Simultaneous measurements of Pa02; Pacc>2; pH; and serum concentrations of phosphorus, calcium, and potassium were made at admission and then 3, 6, 12, and 24 hours after the start of treatment. None of the patients received phosphorus supply during the 24 hours after admission. Serum phosphorus levels were measured using a Hitachi 705 analyzer (BuehringerMannheim SA, Meylan, France). All patients were treated intravenously with terbutaline (0.08 dz 0.05 jug/kg . min), dexamethasone (53 ± 11 m g / 2 4 h ) , and aminophylline (serum theophylline level, 13.2 + 4.1 jLig/mL). Results
Hypophosphatemia Complicating Management of Acute Severe Asthma Jean-Pierre Laaban, MD; Myrna Waked, MD; Muriel Laromiguiere, PharmD; Tu-Khanh Vuong, MD; and Jacques Rochemaure, M D Annals of Internal Medicine. 1990;112:68-69. The correction of acute respiratory acidosis by mechanical ventilation in patients with chronic obstructive pulmonary disease has been shown to induce hypophosphatemia (1-3). In patients with acute respiratory failure, hypophosphatemia may have harmful effects because it may decrease diaphragmatic contractility (4) and impair tissue oxygenation by causing a decrease in the erythrocyte 2,3-diphosphoglycerate concentration ( 5 ) . However, the variations in serum phosphorus levels have not been studied in other settings of acute respiratory acidosis. We aimed to determine whether hypophosphatemia may develop during the treatment of acute severe asthma.
The mean values for serum phosphorus, calcium, and potassium as well as for pH and Pacc>2 at admission and after treatment are summarized in Table 1. Phosphorus and blood gas levels were all measured as scheduled except for two patients at hour 3, three patients at hour 6, and two patients at hour 12. Serum phosphorus levels at admission were in the normal range (0.9 to 1.3 m m o l / L ) in ten patients, above 1.3 m m o l / L in seven patients, and below 0.9 m m o l / L in one patient (0.88 m m o l / L ) . Serum phosphorus levels decreased significantly in all patients after treatment began. The 17 patients with normal or high phosphorus levels at admission developed hypophosphatemia within 24 hours after the start of treatment. In the patient who had a low phosphorus level at admission, a further decrease was observed. Hypophosphatemia was noted early on, at hour 3, in 11 of the 18 patients. In 4 patients, the phosphorus level declined severely ( < 0.3 m m o l / L ) : The lowest value, recorded at hour 12 in 1 patient, was 0.17 mmol/L. The Paco2 and pH values increased significantly during treatment, but the highest pH value was only 7.47. The decrease in serum phosphorus levels during treatment was significantly correlated with the increase in pH (r = 0.58; P < 0.001) and the decrease in Pacc>2 (r = 0.52; P < 0.001). The serum calcium concentrations did not vary significantly (Table 1). The serum potassium concentrations, however, increased significantly at hours 12 and 24, but all patients had had systematic potassium supplementation.
Patients and Methods We did a prospective study of 18 consecutive patients (10 men, 8 women; age [mean ± S D ] , 4 2 + 1 6 years) admitted to our intensive care unit with acute severe asthma. At admission, mean values ( + S D ) of arterial carbon dioxide partial pressure (PaC02), pH, and arterial oxygen partial pressure (Pac>2) were 53 ± 19 mm Hg, 7.28 ± 0.13, and 81 ± 18 mm Hg, respectively, with 7 patients on room air, 9 on nasal oxygen, and 2 on mechanical ventilation. A third patient required mechanical ventilation within 24 hours after admission. From Hotel-Dieu de Paris, Paris, France. For current author addresses, see end of text.
