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Cerebral Edema in Diabetic Ketoacidosis: A Look Beyond Rehydration

Department of Pediatrics University of Florida Gainesville, Florida 32610

	Introduction

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

 
INJUDICIOUS fluid resuscitation is frequently suggested as the cause of the cerebral edema that is the most common cause of mortality among pediatric patients with diabetic ketoacidosis (DKA) (1). The evidence, however, supports the hypothesis that neurological demise in DKA is a multifactorial process that cannot be reliably prevented by cautious rehydration protocols. Mortality and severe morbidity can, however, be reduced when healthcare providers watch vigilantly for and respond rapidly to the sentinel neurological signs and symptoms that precede, often by hours, the dramatic collapse that is typically described in these patients.

Children being treated for DKA develop clinically important neurological compromise about 0.2–1.0% of the time (2). Subclinical neurological pathology, causing raised intracranial pressure, likely precedes the initiation of therapy in almost all cases of DKA (3, 4, 5). Intracranial hypertension has been considered to be aggravated by therapy of the DKA (4, 6, 7), but in keeping with the physicians’ perplexity about the problem, even this widely held tenet has recently been challenged (8).

The pathogenic mechanism for this terrifying complication remains unknown. Hypothetical causes of cerebral edema in children with DKA must account for: 1) its occurrence (with rare exceptions; Refs. 9, 10) after the onset of therapy; 2) the preponderance of children over adults being affected, and as will be discussed later; 3) profound neurological dysfunction in the presence of minimal or no radiologically visible cerebral edema; and 4) initial pathological changes in the basal regions of the brain. Ideally, hypotheses would also explain the existence of edema in most cases of DKA and of neuropathology arising before treatment. These last two features, however, could occur independently of the disease process that causes "brain liquefaction" in children. A summary of the discussion that follows is presented in Table 1.

	Why not fluid management?

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

In a review of nine cases of symptomatic DKA-related cerebral edema, Duck et al. (11) noted that more than 4 L/m2·day of rehydration were always provided and that each affected child had hyponatremia at or near the time of herniation. Neither of these associations was confirmed by Rosenbloom et al. (12) in an analysis of 17 cases of cerebral edema. These latter investigators also commented that the lowered serum sodium levels observed by Duck et al. (11) were not reflected in concurrent decreases of serum osmolality. In a subsequent review of 42 cases (9 previously unpublished), Duck and Wyatt (13) reiterated concern about excess hydration and the development of hyponatremia during therapy. Importantly, 4 of these 42 patients had received less than 4 L/m2·day of fluid, and, as in the 1976 paper, changes in sodium concentration were not mirrored by alterations of the calculated osmolality.

Falls in intravascular osmolality during the treatment of DKA have also been associated with symptomatic cerebral edema in four papers from three independent institutions. The retrospective case-control analysis of Bello and Sotos (14) compared 70 clinical parameters between a group of 8 patients with DKA who had cerebral edema and a group of 20 children who had no neurological complications during their DKA management. They found a significant correlation between cerebral edema and the absolute decrease of serum osmolality. This association may have been spurious because the children who suffered complications had more prolonged symptoms before presentation, were younger, and, most importantly, had higher initial glucose-corrected serum sodium concentrations (152 vs. 144 mmol/L) than did the controls. In two reports, Harris et al. (15, 16) have presented 184 cases of DKA, 20 of which were complicated by neurological symptoms. They noted higher rates of complications among patients who were rehydrated with iv fluids containing 75 mmol/L and among those whose serum sodium concentration did not rise as the serum glucose concentration fell. It is noteworthy that 13 of the 20 complicated patients had only headache. The remaining seven patients had more specific signs of neurological compromise; but the potential for inclusion bias cannot be overlooked. Five of the seven cases were identified solely by investigator recall of the case. Owing to the small number of cases, the authors’ conclusions about sodium trends clearly require independent validation. In their own prospective trial, the authors presented a fluid replacement protocol that prevented a decline of serum sodium concentration in 90% of 231 consecutive cases of DKA in 149 pediatric patients. Despite the well-guarded serum sodium concentrations, mannitol was administered in six of these cases for mental status changes. Five of these patients had positive serum sodium trends at the time of treatment. Thus, the authors were unable to substantiate their initial observation in a prospective manner.

