Hyperglycemia: An Independent Risk Factor for Poor Outcome in Children With Traumatic Brain Injury* Benjamin Elkon, MD1; Jay Riva Cambrin, MD, MSc2; Eliotte Hirshberg, MD1,3; Susan L. Bratton, MD, MPH1
Objective: We sought 1) to describe the severity and duration of hyperglycemia among surviving and dying children after traumatic brain injury; 2) to evaluate whether persistent severe hyperglycemia (averaged blood glucose > 200 mg/dL [11 mmol/L] during the first 12 hr after injury) is independently associated with poor Glasgow Outcome Score; and 3) to evaluate different definitions and the prevalence of poor Glasgow Outcome Score to better understand measurement and potential hyperglycemia treatment evaluation. Design: Retrospective cohort. Setting: Level I American College of Surgery verified pediatric trauma center. Patients: Children admitted to intensive care with moderate-tosevere traumatic brain injury. Interventions: None. Measurements and Main Results: Time course for glucose changes was compared by survival and blood glucose groups. Twelve-hour averaged patient blood glucoses were categorized as persistent: severe hyperglycemia (> 200 mg/dL [11 mmol/L]), moderate hyperglycemia (161–200 mg/dL [9–11 mmol/L]), mild hyperglycemia (110–160 mg/dL [6–9 mmol/L]), normal glycemia (80–109 mg/ dL [4–6 mmol/L]), or hypoglycemia (< 80 mg/dL [ 200 mg/dL [11 mmol/L]) was brief but remained independently associated with poor outcome. (Pediatr Crit Care Med 2014; 15:623–631) Key Words: hyperglycemia; outcome; traumatic brain injury
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raumatic brain injury (TBI) is the leading cause of injury-related death and disability in children and young adults in the United States, accounting for 40% of injuryrelated deaths (1, 2). Approximately 475,000 TBIs occur annually in children younger than 15 years. Each year, over 2,000 children die of TBI, and 42,000 require hospitalization (3). In addition to the primary injury, secondary brain injury may evolve over the ensuing hours and days. Those with severe TBI frequently develop hyperglycemia (75%) (4), which has been used as a marker for increased risk of death. However, whether severe hyperglycemia is a manifestation of stress responses related to severe injury or if it independently contributes to secondary brain injury remains unanswered. Hyperglycemia is often considered an adaptive response that maintains intravascular volume and increases energy delivery to vital organs. Although the adaptive response of supraphysiologic cardiac output is associated with improved survival during some pathologic states such as shock (5, 6), numerous observational studies have shown worse morbidity and mortality for both children (7–12) and adults (13) with hyperglycemia after head injury. However, the clinical enthusiasm for glucose control in critical injury and illness has decreased. Although an initial trial in critically ill pediatric patients (primarily cardiac surgical) www.pccmjournal.org
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(14) suggested clinical benefit, subsequent trials in children after heart surgery (15) and general critical illness have not (16). Furthermore, recent studies of adult TBI patients treated with insulin targeting tight glucose control reported reduced cerebral extracellular glucose availability and increased prevalence of brain energy crises among those treated with “tight” glucose control (17–20). Holbein et al (20) reported that patients treated with insulin targeting slightly elevated blood glucose (BG) (108–144 mg/dL [6–8 mmol/L]) had increased cerebral glucose uptake, decreased cerebral lactate production, reduced oxygen consumption, negative lactate glucose index, and decreased cerebral carbon dioxide/bicarbonate production compared with the tight control group. We evaluated whether severe hyperglycemia early after TBI was independently associated with poor outcome in pediatric TBI compared with those with mild hyperglycemia adjusted for severity of injury. We also examined our patient data comparing differing definitions of hyperglycemia and the prevalence of poor outcome.