68
Discussion This study shows that a noteworthy decrease in the serum phosphorus level is a constant finding after the treatment of acute severe asthma. A severe decline in the phosphorus level was observed in 4 of the 18 patients. What mechanisms accounted for the development of hypophosphatemia in our patients? We found a significant correlation between the decrease in serum phosphorus levels and the rise in serum pH, which suggests an intracellular shift of phosphorus related to the correction of respiratory acidosis. Traditionally, it has been believed that only severe and prolonged respiratory alkalosis may lead to a marked hypophosphatemia (5, 6 ) . Our study, however, as well as those
1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1
Downloaded From: https://annals.org/ by a University of Texas User on 10/02/2018
Table 1: Mean Values for Serum Phosphorus, Calcium, and Potassium,• pH; and PaCOj at Admission, and during Treatment* Variable
Hour 0
Serum phosphorus, mmol/L PH Pacc>2, mm Hg§ Serum calcium, mmol/L Serum potassium, mmol/L
1.40 7.28 53 2.12 3.26
± 0.45 ± 0.13 ± 19 ±0.13 ±0.51
0.80 7.36 39 2.10 3.30
± 0.44| ± 0.06t ± 9% ±0.19 ± 0.50
0.60 7.35 39 2.18 3.32
± 0.24t ± 0.06f ± 13J ±0.18 ± 0.48
24
12
6
3
0.60 7.37 38 2.18 3.57
± 0.32t ± 0.08t ± 15J ± 0.20 ± 0 . 6 3 ||
0.57 7.40 36 2.26 3.78
± ± ± ± ±
0.26t 0.07| 10t 0.19 0.47t
* All values are expressed as mean ± SD. t P < 0.001 by the Student Mest. %P < 0.01. § PaC0 2 = arterial carbon dioxide partial pressure. || P < 0.05.
done in patients with chronic airflow obstruction undergoing mechanical ventilation (1-3), shows that severe hypophosphatemia can develop after recovery from respiratory acidosis and hypercapnia, even in the absence of significant respiratory alkalosis and hypocapnia. In patients receiving mechanical ventilation, the occurrence of hypophosphatemia after recovery from respiratory acidosis has been associated with a marked decrease in urinary phosphorus concentration (2, 3), strongly suggesting an intracellular shift as the mechanism. The reason for higher than normal serum phosphorus levels in several patients at admission may be the associated hypercapnia ( 7 ) . N o patient received insulin or total parenteral nutrition. Gastrointestinal losses due to vomiting, diarrhea, or nasogastric suction were not seen in our patients. N o patient received antacids. Hypophosphatemia may result from increased urinary phosphate loss ( 5 ) . However, no patient received diuretics. Although corticosteroids were administered to all patients, only their long-term use induces hypophosphatemia. The bronchodilator drugs may have played a role in the genesis of hypophosphatemia (8, 9 ) ; however, it is not known whether significant hypophosphatemia can result from the infusion of theophylline or beta-2 agonists in acutely ill patients. Hypophosphatemia may lead to various complications. Because, in our study, there was no apparent evidence of cellular damage attributable to severe hypophosphatemia (seizures, rhabdomyolysis, or hemolysis), one may question the clinical relevance of this biologic disorder. Indeed, there is evidence that acute hypophosphatemia alone, when of short duration, does not cause cellular damage ( 5 ) . Only one of our patients had a history that might account for a previous phosphorus deficiency; this patient suffered from severe chronic alcoholism. Furthermore, the serum phosphorus concentration returned to normal spontaneously within a few days in all cases without phosphorus replacement, which might be explained by a rapid mobilization of phosphorus from the bone ( 5 ) . However, changes in muscle cell composition have
been reported in patients with acute hypophosphatemia, even in those without chronic phosphorus depletion ( 1 0 ) . Thus, acute hypophosphatemia may possibly promote the development or aggravation of diaphragmatic fatigue ( 4 ) . Because all our patients developed acute hypophosphatemia, we suggest that the serum phosphorus concentration be monitored during treatment of acute severe asthma. Requests for Reprints: Jean-Pierre Laaban, M D , Department of Pneumology and Intensive Care, Hotel-Dieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France. Current Author Addresses: Drs. Laaban, Waked, Vuong, and Rochemaure: Department of Pneumology and Intensive Care, Hotel-Dieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France. Dr. Laromiguiere: Department of Biochemistry and Toxicology, HotelDieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France.
