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Intracranial hemorrhages in kittens: Hypernatremia versus hypoxia
August 1976
294
TheJournalofPEDIATRICS
Intracranial hemorrhages in kittens: Hypernatremia versus hypoxia Although CNS hemorrhages have long been observed in infants with hyaline membrane disease, the etiology of these hemorrhages is still unknown. Two proposed etiologies are hypoxia with acidosis and iatrogenic hypernatremia secondary to sodium bicarbonate therapy. An experiment on kittens comparing these two hypotheses suggested that intracranial hemorrhages were related only to elevated serum sodium concentrations. The CNS hemorrhages were independent of experimentally induced hypoxemia and its consequent acidosis.
David F. Turbeville, M.D., Frank W. Bowen, Jr., M.D., and Allen P. Killam, M . D . , E l Paso, T e x a s
INTRACRANIAL HEMORRHAGE has long been observed in neonates with clinical hyaline membrane disease?. 2 Tsiantos and associates2 have shown that ICH may be independent of the severity of lung disease and therefore a major contributor to the mortality rate of clinical HMD. If the preceding proves to be a consistent finding, then elucidation of the etiology of ICH becomes extremely important. There are at present two related hypotheses regarding the etiology of intracranial hemorrhage. Avery 3 has postulated that a major contributing factor is tissue hypoxia and consequent metabolic acidosis. Simmons and associates, ' however, have recently shown that ICH may be related to the use of hypertonic bicarbonate therapy. Since the finding of metabolic acidosis frequently leads to hypertonic bicarbonate therapy, it is difficult to clinically separate these two hypotheses in the human being. This study was conducted to separate the two modalities of acidosis and hypernatremia. We used the kitten model, previously described, 5,~ in a controlled experiment that tests the relationship of intracranial hemorrhage to hypertonic bicarbonate infusion versus acidosis.
From the Departments of Pediatrics and Obstetrics and Gynecology, Perinatology Service, William Beaumont Army Medical Center. Reprints address: Department of Pediatrics, William Beaumont Army Medical Center, El Pas~, Texas 79920.
Vol. 89, No. 2, pp. 294-297
METHODS
AND MATERIALS
Thirty-two mixed breed kittens were obtained from an animal supply house and used as experimental subjects. The kittens ranged in weight from 550 to 2,500 gm. All were observed for one week and examined by a veterinarian for evidence of disease or neurologic abnormality prior to their use as experimental subjects. The composition of each group was matched as to weight and sex. All Abbreviations used ICH: intracranial hemorrhage HMD: hyaline membrane disease CNS: central nervous system subjects were anesthetized with 40 mg/kg of ketamine intramuscularly and ~ paralyzed with succinylcholine throughout the duration of the study. Once anesthetized and Paralyzed, the kittens were intubated and maintained on a Bourns respirator with controlled respirations, a 1:4 inspirations/expiration ratio, and a minute volume adequate to maintain the Paco ~ between 30 to 40 mm Hg. A No. 5 French polyethylene aortic catheter was placed through an abdominal incision and advanced to the midthoracic aorta. This procedure was accomplished Without significant blood loss in all cases. The catheter was used for blood sampling, infusion, and blood pressure monitoring. At the conclusion of the study, the animals were first exsanguinated through the aortic catheter, then
Volume 89 Number 2
Intraeranial hemorrhages in kittens
295
Table I
Group I: Hypoxemie and NaHCOa Weight-grams pH Pao2 mm Hg Paco ~ mm Hg Base deficit Hematocrit (vol%) Serum NA
1,587 7.22 42.2 33.5 -13 38.6 164
Group H: Normoxemie and NaHCOa
Group III: Hypoxemic and saline
_+ 139.0 1,204 _+ 941 _+ 0.14 7.38 _+ 0.18 _+ 8.0 94.3 _+ 1--.3 + 8.6 35.5 _+ 15:7 + 3.5 --2 _+ 2.9 _+ 4.2 40.0 _+ 3.3 _+ 19.7 159 _+ 18.5 Mean + 2 SD for each group of kittens N equals 8 in each group
Group IV." Normoxemic and saline
1,486 _+ 11.8 7.22 _+ 0.16 41.7 _+ 7.48 33.4 _+ 14,2 --15 _+ 5.2 39.5 _+ 3.2 139 _+ 8.6 studied
1,375 7.40 98.6 35.6 --1 38.7 141
_+ 575 _+ 0.08 _+ 14.0 _+ 9.28 _+ 6.8 _+ 3.1 _+ 9.9