METHODS Study Design This is a retrospective cohort study of infants and children younger than 18 years admitted to the PICU at Primary Children’s Hospital (PCH) from January 2002 to September 2006 with moderate or severe TBI. Some of the data for this study were collected for other studies evaluating both complications and factors associated with outcome after TBI (21–23). PCH is a free-standing, American College of Surgeons– certified level 1 pediatric trauma center in Salt Lake City, UT, serving five western states, and admitting approximately 630 trauma patients annually, with approximately 200 requiring admission to the PICU. The University of Utah Institutional Review Board approved this study and waived the need for informed consent. Data were obtained from the hospital’s traumatic injury database and hospital medical records. Moderate and severe TBI were defined as postresuscitation Glasgow Coma Scale (GCS) assigned by the pediatric trauma surgeon in the emergency department (ED), categorized as 9–12 and 3–8. Patient injuries were enumerated and an Injury Severity Score (ISS) Table 1.
calculated at discharge. CT scans obtained within the prehospital/ED time had previously been reviewed and graded using the Rotterdam scoring system (24) by a pediatric neurosurgeon (J.R.C.) blinded to the clinical outcomes when he reviewed the studies. Prehospital vital signs and episodes of hypotension, hypoxia, or apnea and cardiac arrest were previously collected from emergency medical services records (21). Exposure Definitions All BG values measured at PCH were obtained and elapsed time after injury calculated. BG measurements were obtained based on clinical decision making, and although testing was not standardized, measurements were frequent, as shown in Table 1. During the study time period, no guideline or protocol was in place for treatment of hyperglycemia. To standardize evaluation of BG levels and duration of elevation for our first objective, BG values were averaged over 4-hour blocks following injury for each patient. For our primary analysis (objective 2), we calculated the mean BG for each patient during the 0- to 12-hour period postinjury to compare with Glasgow Outcome Scale (GOS) at discharge. Patients were then categorized into either severe, moderate, and mild elevations; normal glucose; or hypoglycemia for analysis. Severe hyperglycemia was defined as the averaged value more than 200 mg/dL (11 mmol/L), whereas moderate hyperglycemia was between 161 and 200 mg/dL (9–11 mmol/L), mild hyperglycemia between 110 and 160 mg/dL (6–9 mmol/L), normal hyperglycemia between 80 and 109 mg/dL (4–6 mmol/L), and hypoglycemia as less than 80 mg/dL ( 200 mg/dL or 11 mmol/L) after injury as a single predictor of poor GOS. The sensitivity of severe BG elevation for poor outcome was 55%, specificity 91%, positive predictive value 68%, and negative predictive value 87%. Definition of Hyperglycemia: Magnitude, Duration, and Associated Prevalence of Poor GOS We evaluated BG values measured in the first 6 hours after injury in order to assess different criteria for hyperglycemia defined in a shorter clinical window with outcomes in our study population. Table 4 compares the proportion of patients with hyperglycemia and the prevalence of bad outcome. Our trauma center serves a large geographic area, and 32 patients did not have two BG and 31 did not have a single measurement at the trauma hospital during this time window. The table highlights issues with defining hyperglycemia in patients with TBI. Nearly all patients have BG measurements more than 110 mg/dL (6 mmol/L). The prevalence of hyperglycemia varied from 28% to 60% of patients, depending on the classification used during the first 6 hours after injury. Requiring two measurements more than 200 mg/dL (11 mmol/L) performed well compared with other classifications. The positive predictive values of the hyperglycemia definitions during the 6-hour assessment window ranged from 32% to 50% and negative predictive value from 87% to 90%. Clinical criteria that define hyperglycemia by greater BG concentration for longer times after injury (12 hr vs 6 hr) were more specific with greater positive predictive values but were less sensitive.