References 1. Storm TL. Severe hypophosphataemia during recovery from acute respiratory acidosis. Br Med J [Clin Res]. 1984;289:456-7. 2. Squara P, Bleichner G, Aubier M, Parent A, Sollet JP, Murciano D. Hypophosphoraemia during mechanical ventilation for chronic obstructive pulmonary disease. Presse Med. 1985;14:1225-8. 3. Laaban JP, Grateau G, Psychoyos I, Laromiguiere M, Vuong TK, Rochemaure J. Hypophosphatemia induced by mechanical ventilation in patients with chronic obstructive pulmonary disease. Crit Care Med. 1989; [In press]. 4. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. NEnglJMed. 1985;313:420-4. 5. Knochel JP. Deranged phosphorus metabolism. ImSeldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York:Raven Press;1985:1397-416. 6. Mostellar M E , Tuttle EP. Effects of alkalosis on plasma concentration and urinary excretion of inorganic phosphate in man. / Clin Invest. 1964;43:138-49. 7. Guntupalli J, Matthews B, Carlin B, Bourke E. Effect of acute hypercapnia on PTH-stimulated phosphaturia in dietary Pi-deprived rat. Am J Physiol. 1987;253:F34-40. 8. Colin A A, Kraiem Z, Kahana L, Hochberg Z. Effects of theophylline on urinary excretion of cyclic AMP, calcium, and phosphorus in normal subjects. Miner Electrolyte Metab. 1984;10:359-61. 9. Body J J, Cryer PE, Offord KP, Heath H 3d. Epinephrine is a hypophosphatemic hormone in man. Physiological effects of circulating epinephrine on plasma calcium, magnesium, phosphorus, parathyroid hormone, and calcitonin. J Clin Invest. 1983;71:572-8. 10. Montanari A, Borghi L, Curti A, et al. Skeletal muscle cell abnormalities in acute hypophosphatemia during total parenteral nutrition. Miner Electrolyte Metab. 1984;10:52-7. © 1990 American College of Physicians
1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1
Downloaded From: https://annals.org/ by a University of Texas User on 10/02/2018
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Hypophosphatemia Complicating Management of Acute Severe Asthma Jean-Pierre Laaban, MD; Myrna Waked, MD; Muriel Laromiguiere, PharmD; Tu-Khanh Vuong, MD; and Jacques Rochemaure, M D Annals of Internal Medicine. 1990;112:68-69. The correction of acute respiratory acidosis by mechanical ventilation in patients with chronic obstructive pulmonary disease has been shown to induce hypophosphatemia (1-3). In patients with acute respiratory failure, hypophosphatemia may have harmful effects because it may decrease diaphragmatic contractility (4) and impair tissue oxygenation by causing a decrease in the erythrocyte 2,3-diphosphoglycerate concentration ( 5 ) . However, the variations in serum phosphorus levels have not been studied in other settings of acute respiratory acidosis. We aimed to determine whether hypophosphatemia may develop during the treatment of acute severe asthma.
The mean values for serum phosphorus, calcium, and potassium as well as for pH and Pacc>2 at admission and after treatment are summarized in Table 1. Phosphorus and blood gas levels were all measured as scheduled except for two patients at hour 3, three patients at hour 6, and two patients at hour 12. Serum phosphorus levels at admission were in the normal range (0.9 to 1.3 m m o l / L ) in ten patients, above 1.3 m m o l / L in seven patients, and below 0.9 m m o l / L in one patient (0.88 m m o l / L ) . Serum phosphorus levels decreased significantly in all patients after treatment began. The 17 patients with normal or high phosphorus levels at admission developed hypophosphatemia within 24 hours after the start of treatment. In the patient who had a low phosphorus level at admission, a further decrease was observed. Hypophosphatemia was noted early on, at hour 3, in 11 of the 18 patients. In 4 patients, the phosphorus level declined severely ( < 0.3 m m o l / L ) : The lowest value, recorded at hour 12 in 1 patient, was 0.17 mmol/L. The Paco2 and pH values increased significantly during treatment, but the highest pH value was only 7.47. The decrease in serum phosphorus levels during treatment was significantly correlated with the increase in pH (r = 0.58; P < 0.001) and the decrease in Pacc>2 (r = 0.52; P < 0.001). The serum calcium concentrations did not vary significantly (Table 1). The serum potassium concentrations, however, increased significantly at hours 12 and 24, but all patients had had systematic potassium supplementation.