Table II. Statistical analysis by Student's T test o f the group means
Group I vs II I vs III I vs I V
II vs III II vs IV HI vs IV Hemorrhage vs no hemorrhage
Weight
I Blood pressure
NS NS NS NS NS NS NS
NS NS NS NS NS NS NS
Hemato- I crit Paco 2 NS NS NS NS NS NS NS
the jugular veins were exposed and cut, and saline was infused through the aortic catheter until the fluid from the jugular veins was clear of any gross blood. Then 50 ml of formaldehyde was infused through the aortic catheter for brain fixation. After fixation, the brains were exposed, examined, and graded independently by one o f us for evidence of CNS hemorrhage. The hemorrhages were graded as mild hemorrhage (small a m o u n t of blood on one or both hemispheres), moderate hemorrhage (a large amount of blood on one or both hemispheres), severe hemorrhage (blood completely covering one or both hemispheres), and intraventricular hemorrhage. In order to include all the possibilities of hypoxia and hypernatremia, the kittens were divided into the following four groups. Group I--hypoxemic plus hypernatremic: Eight kittens were rendered hypoxemic by using 0.1 FIo~ through the respirator. Each kitten received intra-arterial doses o f 5 m l / k g o f 0.892 m E q / m l o f sodium bicarbonate over a one-minute period at three 90-minute intervals. Blood pressure, pH, Pao~, P a c o 2 and base deficit measurements were obtained prior to administration of the sodium bicarbonate. One hour after the last dose of sodium bicarbonate, blood samples for serum sodium concentration were obtained and the animals were sacrificed.
NS NS NS NS NS NS NS
Pao~
pH
Base deficit
< 0.001 NS
< 0.001 NS
< 0.001 NS
< 0.001
< 0.001
< 0.001 NS < 0.001 NS
< 0.001 NS < 0.001 NS
CNS Sodium hemorrhage NS
NS
< 0.001
< 0.001 < 0.001
< 0.001 < 0.001
-< 0.001 NS < 0.001 NS
< 0.001 < 0.001 NS < 0.001
< 0.001 < 0.001 NS < 0.001
Group H - n o r m o x e m i c and hypernatremic: Eight kittens were maintained n o r m o x e m i c by using 0.2 Fro~ through the respirator. Each kitten received intra-arterial doses of 5 ml/kg, of 0.892 m E q / m l sodium bicarbonate over a one-minute period at three 90-minute intervals. Subsequently, the same measurements were carried out as for Group I. Group III-hypoxemic and normonatremic group: Eight kittens were rendered hypoxemic by using 0.1 Fio~ 'through the respirator. Each kitten received intra-arterial doses of 5 m l / k g of 0.9% sodium chloride over a oneminute period at three 90-minute intervals and thereafter was managed in the same m a n n e r as Groups I and II. Group I V (control g r o u p ) - n o r m o x e m i c and normonatremic group: Eight kittens were maintained normoxemic by using 0.2 Fio~ through the respirator. Each kitten received intra-arterial doses of 5 m l / k g of 0.9% sodium chloride over a one-minute period at three 90-minute intervals and thereafter was managed in the same m a n n e r as Groups I, II, and III. In all hypoxemic animals, 0.l FIo~ was chosen because in preliminary trials a lesser coitcentration of o~ produced such profound hypoxemia and acidosis that cardiac arrest occurred prior to the end of the study period. In the normonatremic animals, 0.9% NaC1 was chosen
296
Turbeville, Bowen, and Killam
so the volumes infused between the groups would be constant, therefore controlling for comparable values of blood pressure and hematocrit. RESULTS The data for each group's means are summarized in Table I. In Group I (hypoxemic and hypernatremic), seven of eight kittens demonstrated intracranial hemorrhages ranging from mild to severe. In Group II (normoxemic and hypernatremie), seven of eight kittens demonstrated intracranial hemorrhages ranging from mild to severe. One kitten in each of Groups I and II had intraventricular hemorrhage. In Group III (hypoxemic and normonatremic), two of eight kittens demonstrated intracranial hemorrhages both of which were mild. In Group IV (normoxemic and normonatremic), none of the eight kittens demonstrated intracranial hemorrhage. Further statistical analysis of the data as undertaken with reference to the weight of the experimental subjects, blood pressure, pH, Paco2, Pao2 , base deficit, serum sodium concentrations, hematocrit values, and incidence of intracranial hemorrhage. The analysis was by the unpaired