DISCUSSION We found that severe BG elevation in the first 12 hours after injury occurred in a quarter of children with severe TBI (23%) treated in a PICU while the proportion with normal BG levels was less common (6%). Severe BG elevation was independently associated with both poor outcome at hospital discharge and death compared with outcomes of children with mild BG elevation after injury. However, the duration of BG elevation more than 200 mg/dL (11 mmol/L) after injury was less than 24 hours after injury. One third of children in the severe BG elevation group died within a day of injury. On the other hand, 87% of children with mild to moderate average BG elevation in the first 12 hours after injury had a good outcome. Although our findings suggest that BG levels may help in assessing prognosis for pediatric patients with severe TBI, they do not Pediatric Critical Care Medicine
provide evidence that BG treatment is beneficial. Furthermore, the duration of severe hyperglycemia is brief. Our threshold for defining severe hyperglycemia, more than 200 mg/dL (11 mmol/L), was chosen to emulate other studies regarding hyperglycemia as an independent marker for poor outcome in TBI (25, 26, 28). We reasoned if hyperglycemia causes secondary brain damage after TBI that both the degree of hyperglycemia and the duration would be associated with worse injury. We found that sustained hyperglycemia for 12 hours was associated with a higher proportion of children suffering death or poor outcome at hospital discharge. Furthermore, that averaged BG elevation more than 200 mg/dL (11 mmol/L) for 12 hours had greater precision for prediction of poor outcome than either two BG measurements more than 200 mg/dL (11 mmol/L) or a single BG more than 200 mg/d during the initial 6 hours after injury. However, because of the retrospective nature of this analysis, BG was not continuously assessed, the frequency of BG measurements was not standardized, and long patient transport times may have introduced bias in ascertainment of hyperglycemia exposure. Our study definition cannot be directly compared with the integration of time and duration of hyperglycemia (i.e., area under the curve) which has become a standard measurement in prospective clinical trials (15). We used the mild BG group as our reference group, due to the small sample size of the normal BG group and concern that the normal BG group tended to have a larger fraction of high-risk patients (infants/toddlers with NAT). This choice of a comparison group is supported by both the prevalence of mild hyperglycemia in children after severe TBI and the reports in adults with TBI that mild hyperglycemia is associated with better cerebral metabolism (17–20). Neither mortality nor outcome differed when between those with moderate BG elevation to mild BG elevation. The prevalence of hyperglycemia in our study depended on the definition applied. Our data are consistent with past reports of hyperglycemia among head-injured children. Other studies defined hyperglycemia as a BG measurement more than 200 mg/dL (11 mmol/L), but it differed on duration of BG measurements or patients studied. Melo et al (26) used only the initial BG measurement and reported 34% of patients with severe TBI had hyperglycemia, whereas Sharma et al (28) evaluated children with TBI and emergency surgery and reported that 45% had hyperglycemia, and Smith et al (25) included all BG values for 2 days after injury and reported that 61% of severe TBI patients had hyperglycemia. An important observation in our study is the relatively short period of hyperglycemia. In most cases, average glucose over 200 mg/dL (11 mmol/L) persisted only 12–16 hours, and average glucose over 150 mg/dL (8 mmol/L) persisted less than 24 hours. The fall in glucose concentration followed a sigmoid shape with a relatively rapid initial fall. Thus, the window for potential therapy to lessen pathologic effects of severe hyperglycemia is brief. Other studies also examined the period of hyperglycemia but reported less detail. Melo et al (26) reported that 75% normalized in 2 days but did not describe changes. Smith et al (25) compared early versus late hyperglycemia, www.pccmjournal.org
