX~ 221. McAllen, P. M. (I951) Brit. Heart 07., xxn, I59. Roussak, N.J. (1952) Brit. Med..7,., z, 360. Seldin, D. W., et al. 0951) 07. Clin. lnrest., xxx, 673. Strong, J. A. (1951) Brit. Med. 07, u, 998. Thorn, G. W., and Firor, W. M. (I94o) o7. Amer. Med. Ass., cxIv, 2517.