Student's T test comparing differences between means of the groups. Results of the statistical analyses are summarized in Table II. T h e analysis by Student's T test clearly Shows no difference between the groups with reference to weight, blood pressure, and P~r The hypoxemic groups (I and III) are significantly different from the nonhypoxemic groups (II and IV) with reference to the Pao2 ' pH, and base deficit. The hypernatremic groups (I and II) are significantly different from the normonatremic groups (III and IV) only with reference to the serum sodium concentrations. The kittens with intracranial hemorrhage are significantly different from the kittens without hemorrhages only in the serum sodium concentrations. Therefore, the data confirmed in this experimental model that intracranial hemorrhage was related only to elevated serum sodium concentrations. The CNS hemorrhages were independent of experimentally induced hypoxemia and its consequent acidosis. DISCUSSION Sodium bicarbonate has long been advocated in the treatment of metabolic acidosis in newborn infants. ~. 7-11 Over the years, several treatment regimens for varying degrees of acidosis have been advocated 1~ 11 One of the bases of the use of NaHCO3 has been that acidosis alone is perhaps the trigger that causes intracranial hemorrhage, either through the mechanism of disseminated intravascular coagulation or the associated tissue hypoxia.
The Journal of Pediatrics August 1976
Odel112 takes exception to this viewpoint by showing that the use of intravenous NaHCO:~ will result in the transfer of water from the brain to the bloodstream with resultant brain shrinkage and consequent tearing of bridging veins and resultant subdural hemorrhage. Simmons and associate's4 retrospective data on neonates born at different times (1966-67) and (1970-71) provide clinical support for Odell's dataY In Simmons and associate's4 study, the first group represented a time of liberal sodium bicarbonate therapy and the second a time of restricted sodium bicarbonate therapy. Although their data are quite impressive in indicating sodium bicarbonate as the offending agent, there remains the argument that many changes in the therapy of neonates with hyaline membrane disease occurred between 1966 and 1971; consequently, it is difficult to say that the decreased incidence of intracranial hemorrhages w h i c h t h e y observed was solely related to the decreased use of sodium bicarbonate. This experimental model supports the role of hypernatremia in intracranial hemorrhage as opposed to moderate acidosis. In this model, tissue hypoxia induced by a decreased Pao2 was the unifying cause of metabolic acidosis. Other etiologies of metabolic acidosis such as anemia, shock, hypovolemia, and abnormal hemoglobin disassociation curves were controlled. All or any of these defects can cause metabolic acidosis in the human neonate with idopathic respiratory distress syndrome. 13 With these data and the retrospective data of Simmons and associates~ there is now increasing evidence that some intracranial hemorrhage s seen in the neonate with hyaline membrane disease may be iatrogenically induced by the use of sodium bicarbonate therapy for metabolic acidosis. These data suggest that the treatment of acidosis be directed toward the correction of the underlying cause of the acidosis. Certainly, the detection of the etiology of metabolic acidosis is well within the scope of modern neonatal care. The use of recognized therapeutic modalities to prevent or cQrrect hypoperfusion, hypoxemia, hemoglobin affinity differences, anemia, and shock are more physiologic than the indiscriminate use of a hyperosmolar buffer to treat a laboratory finding related to such a varied pathophysiology. CONCLUSIONS Although we are completely cognizant that kittens and human infants are not similar, we have shown by producing a condition (metabolic acidosis secondary to hypoxemia) common to both, that intracranial hemorrhage only occurred secondary to iatrogenically induced hypernatremia. The addition of the experimental model
Volume 89 Number 2
presented here strengthens other evidence ~ 12 that sodium bicarbonate may iatrogenically induce intracranial hemorrhage in neonatal hyaline m e m b r a n e disease.