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Table 2. Demographic, Clinical Features, and Outcomes of Head-Injured Children by Glucose Groupsa Normal Glycemia BG, 80–109 mg/dL (n = 19)
Variable
Age
4.6 (1.2, 10.9)
< 2 yr
Mild Hyperglycemia BG, 110–160 mg/dL (n = 132)
Moderate Hyperglycemia BG, 161–200 mg/dL (n = 66)
6.8 (3.1, 12.0)
8.5 (3.5, 12.0)
Severe Hyperglycemia BG, > 200 mg/dL (n = 53)
6.1 (1.9, 10.5)
6 (32)
19 (14)
8 (12)
13 (25)
11 (58)
80 (61)
43 (65)
35 (66)
Nonaccidental trauma
4 (21)
11 (8)
4 (6)
10 (19)
Motorized
6 (32)
48 (36)
35 (53)
29 (55)
Nonmotorized
9 (47)
73 (55)
27 (41)
14 (26)
Prehospital hypoxia/apnea
7 (37)
39 (30)b
27 (41)c
35 (66)
Prehospital hypotension
9 (47)
34 (26)
20 (30)
28 (53)
Cardiac arrest
1 (5)
3 (2)
0
1 (2)
Moderate traumatic brain injury
5 (26)
Male Mechanism of injury
b
Severity of injury
25 (17, 27)
Isolated head injury
11 (60)
c
31 (24)
d
Injury Severity Score (median IQR) pH in emergency department (median IQR)
b
15 (23)
b
25 (16, 29)
b
7.36 (7.33, 7.47)
25 (16, 34)
29 (25, 35)
40 (61)
32 (60)
c
66 (50) d
2 (4)
c
7.35 (7.30, 7.39)
b
7.29 (7.24, 7.35)
7.24 (7.15, 7.38)
Rotterdam scorec 1
1 (6)
5 (4)
4 (6)
1 (2)
2
9 (47)
70 (53)
29 (44)
11 (21)
3
7 (37)
41 (31)
19 (29)
10 (19)
4
1 (5)
12 (9)
13 (20)
15 (28)
5
1 (5)
4 (3)
1 (2)
15 (28)
6
0
0
0
1 (2)
b
c
Intracranial pressure monitors Fiber optic
6 (32)
21 (16)
7 (11)
9 (17)
External ventricular drain
2 (11)
4 (3)
8 (12)
10 (19)
Both
1 (5)
24 (18)
12 (18)
12 (23)
10 (53)
83 (63)
39 (59)
22 (42)
0
8 (6)
1 (2)
1 (2)
Any neurosurgery
5 (26)
30 (23)
23 (35)
11 (21)
Insulin
1 (6)b
10 (8)c
10 (15)
16 (31)
0c
17 (32)
Not monitored Surgery in first 12 hr
Death in 24 hr
0d
b
2 (2)b
Outcomes PICU length of stay (days: median IQR)
5 (1, 8)
2 (1, 6)
3 (1, 8)
1 (1, 7)
(Continued)
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Table 2. (Continued). Demographic, Clinical Features, and Outcomes of Head-Injured Children by Glucose Groupsa Normal Glycemia BG, 80–109 mg/dL (n = 19)
Mild Hyperglycemia BG, 110–160 mg/dL (n = 132)
14 (74)
103 (78)
49 (74)
13 (25)
Rehabilitation or nursing home
4 (21)
19 (14)
15 (23)
10 (19)
Death
1 (5)
10 (8)
2 (3)c
30 (57)
Poor Glasgow Outcome Scorec
5 (26)d
17 (13)b
8 (12)c
36 (68)
Variable
Moderate Hyperglycemia BG, 161–200 mg/dL (n = 66)
Severe Hyperglycemia BG, > 200 mg/dL (n = 53)
Disposition Home
BG = blood glucose, IQR = interquartile range. a One toddler < 80 mg/dL excluded from group analysis expired from nonaccidental trauma. b BG 110–160 mg/dL (6–9 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017. c BG 161–200 mg/dL (9–11 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017. d BG 80–109 mg/dL (4–6 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017.
using a cutoff of 48 hours. Sharma et al (28) showed that peak glucose more than 200 mg/dL (11 mmol/L) was persistent in only 17% of patients from preoperative through postoperative measurements, while 28% had transient hyperglycemia.
Multivariable Analysis for Factors Independently Associated With Poor Glasgow Outcome Table 3.
Factor
Adjusted Odds Ratio
95% CI
12 hr after injury mean glucose groupa Normal
1.3
0.3–5.6
Mild
1
Moderate
0.6
0.2–1.8
Severe
3.5
1.2–10.3
Reference group
Traumatic brain injury severity Moderate
1
Reference group
Severe
0.5
0.1–2.4
Rotterdam score
2.8
1.8–4.4
Hypotension prehospital
3.6
1.5–8.5
Hypoxia prehospital
3.2
1.3–7.9
Injury Severity Score
1.1
1.0–1.1
Nonaccidental trauma
8.7
2.5–30.3
Motorized mechanism
0.9
0.3–2.5
Nonmotorized
1
Mechanism of injury
Reference group
Excludes one child with hypoglycemia. Poor Glasgow outcome as 1 (dead), 2 (vegetative), or 3 (severely disabled) versus “favorable” outcome as 4 (moderate disability) or 5 (good recovery). Normal, 80–109 mg/dL (4–6 mmol/L); mild hyperglycemia, 110–160 mg/ dL (6–9 mmol/L); moderate hyperglycemia, 161–200 mg/dL (9–11 mmol/L); severe hyperglycemia, > 200 mg/dL (11 mmol/L).