In a retrospective case-control study, Hale et al. (17) found significantly lower serum sodium concentrations and serum osmolality in three patients with DKA and cerebral edema compared with 10 patients who had uncomplicated DKA, but not until after 8 h of therapy. A fourth case of cerebral edema was recognized 3 h after treatment was started, and the corrected serum sodium concentration in this 21-month-old male had fallen from 142 mmol/L at admission to 133 mmol/L. There were no differences in the fluid therapy provided to the two study groups. The importance of an age bias between the cases and controls cannot be overlooked because symptoms of cerebral edema may not arise in very young children if pressure can be vented through their open fontanelles. Of the 10 controls in the study of Hale et al. (17), 6 were younger than 18 months and only 1 was older than 3 yr. The children with cerebral edema who survived beyond 8 h of therapy were 13 months, 3.25 yr, and 3.9-yr-old.

In a review that contradicted these four reports, Rosenbloom (18) examined the records and reports of 69 cases of DKA with intracerebral complications, including 29 that were not yet published. Once again, no association with status or management of fluid and electrolytes/osmolytes was found. He found no significant link with altered pH or the rate of decline of the blood glucose concentration. Glucose concentration declined at a rate below 2.8 mmol/L/h in 37 of 63 patients in whom this parameter could be determined. Rosenbloom (18) also reported that hyponatremia, fluid administration rate, and iv fluid tonicity did not predict cerebral demise. Between the time of initial laboratory results and the time of neurological presentation, 21 of 52 patients had either a rise of their sodium concentration or a fall less than 4 mmol/L when correction was made for the diluting effect of hyperglycemia. Rehydration rates varied from 30–450% of a designated standard protocol, and neither time to collapse nor final outcome was predicted by the fluid therapy.

In the absence of empiric clinical data to definitively implicate fluid therapy as the cause of cerebral edema in DKA, many have turned to established physiological principles to explain the disease. The generation of intracellular organic osmolytes by brain cells within a few hours of exposure to hypertonic extracellular fluid maintains normal cell volumes. During rapid iv hydration with hypotonic fluids, the kinetics of intracellular osmol reduction lags behind that of the extracellular fluid. An osmotic shift of water into cells may result (19, 20, 21, 22). Although this theory seems logical, the contribution of organic osmoles to cerebral edema during the treatment of DKA has not been confirmed experimentally. Accumulation of water in the brains of rats with chemically induced diabetic ketoacidosis was higher after very aggressive rehydration with hypotonic fluid than it was with isotonic fluid. The mechanism for this effect could not be explained, however, by the retention of intracellular organic osmolytes, rates of change of blood glucose, or by sodium influx to brain (23). Magnetic resonance spectroscopy now allows in vivo derivation of the cerebral contents of a number of compounds, including water and inorganic osmolytes. In an 18-month-old female receiving treatment for diabetes insipidus and severe hypernatremic dehydration, increases of intracerebral myo-inositiol, choline, scyllo-inositol, creatine, and glutamine (+ glutamate) were noted (24). Similar examinations of patients recovering from DKA however, demonstrated only increases of brain choline when compared with patients with well-controlled diabetes (25). Additional investigations with magnetic resonance spectroscopy and other modern noninvasive techniques (e.g. flare magnetic resonance imaging, a sensitive method of detecting cerebral edema) should lead to a better understanding of the intracerebral complications of DKA.

	The case for a multifactorial pathogenesis

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

 
Despite its diagnostic label as "cerebral edema," the profound neurological collapse suffered by these patients is often accompanied by minimal or no abnormality in initial radiographic examinations. Rosenbloom (18) reported that 9 of 30 patients who had CT scans performed during the "acute phase" of their severe compromise had no edema and six scans were read as normal. Diffuse cerebral edema was reported in 17 patients, and 4 more scans showed edema localized to the base of the brain (18). From a series of 12 unpublished cases of cerebral edema that were reviewed at our institution for litigation elsewhere, reports of head CT scans that were performed 2.5–8 h after the onset of coma were available from nine patients (see Fig. 1). Despite severe neurological depression in all of these children, the initial study was interpreted by the radiologist as showing no cerebral edema in five of them. Whereas diffuse edema was observed in one scan, the other three scans showed edema in basal brain structures only (inferior temporal lobes and cerebellum in one; hypothalamus, right basal ganglia, and right occipital lobe in another; and basal cerebrum in the third). Multiple infarcts in the basal ganglia and thalami were noted on the initial scans of two children. Five of the children had serial CT examinations. Progressive cerebral edema was reported in only three of these cases. All five children had infarcts of basal structures (basal ganglia, brainstem, thalamus, inferior cerebrum, and occipital lobes). It is often impossible to distinguish whether these are primary lesions or whether they arose as a result of compression of vasculature secondary to edema or herniation.