REFERENCES 1. Ambrus CM, Weintraub DH, Dunphy D, et al: Studies of hyaline membrane disease. I. The fibrinolysin system in pathogenesis and therapy, Pediatrics 32:10, 1963. 2. Tsiantos A, Victorin L, Relier JP, Dyer N, Sundell H, Brill AB, and Stahlman M: Intracranial hemorrhage in the prematurely born infant, J PED~ATR85:854, 1974. 3. Avery ME: The lung and its disorders in the newborn infant, 2, Philadelphia, 1968, WB Saunders Company. 4. Simmons MA, Adcock EW, Bard H, et al: Hypernatremia and intracranial hemorrhage in neonates, N Engl J Med 291:6, 1974. 5. Luttrell CN, Finberg L, and Drawdy LP: Hemorrhagic encephalopathy induced by hypernatremia, Arch Neurol 1:153, 1959. 6. Kravath RE, Aharon AS, Abal G, and Finberg L: Clinically significant physiologic changes from rapidly administered
Intracranial hemorrhages in kittens
7.
8.
9.
10.
11.
12.
13.
297
hypertonic solutions: Acute osmol poisoning, Pediatrics 46:267, 1970. Baum JD, and Robertson NRC: Immediate effects of alkaline infusion in infants with respiratory distress syndrome, J P~DIATR87:255, 1975. Russell G, and Cotton EK: Effects of sodium bicarbonate by rapid injection and of oxygen in high concentration in respiratory distress syndrome of the newborn, Pediatrics 41:1063, 1968. Oppe TE, Priestley BL, and Redstone D: Metabolic changes in the infant with respiratory failure, Pediatr Clin N A m e r 12:723, 1965. Hutchinson JH, Kerr MM, Douglas TA, et al: A therapeutic approach in 100 cases of the respiratory distress syndrome of the newborn infant, Pediatrics 33:956, 1964. Oh W: Fluid and electrolyte management in Avery GB, editor: Neonatology, Philadelphia, 1975, JB Lippincott Company. Odell GB: Therapeutic misadventures in neonatal care, in Gtuck L, Editor: Modern perinatal medicine, Chicago 1974, Year Book Medical Publishers, Inc., pp 323-332. Duc G: Assessment of hypoxia in the newborn, Pediatrics 148:469, 1971.
294
TheJournalofPEDIATRICS
Intracranial hemorrhages in kittens: Hypernatremia versus hypoxia Although CNS hemorrhages have long been observed in infants with hyaline membrane disease, the etiology of these hemorrhages is still unknown. Two proposed etiologies are hypoxia with acidosis and iatrogenic hypernatremia secondary to sodium bicarbonate therapy. An experiment on kittens comparing these two hypotheses suggested that intracranial hemorrhages were related only to elevated serum sodium concentrations. The CNS hemorrhages were independent of experimentally induced hypoxemia and its consequent acidosis.
David F. Turbeville, M.D., Frank W. Bowen, Jr., M.D., and Allen P. Killam, M . D . , E l Paso, T e x a s
INTRACRANIAL HEMORRHAGE has long been observed in neonates with clinical hyaline membrane disease?. 2 Tsiantos and associates2 have shown that ICH may be independent of the severity of lung disease and therefore a major contributor to the mortality rate of clinical HMD. If the preceding proves to be a consistent finding, then elucidation of the etiology of ICH becomes extremely important. There are at present two related hypotheses regarding the etiology of intracranial hemorrhage. Avery 3 has postulated that a major contributing factor is tissue hypoxia and consequent metabolic acidosis. Simmons and associates, ' however, have recently shown that ICH may be related to the use of hypertonic bicarbonate therapy. Since the finding of metabolic acidosis frequently leads to hypertonic bicarbonate therapy, it is difficult to clinically separate these two hypotheses in the human being. This study was conducted to separate the two modalities of acidosis and hypernatremia. We used the kitten model, previously described, 5,~ in a controlled experiment that tests the relationship of intracranial hemorrhage to hypertonic bicarbonate infusion versus acidosis.
From the Departments of Pediatrics and Obstetrics and Gynecology, Perinatology Service, William Beaumont Army Medical Center. Reprints address: Department of Pediatrics, William Beaumont Army Medical Center, El Pas~, Texas 79920.