a
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In this study, we found an unadjusted mortality of 57% among those with persistent severe BG elevation using the 12-hour window after TBI. This is slightly lower than reported by Melo et al (26) (70%) in a cohort restricted to only severe TBI. Sharma et al (28) reported an unadjusted mortality of 26%. However, this study was limited to surgical patients, and not all patients had severe TBI (mean GCS, 8.8). Michaud et al (29) reported that 30% of pediatric patients with severe TBI had a poor outcome defined as either death or vegetative survival. Like previous studies, we found a persistent association between severe BG elevation with poor outcome and death after adjustment for severity of illness. The magnitude of the association with death was 4.5-fold, which is less than the adjusted odds of death (6.1) reported by Melo et al (26). In addition to physiological markers of injury severity and cardiorespiratory instability (ISS, hypotension, hypoxia, and mechanism of injury), we also adjusted for radiographic severity of injury on the initial cranial CT using Rotterdam scores. Despite consistent confirmation of an association between hyperglycemia and death or poor outcome (7–12, 25, 26, 28, 29), a causal relationship cannot be concluded from these retrospective analyses. We explored multiple definitions for hyperglycemia exposure and reasoned that a time frame of 6 hours after injury was more reasonable to qualify potential subject exposure to allow for injury evaluation and intervention initiation. In similar randomized controlled trials of therapeutic hypothermia for pediatric TBI, 6-hour (30, 31) or 8-hour windows (32) were used. Similarly, a 6-hour window was also used for hypothermia in asphyxiated neonates with hypoxic ischemic encephalopathy (33). Even shorter time frames, with treatment initiation within 2 hours, were used to study hypothermia after cardiac arrest in children (34) and adults (35). We found that when using either lower concentrations of BG or a single qualifying measurement, more patients would qualify to be eligible for potential treatment. The very high rate of good outcome predicted by 12-hour average definition suggests that these may have low potential for treatment benefit, but they do have potential for harm as www.pccmjournal.org
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Table 4. Classifications of Hyperglycemia 6 Hours After Injury: Prevalence, Association With Poor Outcome,a and Test Characteristics
Hyperglycemic
Poor Outcome
Positive Predictive Value (%)
Negative Predictive Value (%)
Positive Likelihood Ratio
Sensitivity (%)
Two blood glucose > 200 mg/dL (11 mmol/L)
68/239b (28)
34/55 (62)
50
88
2.3
62
82
Any > 200 mg/dL (11 mmol/L)
96/240 (40)
42/56 (75)
44
90
2.0
85
77
Any > 160 mg/dL (9 mmol/L)
146/240 (60)
47/56 (84)
32
90
1.6
84
46
All > 140 mg/dL (8 mmol/L)
119/240 (50)
41/56 (73)
34
87
1.7
73
57
Hyperglycemia Definition
Specificity (%)
Poor outcome: 1 (dead), 2 (vegetative), or 3 (severely disabled) at discharge from hospital. b One patient with blood glucose (BG) > 200 mg/dL only had one BG measurement and was excluded. a
severe hypoglycemia is greater among pediatric patients treated with insulin for tight control (14, 16). We found that over 90% of children with average BG concentration between 110 and 200 mg/dL (6–11 mmol/L) by 12 hours after injury survived and 87% had a good outcome at discharge. Other important findings were that few children admitted to ICU after TBI had normal BG concentrations during the first 12 hours compared with children with mild to moderate BG elevations; however, they tended to have worse unadjusted poor GOS compared with the those with mild or moderate BG elevation. Finally, infants and toddlers with NAT had over eight-fold increased adjusted odds of poor outcome, and these factors would need to be evaluated separately in future studies that seek to evaluate benefit from hyperglycemia treatment. Study limitations should be emphasized. This