Patients and Methods We did a prospective study of 18 consecutive patients (10 men, 8 women; age [mean ± S D ] , 4 2 + 1 6 years) admitted to our intensive care unit with acute severe asthma. At admission, mean values ( + S D ) of arterial carbon dioxide partial pressure (PaC02), pH, and arterial oxygen partial pressure (Pac>2) were 53 ± 19 mm Hg, 7.28 ± 0.13, and 81 ± 18 mm Hg, respectively, with 7 patients on room air, 9 on nasal oxygen, and 2 on mechanical ventilation. A third patient required mechanical ventilation within 24 hours after admission. From Hotel-Dieu de Paris, Paris, France. For current author addresses, see end of text.
68
Discussion This study shows that a noteworthy decrease in the serum phosphorus level is a constant finding after the treatment of acute severe asthma. A severe decline in the phosphorus level was observed in 4 of the 18 patients. What mechanisms accounted for the development of hypophosphatemia in our patients? We found a significant correlation between the decrease in serum phosphorus levels and the rise in serum pH, which suggests an intracellular shift of phosphorus related to the correction of respiratory acidosis. Traditionally, it has been believed that only severe and prolonged respiratory alkalosis may lead to a marked hypophosphatemia (5, 6 ) . Our study, however, as well as those
1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1
Downloaded From: https://annals.org/ by a University of Texas User on 10/02/2018
Table 1: Mean Values for Serum Phosphorus, Calcium, and Potassium,• pH; and PaCOj at Admission, and during Treatment* Variable
Hour 0
Serum phosphorus, mmol/L PH Pacc>2, mm Hg§ Serum calcium, mmol/L Serum potassium, mmol/L
1.40 7.28 53 2.12 3.26
± 0.45 ± 0.13 ± 19 ±0.13 ±0.51
0.80 7.36 39 2.10 3.30
± 0.44| ± 0.06t ± 9% ±0.19 ± 0.50
0.60 7.35 39 2.18 3.32
± 0.24t ± 0.06f ± 13J ±0.18 ± 0.48
24
12
6
3
0.60 7.37 38 2.18 3.57
± 0.32t ± 0.08t ± 15J ± 0.20 ± 0 . 6 3 ||
0.57 7.40 36 2.26 3.78
± ± ± ± ±
0.26t 0.07| 10t 0.19 0.47t
* All values are expressed as mean ± SD. t P < 0.001 by the Student Mest. %P < 0.01. § PaC0 2 = arterial carbon dioxide partial pressure. || P < 0.05.