Vol. 89, No. 2, pp. 294-297
METHODS
AND MATERIALS
Thirty-two mixed breed kittens were obtained from an animal supply house and used as experimental subjects. The kittens ranged in weight from 550 to 2,500 gm. All were observed for one week and examined by a veterinarian for evidence of disease or neurologic abnormality prior to their use as experimental subjects. The composition of each group was matched as to weight and sex. All Abbreviations used ICH: intracranial hemorrhage HMD: hyaline membrane disease CNS: central nervous system subjects were anesthetized with 40 mg/kg of ketamine intramuscularly and ~ paralyzed with succinylcholine throughout the duration of the study. Once anesthetized and Paralyzed, the kittens were intubated and maintained on a Bourns respirator with controlled respirations, a 1:4 inspirations/expiration ratio, and a minute volume adequate to maintain the Paco ~ between 30 to 40 mm Hg. A No. 5 French polyethylene aortic catheter was placed through an abdominal incision and advanced to the midthoracic aorta. This procedure was accomplished Without significant blood loss in all cases. The catheter was used for blood sampling, infusion, and blood pressure monitoring. At the conclusion of the study, the animals were first exsanguinated through the aortic catheter, then
Volume 89 Number 2
Intraeranial hemorrhages in kittens
295
Table I
Group I: Hypoxemie and NaHCOa Weight-grams pH Pao2 mm Hg Paco ~ mm Hg Base deficit Hematocrit (vol%) Serum NA
1,587 7.22 42.2 33.5 -13 38.6 164
Group H: Normoxemie and NaHCOa
Group III: Hypoxemic and saline
_+ 139.0 1,204 _+ 941 _+ 0.14 7.38 _+ 0.18 _+ 8.0 94.3 _+ 1--.3 + 8.6 35.5 _+ 15:7 + 3.5 --2 _+ 2.9 _+ 4.2 40.0 _+ 3.3 _+ 19.7 159 _+ 18.5 Mean + 2 SD for each group of kittens N equals 8 in each group
Group IV." Normoxemic and saline
1,486 _+ 11.8 7.22 _+ 0.16 41.7 _+ 7.48 33.4 _+ 14,2 --15 _+ 5.2 39.5 _+ 3.2 139 _+ 8.6 studied
1,375 7.40 98.6 35.6 --1 38.7 141
_+ 575 _+ 0.08 _+ 14.0 _+ 9.28 _+ 6.8 _+ 3.1 _+ 9.9
Table II. Statistical analysis by Student's T test o f the group means
Group I vs II I vs III I vs I V
II vs III II vs IV HI vs IV Hemorrhage vs no hemorrhage
Weight
I Blood pressure
NS NS NS NS NS NS NS
NS NS NS NS NS NS NS
Hemato- I crit Paco 2 NS NS NS NS NS NS NS
the jugular veins were exposed and cut, and saline was infused through the aortic catheter until the fluid from the jugular veins was clear of any gross blood. Then 50 ml of formaldehyde was infused through the aortic catheter for brain fixation. After fixation, the brains were exposed, examined, and graded independently by one o f us for evidence of CNS hemorrhage. The hemorrhages were graded as mild hemorrhage (small a m o u n t of blood on one or both hemispheres), moderate hemorrhage (a large amount of blood on one or both hemispheres), severe hemorrhage (blood completely covering one or both hemispheres), and intraventricular hemorrhage. In order to include all the possibilities of hypoxia and hypernatremia, the kittens were divided into the following four groups. Group I--hypoxemic plus hypernatremic: Eight kittens were rendered hypoxemic by using 0.1 FIo~ through the respirator. Each kitten received intra-arterial doses o f 5 m l / k g o f 0.892 m E q / m l o f sodium bicarbonate over a one-minute period at three 90-minute intervals. Blood pressure, pH, Pao~, P a c o 2 and base deficit measurements were obtained prior to administration of the sodium bicarbonate. One hour after the last dose of sodium bicarbonate, blood samples for serum sodium concentration were obtained and the animals were sacrificed.