was a retrospective analysis of glucose measurements collected for routine care. Although measurements were frequent, there was no regularity to measurements and patients with marked elevation had more measurements. Our analysis using patient averages in time blocks prevented individual patients to unduly influence the results due to more measurements, but averaging patient averages to determine group values decreased measurement variability and is not comparable to the time weighted averages reported by Agus et al (15). Administration of neither dextrose nor insulin was standardized, and although hypoglycemia (BG < 80 mg/dL) was uncommon in the first days after injury, recent studies of brain metabolism in adults with TBI have raised concern that glucose concentrations in the lower “normal” range may be harmful. Thus, treatment with insulin which was most common in the severe BG elevation group might have been harmful. Although normal saline administration is routinely used for fluid administration, some providers add dextrose when caring for infants and young toddlers; likewise treatment of hyperglycemia with insulin was infrequent and not standardized in our study. Furthermore, because treatment of hyperglycemia in children is less common than in adults, accepted thresholds for treatment initiation and cessation remain unclear currently (35, 36). The changes in glucose concentration for a given patient may have been affected by stress associated with TBI and other factors including administration of glucose and catecholamines to raise cerebral perfusion 630
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pressure. The definitions for BG groups were retrospectively defined. The assessment of outcome was at hospital discharge, and we used a grouped outcome which prevented assessment of either recovery or finer cognitive evaluation. Treatment with insulin was more common in the severe hyperglycemia. Finally, this is a single-center report with both obvious factors such as serving a large catchment area, which affects admission time in relation to time from injury, and less obvious care features, such as routine use of norepinephrine rather than phenylephrine to raise cerebral perfusion pressure (37). In conclusion, we found that severe BG elevation during the initial 12 hours was independently associated with both poor outcome and mortality in children after TBI. If patients dying during the first day after injury were excluded, an independent association with poor outcome was no longer statistically significant. Averaged BG elevations less than 200 mg/dL during the initial 12 hours after injury had no demonstrable association with mortality, but the majority of children with severe TBI did not have normal BG values during this time frame. Nevertheless the duration of severe hyperglycemia is relatively short (< 24 hr), and over 90% of children whose averaged BG measurements during the initial 12 hours after injury were less than 200 mg/dL survived.
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Objective: We sought 1) to describe the severity and duration of hyperglycemia among surviving and dying children after traumatic brain injury; 2) to evaluate whether persistent severe hyperglycemia (averaged blood glucose > 200 mg/dL [11 mmol/L] during the first 12 hr after injury) is independently associated with poor Glasgow Outcome Score; and 3) to evaluate different definitions and the prevalence of poor Glasgow Outcome Score to better understand measurement and potential hyperglycemia treatment evaluation. Design: Retrospective cohort. Setting: Level I American College of Surgery verified pediatric trauma center. Patients: Children admitted to intensive care with moderate-tosevere traumatic brain injury. Interventions: None. Measurements and Main Results: Time course for glucose changes was compared by survival and blood glucose groups. Twelve-hour averaged patient blood glucoses were categorized as persistent: severe hyperglycemia (> 200 mg/dL [11 mmol/L]), moderate hyperglycemia (161–200 mg/dL [9–11 mmol/L]), mild hyperglycemia (110–160 mg/dL [6–9 mmol/L]), normal glycemia (80–109 mg/ dL [4–6 mmol/L]), or hypoglycemia (< 80 mg/dL [ 200 mg/dL [11 mmol/L]) was brief but remained independently associated with poor outcome. (Pediatr Crit Care Med 2014; 15:623–631) Key Words: hyperglycemia; outcome; traumatic brain injury
