- Email: [email protected]
Management of severe hyponatremia
CORRESPONDENCE
STEPHAN A. BILLSTEIN, M.D. THADDEUS E. SUDOL, R.Ph., M.S. Roche Laboratories Nutley, New Jersey 1. Antibiotic-induced neutropenia. Lancet 1985; 2: 814. 2. Kissling M, Bergstrasser M: Tolerability of Rocephin. A literature survey of 486 clinical publications. Unpublished data on file. Hoffman-La Roche Inc. Submitted December28, 1989, and accepted February 12, 1990
The Reply: Billstein and Sudol essentially question whether the neutropenia observed in our patient was due to ceftriaxone. Unfortunately, they did not read the case report (Am J Med 1989; 87: 591-592) carefully, since they wrote that "the patient had received 6 days of cefotaxime therapy, followed by 4 days of ceftriaxone therapy." The ceftriaxone therapy lasted 15 days. The leukocyte count was normal 6 days after the change from cefotaxime to ceftriaxone (Figure 1 in our report). It is more than reasonable to think that ceftriaxone was responsible for the observed neutropenia. We are aware of the kinetics of ceftriaxone, which is not metabolized in blood. However, we know nothing about a possible late intestinal absorption of inactive compounds that are found in the feces. (Several metabolites are found in the feces, one of them with chromatographic behavior identical to that of a urinary metabolite [1].) It is for this reason that we wrote "we cannot formally exclude the possibility that some potential degradation products of the drug were still present in the serum n°l sample...." We thank Billstein and Sudol for trying to keep the significance of this report in perspective. However, it is clear that the goal of our case report was to describe a peculiar mechanism of drug-induced neutropenia, and not to point out the frequency of this adverse effect, which is effectively low. We think that apart from the two classical mechanisms for ~-lactam-induced neutropenia [2,3], this case report suggests a new, more complex mechanism that is not perhaps limited to ceftriaxone. JEAN-LOUIS PASQUALI, M.D., Ph.D.
Hospices Civils De Strasbourg Centre Hospitalier R~gional et Universitaire Strasbourg, France 1. Patel IH, KaplanSA: Pharmacokineticprofile of ceftriaxone in man. Am J Med 1984; 77 (suppl 4C): 1725.
702
2. Murphy MF, Metcalfe P, Grint PCA, etal:Cephalosporin-induced immune neutropenia. Br J Haematol 1985; 59: 9-14. 3. Neftel KA, HauserSP, Muller MR: Inhibition of granulopoiesis in vivo and in vitro by fl-lactam antibiotics. J Infect Dis 1985; 152: 90-98.
MANAGEMENT OF SEVERE HYPONATREMIA To the Editor: In their excellent review, Cluitmans and Meinders (Am J Med 1990; 88: 161-166) suggest that chronic hyponatremia should be corrected more slowly than hyponatremia that occurs acutely. The authors state that "...administration of furosemide prevents neurologic damage after rapid correction of severe chronic hyponatremia with (hypertonic) saline." They imply that hypertonic saline alone (without furosemide) is more likely to be associated with neurologic sequelae and that the difference in these regimens is that negative water balance is created with the hypertonic saline plus furosemide regimen, whereas positive sodium balance results from hypertonic saline alone. The protection against adverse effects of hypo-osmolality when hyponatremia develops more slowly (chronic hyponatremia) appears to be due to a reduction in brain swelling. This return of brain volume toward normal is due to the loss of solutes from the cells, initially sodium and potassium salts and then free amino acids [1]. The moderation of these changes in acute hyponatremia probably accounts for the margin of safety that permits more rapid correction in this condition. Based on these observations, neurologic dysfunction (due to osmotic demyelination) in chronic hyponatremia is more likely to occur if the plasma sodium c o n c e n t r a t i o n increases more quickly [2]. Furosemide, when added to hypertonic saline in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), should cause the plasma sodium concentration to rise faster than with hypertonic saline alone. A decrease in urine osmolality from 500 mOsm/ kg (before furosemide) to 250 mOsm/kg (after furosemide) permits the excretion of twice as much water with a given solute load. Moreover, the diuresis induced by furosemide reduces the plasma volume so that some of the administered saline is retained. The net ef-
June 1990 The American Journal of Medicine Volume 88
fect is usually a prompt increase in the plasma sodium concentration. By comparison, the administration of hypertonic saline alone is likely to correct the plasma hypoosmolality more slowly. Furthermore, the initial action of hypertonic saline in the SIADH is not to increase body sodium levels [3]; since renal perfusion is normal in this condition, all administered saline should be excreted in the urine. Thus, the administered solute acts to enhance water excretion. The administration of 1 L of 3% saline (osmolality approximately equal to 1,000 mOsm/kg), for example, would obviate the excretion of 2 L of urine if the urine osmolality were fixed at 500 mOsm/kg. These results suggest that any benefit in the coadministration of hypertonic saline and furosemide compared to hypertonic saline alone is not due to a slower increase in plasma osmolality with the former regimen. Also, in asymptomatic individuals with chronic hyponatremia, the observation that a slower rate of correction is less likely to produce neurologic symptoms indicates that the addition of furosemide should not be considered protective. Last, the use of either regimen in t h e S I A D H i n i t i a l l y removes water and does not significantly increase body sodium. ROBERT M. BLACK, M.D.