NS NS NS NS NS NS NS
Pao~
pH
Base deficit
< 0.001 NS
< 0.001 NS
< 0.001 NS
< 0.001
< 0.001
< 0.001 NS < 0.001 NS
< 0.001 NS < 0.001 NS
CNS Sodium hemorrhage NS
NS
< 0.001
< 0.001 < 0.001
< 0.001 < 0.001
-< 0.001 NS < 0.001 NS
< 0.001 < 0.001 NS < 0.001
< 0.001 < 0.001 NS < 0.001
Group H - n o r m o x e m i c and hypernatremic: Eight kittens were maintained n o r m o x e m i c by using 0.2 Fro~ through the respirator. Each kitten received intra-arterial doses of 5 ml/kg, of 0.892 m E q / m l sodium bicarbonate over a one-minute period at three 90-minute intervals. Subsequently, the same measurements were carried out as for Group I. Group III-hypoxemic and normonatremic group: Eight kittens were rendered hypoxemic by using 0.1 Fio~ 'through the respirator. Each kitten received intra-arterial doses of 5 m l / k g of 0.9% sodium chloride over a oneminute period at three 90-minute intervals and thereafter was managed in the same m a n n e r as Groups I and II. Group I V (control g r o u p ) - n o r m o x e m i c and normonatremic group: Eight kittens were maintained normoxemic by using 0.2 Fio~ through the respirator. Each kitten received intra-arterial doses of 5 m l / k g of 0.9% sodium chloride over a one-minute period at three 90-minute intervals and thereafter was managed in the same m a n n e r as Groups I, II, and III. In all hypoxemic animals, 0.l FIo~ was chosen because in preliminary trials a lesser coitcentration of o~ produced such profound hypoxemia and acidosis that cardiac arrest occurred prior to the end of the study period. In the normonatremic animals, 0.9% NaC1 was chosen
296
Turbeville, Bowen, and Killam
so the volumes infused between the groups would be constant, therefore controlling for comparable values of blood pressure and hematocrit. RESULTS The data for each group's means are summarized in Table I. In Group I (hypoxemic and hypernatremic), seven of eight kittens demonstrated intracranial hemorrhages ranging from mild to severe. In Group II (normoxemic and hypernatremie), seven of eight kittens demonstrated intracranial hemorrhages ranging from mild to severe. One kitten in each of Groups I and II had intraventricular hemorrhage. In Group III (hypoxemic and normonatremic), two of eight kittens demonstrated intracranial hemorrhages both of which were mild. In Group IV (normoxemic and normonatremic), none of the eight kittens demonstrated intracranial hemorrhage. Further statistical analysis of the data as undertaken with reference to the weight of the experimental subjects, blood pressure, pH, Paco2, Pao2 , base deficit, serum sodium concentrations, hematocrit values, and incidence of intracranial hemorrhage. The analysis was by the unpaired Student's T test comparing differences between means of the groups. Results of the statistical analyses are summarized in Table II. T h e analysis by Student's T test clearly Shows no difference between the groups with reference to weight, blood pressure, and P~r The hypoxemic groups (I and III) are significantly different from the nonhypoxemic groups (II and IV) with reference to the Pao2 ' pH, and base deficit. The hypernatremic groups (I and II) are significantly different from the normonatremic groups (III and IV) only with reference to the serum sodium concentrations. The kittens with intracranial hemorrhage are significantly different from the kittens without hemorrhages only in the serum sodium concentrations. Therefore, the data confirmed in this experimental model that intracranial hemorrhage was related only to elevated serum sodium concentrations. The CNS hemorrhages were independent of experimentally induced hypoxemia and its consequent acidosis. DISCUSSION Sodium bicarbonate has long been advocated in the treatment of metabolic acidosis in newborn infants. ~. 7-11 Over the years, several treatment regimens for varying degrees of acidosis have been advocated 1~ 11 One of the bases of the use of NaHCO3 has been that acidosis alone is perhaps the trigger that causes intracranial hemorrhage, either through the mechanism of disseminated intravascular coagulation or the associated tissue hypoxia.