T
raumatic brain injury (TBI) is the leading cause of injury-related death and disability in children and young adults in the United States, accounting for 40% of injuryrelated deaths (1, 2). Approximately 475,000 TBIs occur annually in children younger than 15 years. Each year, over 2,000 children die of TBI, and 42,000 require hospitalization (3). In addition to the primary injury, secondary brain injury may evolve over the ensuing hours and days. Those with severe TBI frequently develop hyperglycemia (75%) (4), which has been used as a marker for increased risk of death. However, whether severe hyperglycemia is a manifestation of stress responses related to severe injury or if it independently contributes to secondary brain injury remains unanswered. Hyperglycemia is often considered an adaptive response that maintains intravascular volume and increases energy delivery to vital organs. Although the adaptive response of supraphysiologic cardiac output is associated with improved survival during some pathologic states such as shock (5, 6), numerous observational studies have shown worse morbidity and mortality for both children (7–12) and adults (13) with hyperglycemia after head injury. However, the clinical enthusiasm for glucose control in critical injury and illness has decreased. Although an initial trial in critically ill pediatric patients (primarily cardiac surgical) www.pccmjournal.org
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(14) suggested clinical benefit, subsequent trials in children after heart surgery (15) and general critical illness have not (16). Furthermore, recent studies of adult TBI patients treated with insulin targeting tight glucose control reported reduced cerebral extracellular glucose availability and increased prevalence of brain energy crises among those treated with “tight” glucose control (17–20). Holbein et al (20) reported that patients treated with insulin targeting slightly elevated blood glucose (BG) (108–144 mg/dL [6–8 mmol/L]) had increased cerebral glucose uptake, decreased cerebral lactate production, reduced oxygen consumption, negative lactate glucose index, and decreased cerebral carbon dioxide/bicarbonate production compared with the tight control group. We evaluated whether severe hyperglycemia early after TBI was independently associated with poor outcome in pediatric TBI compared with those with mild hyperglycemia adjusted for severity of injury. We also examined our patient data comparing differing definitions of hyperglycemia and the prevalence of poor outcome.
METHODS Study Design This is a retrospective cohort study of infants and children younger than 18 years admitted to the PICU at Primary Children’s Hospital (PCH) from January 2002 to September 2006 with moderate or severe TBI. Some of the data for this study were collected for other studies evaluating both complications and factors associated with outcome after TBI (21–23). PCH is a free-standing, American College of Surgeons– certified level 1 pediatric trauma center in Salt Lake City, UT, serving five western states, and admitting approximately 630 trauma patients annually, with approximately 200 requiring admission to the PICU. The University of Utah Institutional Review Board approved this study and waived the need for informed consent. Data were obtained from the hospital’s traumatic injury database and hospital medical records. Moderate and severe TBI were defined as postresuscitation Glasgow Coma Scale (GCS) assigned by the pediatric trauma surgeon in the emergency department (ED), categorized as 9–12 and 3–8. Patient injuries were enumerated and an Injury Severity Score (ISS) Table 1.