View larger version (24K): [in this window] [in a new window]   Figure 1. Radiologic abnormalities in children with cerebral edema and DKA. A summary of results reported by radiologists from centers at which brain imaging studies were performed is presented. Interpretations of nine initial scans and five serial scans are presented. The absolute number of patients fitting each category is provided above the bar. Reports that made no mention of edema were considered to have no edema unless one or more infarcts were present.

Intracranial pressure is determined by the volume of four fluid compartments: intracellular, interstitial, intravascular, and intrathecal. Fluid shifts between these compartments are controlled by a complex network of membrane pumps and channels, including some that are stimulated by insulin or related hormones (i.e. the Na+/H+ antiporter and Na+/K⁺ ATPase pump) (26, 27, 28, 29, 30, 31). A potential role for insulin in the cerebral edema of DKA was suggested by studies in acutely diabetic rabbits. The rapid lowering of their blood glucose concentrations from 54 to 10 mmol/L by insulin injection resulted in accumulation of organic osmolytes and cerebral edema, whereas similar changes of blood glucose concentration brought about by peritoneal dialysis did not raise brain osmolyte content and induced much less water accumulation (32). In addition, Tornheim (33) demonstrated insulin-dependent reductions of gray matter density that occurred first in the basal ganglia and thalami during treatment of diabetic rats. The edema eventually generalized, but became most severe in cortical tissues as treatment times were extended. Infusion of 0.45% saline without insulin induced no change in brain tissue density compared to untreated diabetic rats.

In humans, Van der Meulen (34) suggested that insulin-driven Na+/H+ antiporter activity may increase intracellular fluid by promoting Na+ influx into brain cells. Since the publication of that proposal, both the presence of the antiporter in brain and neuronal swelling in response to in vitro stimulation of the exchanger with insulin have been verified (35, 36). The in vivo relationships may be far more complex, however. The high intracellular sodium concentrations brought about by Na+/H+ exchange stimulate other pumps, including those that influence intracellular ion and water efflux and cytoplasmic calcium levels (26, 27). Thus, insulin injection to rats stimulated the choroid plexus Na+/H+ antiporter, and increased the intracellular sodium. It also caused a "corrective" response that resulted in a net loss of cellular K⁺ and Cl- and a reduction of intracellular volume. Antiporter activity may also induce pH changes that have important effects on brain cell functions that are unrelated to cell volume regulation.(37) The complexity of in vivo function is further illustrated by the 20% reduction of the blood-brain permeability to sodium induced by the hyperglycemia resulting from streptozotocin-induced diabetes in rats. This barrier would reduce the rate of intravascular and interstitial water efflux during treatment of DKA (38).

Hypoxemia, hyperviscous and hypercoagulable blood have been associated with DKA, suggesting that areas of the brain with the highest oxygen demands are at particular risk for ischemic insult (6, 39, 40). The effects of mild hypoxemia may be exaggerated by the apparently increased fuel requirement exhibited by the brains of streptozotocin-treated rats (41). In addition, chronic hyperglycemia exacerbates ischemic brain damage (42, 43). Finally, the regional pattern of brain involvement discussed earlier (basal brain affected first without regard for a single arterial distribution) is consistent with a hypoxemic process rather than vaso-occlusive disease. Among the most attractive features of a hypothesis implicating cerebral hypoxia in the pathogenesis of DKA-associated cerebral edema is the high oxygen requirement of children’s brains (3.3 mL/100g·min in adults, 5.1 mL/100g·min in children) (44). If ischemia does play a role, one may also consider whether acid-base derangement aggravates tissue responses to toxins, such as neuroexcitatory amino acids that are produced in low oxygen environments (45, 46). One may suggest that the prompt response of the patients’ symptoms to mannitol provides evidence against a primary hypoxic event. It is important, therefore, to recall that the earliest clinical benefits of mannitol infusion are not induced by a shift of fluid to the extravascular space, but rather a reduction of blood viscosity, thereby improving intracerebral blood flow (47).