The Journal of Pediatrics August 1976
Odel112 takes exception to this viewpoint by showing that the use of intravenous NaHCO:~ will result in the transfer of water from the brain to the bloodstream with resultant brain shrinkage and consequent tearing of bridging veins and resultant subdural hemorrhage. Simmons and associate's4 retrospective data on neonates born at different times (1966-67) and (1970-71) provide clinical support for Odell's dataY In Simmons and associate's4 study, the first group represented a time of liberal sodium bicarbonate therapy and the second a time of restricted sodium bicarbonate therapy. Although their data are quite impressive in indicating sodium bicarbonate as the offending agent, there remains the argument that many changes in the therapy of neonates with hyaline membrane disease occurred between 1966 and 1971; consequently, it is difficult to say that the decreased incidence of intracranial hemorrhages w h i c h t h e y observed was solely related to the decreased use of sodium bicarbonate. This experimental model supports the role of hypernatremia in intracranial hemorrhage as opposed to moderate acidosis. In this model, tissue hypoxia induced by a decreased Pao2 was the unifying cause of metabolic acidosis. Other etiologies of metabolic acidosis such as anemia, shock, hypovolemia, and abnormal hemoglobin disassociation curves were controlled. All or any of these defects can cause metabolic acidosis in the human neonate with idopathic respiratory distress syndrome. 13 With these data and the retrospective data of Simmons and associates~ there is now increasing evidence that some intracranial hemorrhage s seen in the neonate with hyaline membrane disease may be iatrogenically induced by the use of sodium bicarbonate therapy for metabolic acidosis. These data suggest that the treatment of acidosis be directed toward the correction of the underlying cause of the acidosis. Certainly, the detection of the etiology of metabolic acidosis is well within the scope of modern neonatal care. The use of recognized therapeutic modalities to prevent or cQrrect hypoperfusion, hypoxemia, hemoglobin affinity differences, anemia, and shock are more physiologic than the indiscriminate use of a hyperosmolar buffer to treat a laboratory finding related to such a varied pathophysiology. CONCLUSIONS Although we are completely cognizant that kittens and human infants are not similar, we have shown by producing a condition (metabolic acidosis secondary to hypoxemia) common to both, that intracranial hemorrhage only occurred secondary to iatrogenically induced hypernatremia. The addition of the experimental model
Volume 89 Number 2
presented here strengthens other evidence ~ 12 that sodium bicarbonate may iatrogenically induce intracranial hemorrhage in neonatal hyaline m e m b r a n e disease.
REFERENCES 1. Ambrus CM, Weintraub DH, Dunphy D, et al: Studies of hyaline membrane disease. I. The fibrinolysin system in pathogenesis and therapy, Pediatrics 32:10, 1963. 2. Tsiantos A, Victorin L, Relier JP, Dyer N, Sundell H, Brill AB, and Stahlman M: Intracranial hemorrhage in the prematurely born infant, J PED~ATR85:854, 1974. 3. Avery ME: The lung and its disorders in the newborn infant, 2, Philadelphia, 1968, WB Saunders Company. 4. Simmons MA, Adcock EW, Bard H, et al: Hypernatremia and intracranial hemorrhage in neonates, N Engl J Med 291:6, 1974. 5. Luttrell CN, Finberg L, and Drawdy LP: Hemorrhagic encephalopathy induced by hypernatremia, Arch Neurol 1:153, 1959. 6. Kravath RE, Aharon AS, Abal G, and Finberg L: Clinically significant physiologic changes from rapidly administered
Intracranial hemorrhages in kittens
7.
8.
9.
10.
11.
12.
13.
297
hypertonic solutions: Acute osmol poisoning, Pediatrics 46:267, 1970. Baum JD, and Robertson NRC: Immediate effects of alkaline infusion in infants with respiratory distress syndrome, J P~DIATR87:255, 1975. Russell G, and Cotton EK: Effects of sodium bicarbonate by rapid injection and of oxygen in high concentration in respiratory distress syndrome of the newborn, Pediatrics 41:1063, 1968. Oppe TE, Priestley BL, and Redstone D: Metabolic changes in the infant with respiratory failure, Pediatr Clin N A m e r 12:723, 1965. Hutchinson JH, Kerr MM, Douglas TA, et al: A therapeutic approach in 100 cases of the respiratory distress syndrome of the newborn infant, Pediatrics 33:956, 1964. Oh W: Fluid and electrolyte management in Avery GB, editor: Neonatology, Philadelphia, 1975, JB Lippincott Company. Odell GB: Therapeutic misadventures in neonatal care, in Gtuck L, Editor: Modern perinatal medicine, Chicago 1974, Year Book Medical Publishers, Inc., pp 323-332. Duc G: Assessment of hypoxia in the newborn, Pediatrics 148:469, 1971.