done in patients with chronic airflow obstruction undergoing mechanical ventilation (1-3), shows that severe hypophosphatemia can develop after recovery from respiratory acidosis and hypercapnia, even in the absence of significant respiratory alkalosis and hypocapnia. In patients receiving mechanical ventilation, the occurrence of hypophosphatemia after recovery from respiratory acidosis has been associated with a marked decrease in urinary phosphorus concentration (2, 3), strongly suggesting an intracellular shift as the mechanism. The reason for higher than normal serum phosphorus levels in several patients at admission may be the associated hypercapnia ( 7 ) . N o patient received insulin or total parenteral nutrition. Gastrointestinal losses due to vomiting, diarrhea, or nasogastric suction were not seen in our patients. N o patient received antacids. Hypophosphatemia may result from increased urinary phosphate loss ( 5 ) . However, no patient received diuretics. Although corticosteroids were administered to all patients, only their long-term use induces hypophosphatemia. The bronchodilator drugs may have played a role in the genesis of hypophosphatemia (8, 9 ) ; however, it is not known whether significant hypophosphatemia can result from the infusion of theophylline or beta-2 agonists in acutely ill patients. Hypophosphatemia may lead to various complications. Because, in our study, there was no apparent evidence of cellular damage attributable to severe hypophosphatemia (seizures, rhabdomyolysis, or hemolysis), one may question the clinical relevance of this biologic disorder. Indeed, there is evidence that acute hypophosphatemia alone, when of short duration, does not cause cellular damage ( 5 ) . Only one of our patients had a history that might account for a previous phosphorus deficiency; this patient suffered from severe chronic alcoholism. Furthermore, the serum phosphorus concentration returned to normal spontaneously within a few days in all cases without phosphorus replacement, which might be explained by a rapid mobilization of phosphorus from the bone ( 5 ) . However, changes in muscle cell composition have
been reported in patients with acute hypophosphatemia, even in those without chronic phosphorus depletion ( 1 0 ) . Thus, acute hypophosphatemia may possibly promote the development or aggravation of diaphragmatic fatigue ( 4 ) . Because all our patients developed acute hypophosphatemia, we suggest that the serum phosphorus concentration be monitored during treatment of acute severe asthma. Requests for Reprints: Jean-Pierre Laaban, M D , Department of Pneumology and Intensive Care, Hotel-Dieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France. Current Author Addresses: Drs. Laaban, Waked, Vuong, and Rochemaure: Department of Pneumology and Intensive Care, Hotel-Dieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France. Dr. Laromiguiere: Department of Biochemistry and Toxicology, HotelDieu de Paris, 1 place du Parvis Notre-Dame, F-75181, Paris Cedex 04, France.
References 1. Storm TL. Severe hypophosphataemia during recovery from acute respiratory acidosis. Br Med J [Clin Res]. 1984;289:456-7. 2. Squara P, Bleichner G, Aubier M, Parent A, Sollet JP, Murciano D. Hypophosphoraemia during mechanical ventilation for chronic obstructive pulmonary disease. Presse Med. 1985;14:1225-8. 3. Laaban JP, Grateau G, Psychoyos I, Laromiguiere M, Vuong TK, Rochemaure J. Hypophosphatemia induced by mechanical ventilation in patients with chronic obstructive pulmonary disease. Crit Care Med. 1989; [In press]. 4. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. NEnglJMed. 1985;313:420-4. 5. Knochel JP. Deranged phosphorus metabolism. ImSeldin DW, Giebisch G, eds. The Kidney: Physiology and Pathophysiology. New York:Raven Press;1985:1397-416. 6. Mostellar M E , Tuttle EP. Effects of alkalosis on plasma concentration and urinary excretion of inorganic phosphate in man. / Clin Invest. 1964;43:138-49. 7. Guntupalli J, Matthews B, Carlin B, Bourke E. Effect of acute hypercapnia on PTH-stimulated phosphaturia in dietary Pi-deprived rat. Am J Physiol. 1987;253:F34-40. 8. Colin A A, Kraiem Z, Kahana L, Hochberg Z. Effects of theophylline on urinary excretion of cyclic AMP, calcium, and phosphorus in normal subjects. Miner Electrolyte Metab. 1984;10:359-61. 9. Body J J, Cryer PE, Offord KP, Heath H 3d. Epinephrine is a hypophosphatemic hormone in man. Physiological effects of circulating epinephrine on plasma calcium, magnesium, phosphorus, parathyroid hormone, and calcitonin. J Clin Invest. 1983;71:572-8. 10. Montanari A, Borghi L, Curti A, et al. Skeletal muscle cell abnormalities in acute hypophosphatemia during total parenteral nutrition. Miner Electrolyte Metab. 1984;10:52-7. © 1990 American College of Physicians
1 January 1990 • Annals of Internal Medicine • Volume 112 • Number 1
Downloaded From: https://annals.org/ by a University of Texas User on 10/02/2018
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