St. Vincent Hospital and University of Massachusetts Medical School Worcester, Massachusetts 1. Melton dE, Patlak CS, Pettigrew KD, et al: Volume regulatory loss of Na, CI, and K from rat brain during acute hyponatremia. Am J Physio11987; 252: F661F669. 2. Sterns RH, Thomas DJ, Herndon RM: Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int 1989; 35: 69-75. 3. Black RM: Diagnosis and management of hyponatremia. J Intensive Care Med 1989; 4: 205-220. Submitted February 21, 1990, and accepted March 21, 1990
CORRECTION In the Clinicopathologic Conference "Diarrhea and Weight Loss in a 65-Year-Old Man" (June 1989, pages 696 to 700), Figure 3 on page 700 was inadvertently printed upside down. The top of the figure is actually the bottom, and the bottom of the figure is actually the top. We apologize to the editors and the discussants of this article and to our readers for any confusion this error may have caused.
STEPHAN A. BILLSTEIN, M.D. THADDEUS E. SUDOL, R.Ph., M.S. Roche Laboratories Nutley, New Jersey 1. Antibiotic-induced neutropenia. Lancet 1985; 2: 814. 2. Kissling M, Bergstrasser M: Tolerability of Rocephin. A literature survey of 486 clinical publications. Unpublished data on file. Hoffman-La Roche Inc. Submitted December28, 1989, and accepted February 12, 1990
The Reply: Billstein and Sudol essentially question whether the neutropenia observed in our patient was due to ceftriaxone. Unfortunately, they did not read the case report (Am J Med 1989; 87: 591-592) carefully, since they wrote that "the patient had received 6 days of cefotaxime therapy, followed by 4 days of ceftriaxone therapy." The ceftriaxone therapy lasted 15 days. The leukocyte count was normal 6 days after the change from cefotaxime to ceftriaxone (Figure 1 in our report). It is more than reasonable to think that ceftriaxone was responsible for the observed neutropenia. We are aware of the kinetics of ceftriaxone, which is not metabolized in blood. However, we know nothing about a possible late intestinal absorption of inactive compounds that are found in the feces. (Several metabolites are found in the feces, one of them with chromatographic behavior identical to that of a urinary metabolite [1].) It is for this reason that we wrote "we cannot formally exclude the possibility that some potential degradation products of the drug were still present in the serum n°l sample...." We thank Billstein and Sudol for trying to keep the significance of this report in perspective. However, it is clear that the goal of our case report was to describe a peculiar mechanism of drug-induced neutropenia, and not to point out the frequency of this adverse effect, which is effectively low. We think that apart from the two classical mechanisms for ~-lactam-induced neutropenia [2,3], this case report suggests a new, more complex mechanism that is not perhaps limited to ceftriaxone. JEAN-LOUIS PASQUALI, M.D., Ph.D.
Hospices Civils De Strasbourg Centre Hospitalier R~gional et Universitaire Strasbourg, France 1. Patel IH, KaplanSA: Pharmacokineticprofile of ceftriaxone in man. Am J Med 1984; 77 (suppl 4C): 1725.
