IV Fluids Not Linked to Brain Injury in Children with DKA (CME/CE) | IUK Med Online
Tuesday, June 19, 2018
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IV Fluids Not Linked to Brain Injury in Children with DKA (CME/CE)

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IV Fluids Not Linked to Brain Injury in Children with DKA

Randomized trial appears to exonerate common treatment

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  • by Contributing Writer, MedPage Today
  • This article is a collaboration between MedPage Today® and:

    Medpage Today

Action Points

  • Neither the rate of administration nor the sodium chloride content of intravenous fluids significantly influenced neurologic outcomes of diabetic ketoacidosis (DKA) in children, according to a prospective, randomized trial.
  • Note that early theories of DKA-related brain injury, supported by retrospective studies, suggested that rapid administration of intravenous fluids reduced serum osmolality, which led to brain swelling.

In children with diabetic ketoacidosis (DKA), treatment with intravenous fluids has been suspected as a cause of brain injury, but now a randomized clinical trial has found no evidence for that.

In 1,255 children treated for 1,398 episodes of DKA, neither the rate of administration nor the sodium chloride content of the fluid was associated with neurologic outcomes, reported researchers led by Nathan Kuppermann, MD, of the University of California Davis School of Medicine in Sacramento.

“These findings underscore the lack of a causal association between rapid fluid administration and diabetic ketoacidosis-related brain injury,” the team wrote in the New England Journal of Medicine. Other evidence points to cerebral hypoperfusion and the effects of reperfusion, along with neuroinflammation, as a likely cause.

Brain injuries occur in 0.5-0.9% of DKA episodes in children, the researchers explained. The injuries manifest as sudden neurologic decline and are often associated with morbidity and mortality. Even among patients without obvious neurologic decline, subtle neurologic alterations have been found after recovery, including deficits in memory, attention, and IQ as well as changes in cerebral microstructure.

Early theories of DKA-related brain injury suggested that rapid administration of intravenous fluids reduced serum osmolality, which led to brain swelling. “Therefore, many treatment protocols for DKA in children advocate slow rehydration with isotonic fluids.”

Some retrospective studies have supported the intravenous fluid hypothesis. However, Kuppermann and colleagues noted, those studies were likely affected by bias because higher rates of brain injury were seen in children who were more dehydrated and therefore received larger volumes of fluid. In addition, the studies included patients with severe illness who had been referred from facilities that were not pediatric centers and that therefore used non-pediatric treatment protocols.

“Properly controlled retrospective studies have not shown associations between the fluid administration rate and brain injury. Instead, data suggest that brain injury may result from abnormalities in cerebral perfusion and inflammation that occur during episodes of diabetic ketoacidosis.”

In the trial conducted by Kuppermann and colleagues, the children were randomly assigned to one of four treatment groups in a two-by-two factorial design: 0.9% or 0.45% sodium chloride content and rapid or slow rate of administration. Other treatments for DKA in the four groups, such as insulin, were identical.

Glasgow Coma Scale scores were assessed at enrollment and hourly after that for 24 hours or until the episode of DKA had resolved. Patients ages 3 to 8 were asked to return 2 to 6 months after discharge from the hospital for neurocognitive assessment, which included the Wechsler Abbreviated Scale of Intelligence.

The study’s primary outcome was neurological deterioration as evidenced by two Glasgow Coma Scale scores of less than 14 anytime during treatment, which occurred in 3.5% of episodes. Secondary outcomes included clinically apparent brain injury, which occurred during 0.9% of episodes, and assessment of IQ 2 to 6 months after treatment.

The researchers found no significant differences in the Glasgow Coma Scale scores between children receiving 0.9% versus 0.45% of sodium chloride (relative risk 0.76; 95% CI 0.44-1.33; P=0.34) or those receiving a rapid versus slow rate of administration (RR 0.80; 95% CI 0.46-1.40; P=0.43). There were also no apparent significant differences for any of the secondary outcomes.

Jay Cohen, MD, a spokesperson for the American Academy of Clinical Endocrinologists and medical director of The Endocrine Clinic in Memphis, Tenn., told MedPage Today, “Intravenous fluids are critically important in the treatment and recovery of DKA and dehydration, but the rate and amount of [sodium chloride] concentration, within the parameters studied, were not a factor in neurologic outcomes. The rate of glucose reduction was not studied, however; this may be a significant risk factor for neurologic injury/outcomes.”

The hypothesis that brain injury is caused by the effects of cerebral hypoperfusion, reperfusion, and inflammation is supported by reports that brain injury occurs before treatment for DKA, he said in an email.

The researchers noted that although cerebral edema is a feature of clinically apparent brain injury, edema often develops hours or days after a diagnosis of brain injury — a finding that suggests that edema may be a consequence, rather than the cause, of brain injury.

Cohen agreed, and called the the hypothesis that symptomatic and even fatal brain injury is occurring prior to the initiation of the treatment of DKA “compelling,” adding: “The hypothesis that brain edema may be a consequence, not a cause, of the brain injury is viable. Additional studies to look at brain MRI/PET on admission and during therapy may help in the understanding of neuro-cognitive and neurologic dysfunction in DKA.”

A limitation of the study, Kuppermann et al wrote, was it was not sufficiently powered to detect statistically significant differences in brain injury, since this outcome occurs in less than 1% of episodes. Instead, Glasgow Coma Scale scores were used as an indicator of brain injury. “It is possible that declines in Glasgow Coma Scale scores that occur during treatment for diabetic ketoacidosis reflect physiological processes that are different from those responsible for clinically apparent brain injury.”

The study was funded by the National Institute of Child Health and Human Development and the Health Resources and Services Administration.

Kuppermann and co-authors reported having no financial conflicts of interest.