Whether the introduction of insulin to a metabolism that has adjusted to an insulin-deficient state results in harmful derangements of brain fuel metabolism has not been studied directly. The brains of starving children take up ketones at a rate that is 4–5 times that of adults, and the regional uptake of ketones within the brain corresponds with the areas affected earliest in symptomatic cerebral edema of DKA (48, 49, 50). A relative ketone deficiency induced by insulin therapy should only become a problem, however, if glucose oxidation does not get stimulated rapidly enough after therapy is started to provide for normal brain function. Recall, however, that brain fuel requirements may be exaggerated in the ketoacidotic state (41). Intracellular access to glucose in brain cells is not likely to become a problem because the glucose transporters are not dependent on insulin and because pretreatment hyperglycemia does not down-regulate brain glucose transporters (51, 52). DKA is associated with reduced activities of glycolytic enzymes (e.g. phosphofructokinase, pyruvate dehydrogenase). It is likely, though, that restimulation of these enzymes occurs rapidly enough to allow adequate glycolysis as the brain becomes increasing reliant on glucose oxidation for energy homeostasis (53). The experimental animal models empirically suggest a need for insulin in the evolution of cerebral edema during the treatment of DKA.(32, 33) The mechanism for this requirement however remains elusive.

	What can be done?

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

 
It is commonly stated that cerebral edema presents without warning as a cataclysmic neurological deterioration in patients who are well on their way to recovering from their DKA. Close inspection of clinical records contradicts this concept. In Rosenbloom’s (18) series of 69 cases of neurological complications, warnings of the problem were retrospectively identified at least 1 h before collapse 33 times (18). Glasgow Coma Scale scores are not sensitive enough to reliably detect these changes (54).

Among the 12 unpublished cases of cerebral edema mentioned earlier, clear evidence of neurological impairment was documented in nursing notes a mean ± SD of 2.1 ± 1.2 h (range, 0.25–4.5 h) before their more dramatic presentations. Less specific signs were seen even earlier in some patients. A sudden and persistent drop of the heart rate, not in keeping with the state of rehydration, was the most common sentinel symptom, occurring in 9 of the 12 patients. Importantly, these lower heart rates were not necessarily bradycardic and did not, therefore, prompt a warning to the physician from the patient’s nurse. Typical changes were from 120–140 per min to 70–90 in a 1-h interval. Interestingly, hypertension was rarely associated with this lower heart rate. In 7 of 12 patients, changes in sensorium (e.g. poorly arousable, lethargic, "hallucinations") were recorded in the nursing records long before the patient lost consciousness, but these signs were not consistently reported to physicians. Other precedents included incontinence (4 of 12), headache (4 of 12), and emesis (2 of 12).

It is, therefore, vital that physicians prospectively describe for nurses and parents the early signs and symptoms of cerebral deterioration. In addition, physicians are well advised to read not just the data and graphics, but also the text of nursing notes when they are assessing their patients in DKA. Because of the poor specificity of these signs and symptoms, the decision to treat for cerebral edema can be a difficult one at this early stage. Of the 12 cases reviewed, however, at least two warning signs of neurological compromise or increased intracranial pressure were documented in 10. Of the remaining two patients, one had only a drop in the heart rate and the other had a sudden and persistent tachypnea with a rise in the respiratory rate from 40 to over 80 a full hour before other neurological signs were observed. Because these data are obtained from chart reviews, a bias toward under-reporting of abnormal neurologic findings is possible.

The outstanding survival achieved with patients with DKA at East Carolina University (Greenville, NC) is frequently cited as proof of the value of fluid replacement over a 48-h period with fluids having an osmolality approximating that of the patient (16). Among their ideally treated patients, however, the reported frequency of neurological complications that responded to mannitol infusion was 2 from 209 episodes, a rate very similar to the 1% incidence that is frequently reported in the literature. Frequently overlooked in their protocol (and probably of most importance) is their diligent attention to neurological status and administration of mannitol, even when only modest evidence of brain dysfunction is observed. New analyses of cerebral edema and fluid management of DKA, considering the treatment of patients up to the time that they develop their first sign or symptom of neurological disease, are required.

	Conclusion

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

 
Treatment guidelines for DKA include slow rehydration with the goal of gradually decreasing serum osmolality. In the absence of a good understanding of the pathogenesis of cerebral edema in DKA, this recommendation is prudent. In my own practice, I aim to rehydrate such patients over 36–48 h. This practice should not be viewed, however, as a panacea for preventing neurological disasters in children with diabetes. A heightened awareness of the warning signs of impending problems and a willingness to administer mannitol to patients with convincing signs of acute central nervous system dysfunction will serve patients best until the cause of cerebral edema is better understood.

	References

Top Introduction Why not fluid management? The case for a... What can be done? Conclusion References

 

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