702
2. Murphy MF, Metcalfe P, Grint PCA, etal:Cephalosporin-induced immune neutropenia. Br J Haematol 1985; 59: 9-14. 3. Neftel KA, HauserSP, Muller MR: Inhibition of granulopoiesis in vivo and in vitro by fl-lactam antibiotics. J Infect Dis 1985; 152: 90-98.
MANAGEMENT OF SEVERE HYPONATREMIA To the Editor: In their excellent review, Cluitmans and Meinders (Am J Med 1990; 88: 161-166) suggest that chronic hyponatremia should be corrected more slowly than hyponatremia that occurs acutely. The authors state that "...administration of furosemide prevents neurologic damage after rapid correction of severe chronic hyponatremia with (hypertonic) saline." They imply that hypertonic saline alone (without furosemide) is more likely to be associated with neurologic sequelae and that the difference in these regimens is that negative water balance is created with the hypertonic saline plus furosemide regimen, whereas positive sodium balance results from hypertonic saline alone. The protection against adverse effects of hypo-osmolality when hyponatremia develops more slowly (chronic hyponatremia) appears to be due to a reduction in brain swelling. This return of brain volume toward normal is due to the loss of solutes from the cells, initially sodium and potassium salts and then free amino acids [1]. The moderation of these changes in acute hyponatremia probably accounts for the margin of safety that permits more rapid correction in this condition. Based on these observations, neurologic dysfunction (due to osmotic demyelination) in chronic hyponatremia is more likely to occur if the plasma sodium c o n c e n t r a t i o n increases more quickly [2]. Furosemide, when added to hypertonic saline in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), should cause the plasma sodium concentration to rise faster than with hypertonic saline alone. A decrease in urine osmolality from 500 mOsm/ kg (before furosemide) to 250 mOsm/kg (after furosemide) permits the excretion of twice as much water with a given solute load. Moreover, the diuresis induced by furosemide reduces the plasma volume so that some of the administered saline is retained. The net ef-
June 1990 The American Journal of Medicine Volume 88
fect is usually a prompt increase in the plasma sodium concentration. By comparison, the administration of hypertonic saline alone is likely to correct the plasma hypoosmolality more slowly. Furthermore, the initial action of hypertonic saline in the SIADH is not to increase body sodium levels [3]; since renal perfusion is normal in this condition, all administered saline should be excreted in the urine. Thus, the administered solute acts to enhance water excretion. The administration of 1 L of 3% saline (osmolality approximately equal to 1,000 mOsm/kg), for example, would obviate the excretion of 2 L of urine if the urine osmolality were fixed at 500 mOsm/kg. These results suggest that any benefit in the coadministration of hypertonic saline and furosemide compared to hypertonic saline alone is not due to a slower increase in plasma osmolality with the former regimen. Also, in asymptomatic individuals with chronic hyponatremia, the observation that a slower rate of correction is less likely to produce neurologic symptoms indicates that the addition of furosemide should not be considered protective. Last, the use of either regimen in t h e S I A D H i n i t i a l l y removes water and does not significantly increase body sodium. ROBERT M. BLACK, M.D.
St. Vincent Hospital and University of Massachusetts Medical School Worcester, Massachusetts 1. Melton dE, Patlak CS, Pettigrew KD, et al: Volume regulatory loss of Na, CI, and K from rat brain during acute hyponatremia. Am J Physio11987; 252: F661F669. 2. Sterns RH, Thomas DJ, Herndon RM: Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int 1989; 35: 69-75. 3. Black RM: Diagnosis and management of hyponatremia. J Intensive Care Med 1989; 4: 205-220. Submitted February 21, 1990, and accepted March 21, 1990
CORRECTION In the Clinicopathologic Conference "Diarrhea and Weight Loss in a 65-Year-Old Man" (June 1989, pages 696 to 700), Figure 3 on page 700 was inadvertently printed upside down. The top of the figure is actually the bottom, and the bottom of the figure is actually the top. We apologize to the editors and the discussants of this article and to our readers for any confusion this error may have caused.