1969-12-31T19:00:00-0500

last updated

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Medpage Today

IV Fluids Not Linked to Brain Injury in Children with DKA

Randomized trial appears to exonerate common treatment

MedpageToday

  • register today

    Earn Free CME Credits by reading the latest medical news in your specialty.

    sign up

  • by Contributing Writer, MedPage Today
  • This article is a collaboration between MedPage Today® and:

    Medpage Today

Action Points

  • Neither the rate of administration nor the sodium chloride content of intravenous fluids significantly influenced neurologic outcomes of diabetic ketoacidosis (DKA) in children, according to a prospective, randomized trial.
  • Note that early theories of DKA-related brain injury, supported by retrospective studies, suggested that rapid administration of intravenous fluids reduced serum osmolality, which led to brain swelling.

In children with diabetic ketoacidosis (DKA), treatment with intravenous fluids has been suspected as a cause of brain injury, but now a randomized clinical trial has found no evidence for that.

In 1,255 children treated for 1,398 episodes of DKA, neither the rate of administration nor the sodium chloride content of the fluid was associated with neurologic outcomes, reported researchers led by Nathan Kuppermann, MD, of the University of California Davis School of Medicine in Sacramento.

"These findings underscore the lack of a causal association between rapid fluid administration and diabetic ketoacidosis-related brain injury," the team wrote in the New England Journal of Medicine. Other evidence points to cerebral hypoperfusion and the effects of reperfusion, along with neuroinflammation, as a likely cause.

Brain injuries occur in 0.5-0.9% of DKA episodes in children, the researchers explained. The injuries manifest as sudden neurologic decline and are often associated with morbidity and mortality. Even among patients without obvious neurologic decline, subtle neurologic alterations have been found after recovery, including deficits in memory, attention, and IQ as well as changes in cerebral microstructure.

Early theories of DKA-related brain injury suggested that rapid administration of intravenous fluids reduced serum osmolality, which led to brain swelling. "Therefore, many treatment protocols for DKA in children advocate slow rehydration with isotonic fluids."

Some retrospective studies have supported the intravenous fluid hypothesis. However, Kuppermann and colleagues noted, those studies were likely affected by bias because higher rates of brain injury were seen in children who were more dehydrated and therefore received larger volumes of fluid. In addition, the studies included patients with severe illness who had been referred from facilities that were not pediatric centers and that therefore used non-pediatric treatment protocols.

"Properly controlled retrospective studies have not shown associations between the fluid administration rate and brain injury. Instead, data suggest that brain injury may result from abnormalities in cerebral perfusion and inflammation that occur during episodes of diabetic ketoacidosis."

In the trial conducted by Kuppermann and colleagues, the children were randomly assigned to one of four treatment groups in a two-by-two factorial design: 0.9% or 0.45% sodium chloride content and rapid or slow rate of administration. Other treatments for DKA in the four groups, such as insulin, were identical.

Glasgow Coma Scale scores were assessed at enrollment and hourly after that for 24 hours or until the episode of DKA had resolved. Patients ages 3 to 8 were asked to return 2 to 6 months after discharge from the hospital for neurocognitive assessment, which included the Wechsler Abbreviated Scale of Intelligence.

The study's primary outcome was neurological deterioration as evidenced by two Glasgow Coma Scale scores of less than 14 anytime during treatment, which occurred in 3.5% of episodes. Secondary outcomes included clinically apparent brain injury, which occurred during 0.9% of episodes, and assessment of IQ 2 to 6 months after treatment.

The researchers found no significant differences in the Glasgow Coma Scale scores between children receiving 0.9% versus 0.45% of sodium chloride (relative risk 0.76; 95% CI 0.44-1.33; P=0.34) or those receiving a rapid versus slow rate of administration (RR 0.80; 95% CI 0.46-1.40; P=0.43). There were also no apparent significant differences for any of the secondary outcomes.

Jay Cohen, MD, a spokesperson for the American Academy of Clinical Endocrinologists and medical director of The Endocrine Clinic in Memphis, Tenn., told MedPage Today, "Intravenous fluids are critically important in the treatment and recovery of DKA and dehydration, but the rate and amount of [sodium chloride] concentration, within the parameters studied, were not a factor in neurologic outcomes. The rate of glucose reduction was not studied, however; this may be a significant risk factor for neurologic injury/outcomes."

The hypothesis that brain injury is caused by the effects of cerebral hypoperfusion, reperfusion, and inflammation is supported by reports that brain injury occurs before treatment for DKA, he said in an email.

The researchers noted that although cerebral edema is a feature of clinically apparent brain injury, edema often develops hours or days after a diagnosis of brain injury -- a finding that suggests that edema may be a consequence, rather than the cause, of brain injury.

Cohen agreed, and called the the hypothesis that symptomatic and even fatal brain injury is occurring prior to the initiation of the treatment of DKA "compelling," adding: "The hypothesis that brain edema may be a consequence, not a cause, of the brain injury is viable. Additional studies to look at brain MRI/PET on admission and during therapy may help in the understanding of neuro-cognitive and neurologic dysfunction in DKA."

A limitation of the study, Kuppermann et al wrote, was it was not sufficiently powered to detect statistically significant differences in brain injury, since this outcome occurs in less than 1% of episodes. Instead, Glasgow Coma Scale scores were used as an indicator of brain injury. "It is possible that declines in Glasgow Coma Scale scores that occur during treatment for diabetic ketoacidosis reflect physiological processes that are different from those responsible for clinically apparent brain injury."

The study was funded by the National Institute of Child Health and Human Development and the Health Resources and Services Administration.

Kuppermann and co-authors reported having no financial conflicts of interest.

1969-12-31T19:00:00-0500

last updated

Take Posttest Comments

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.



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