calculated at discharge. CT scans obtained within the prehospital/ED time had previously been reviewed and graded using the Rotterdam scoring system (24) by a pediatric neurosurgeon (J.R.C.) blinded to the clinical outcomes when he reviewed the studies. Prehospital vital signs and episodes of hypotension, hypoxia, or apnea and cardiac arrest were previously collected from emergency medical services records (21). Exposure Definitions All BG values measured at PCH were obtained and elapsed time after injury calculated. BG measurements were obtained based on clinical decision making, and although testing was not standardized, measurements were frequent, as shown in Table 1. During the study time period, no guideline or protocol was in place for treatment of hyperglycemia. To standardize evaluation of BG levels and duration of elevation for our first objective, BG values were averaged over 4-hour blocks following injury for each patient. For our primary analysis (objective 2), we calculated the mean BG for each patient during the 0- to 12-hour period postinjury to compare with Glasgow Outcome Scale (GOS) at discharge. Patients were then categorized into either severe, moderate, and mild elevations; normal glucose; or hypoglycemia for analysis. Severe hyperglycemia was defined as the averaged value more than 200 mg/dL (11 mmol/L), whereas moderate hyperglycemia was between 161 and 200 mg/dL (9–11 mmol/L), mild hyperglycemia between 110 and 160 mg/dL (6–9 mmol/L), normal hyperglycemia between 80 and 109 mg/dL (4–6 mmol/L), and hypoglycemia as less than 80 mg/dL ( 200 mg/dL or 11 mmol/L) after injury as a single predictor of poor GOS. The sensitivity of severe BG elevation for poor outcome was 55%, specificity 91%, positive predictive value 68%, and negative predictive value 87%. Definition of Hyperglycemia: Magnitude, Duration, and Associated Prevalence of Poor GOS We evaluated BG values measured in the first 6 hours after injury in order to assess different criteria for hyperglycemia defined in a shorter clinical window with outcomes in our study population. Table 4 compares the proportion of patients with hyperglycemia and the prevalence of bad outcome. Our trauma center serves a large geographic area, and 32 patients did not have two BG and 31 did not have a single measurement at the trauma hospital during this time window. The table highlights issues with defining hyperglycemia in patients with TBI. Nearly all patients have BG measurements more than 110 mg/dL (6 mmol/L). The prevalence of hyperglycemia varied from 28% to 60% of patients, depending on the classification used during the first 6 hours after injury. Requiring two measurements more than 200 mg/dL (11 mmol/L) performed well compared with other classifications. The positive predictive values of the hyperglycemia definitions during the 6-hour assessment window ranged from 32% to 50% and negative predictive value from 87% to 90%. Clinical criteria that define hyperglycemia by greater BG concentration for longer times after injury (12 hr vs 6 hr) were more specific with greater positive predictive values but were less sensitive.
DISCUSSION We found that severe BG elevation in the first 12 hours after injury occurred in a quarter of children with severe TBI (23%) treated in a PICU while the proportion with normal BG levels was less common (6%). Severe BG elevation was independently associated with both poor outcome at hospital discharge and death compared with outcomes of children with mild BG elevation after injury. However, the duration of BG elevation more than 200 mg/dL (11 mmol/L) after injury was less than 24 hours after injury. One third of children in the severe BG elevation group died within a day of injury. On the other hand, 87% of children with mild to moderate average BG elevation in the first 12 hours after injury had a good outcome. Although our findings suggest that BG levels may help in assessing prognosis for pediatric patients with severe TBI, they do not Pediatric Critical Care Medicine
provide evidence that BG treatment is beneficial. Furthermore, the duration of severe hyperglycemia is brief. Our threshold for defining severe hyperglycemia, more than 200 mg/dL (11 mmol/L), was chosen to emulate other studies regarding hyperglycemia as an independent marker for poor outcome in TBI (25, 26, 28). We reasoned if hyperglycemia causes secondary brain damage after TBI that both the degree of hyperglycemia and the duration would be associated with worse injury. We found that sustained hyperglycemia for 12 hours was associated with a higher proportion of children suffering death or poor outcome at hospital discharge. Furthermore, that averaged BG elevation more than 200 mg/dL (11 mmol/L) for 12 hours had greater precision for prediction of poor outcome than either two BG measurements more than 200 mg/dL (11 mmol/L) or a single BG more than 200 mg/d during the initial 6 hours after injury. However, because of the retrospective nature of this analysis, BG was not continuously assessed, the frequency of BG measurements was not standardized, and long patient transport times may have introduced bias in ascertainment of hyperglycemia exposure. Our study definition cannot be directly compared with the integration of time and duration of hyperglycemia (i.e., area under the curve) which has become a standard measurement in prospective clinical trials (15). We used the mild BG group as our reference group, due to the small sample size of the normal BG group and concern that the normal BG group tended to have a larger fraction of high-risk patients (infants/toddlers with NAT). This choice of a comparison group is supported by both the prevalence of mild hyperglycemia in children after severe TBI and the reports in adults with TBI that mild hyperglycemia is associated with better cerebral metabolism (17–20). Neither mortality nor outcome differed when between those with moderate BG elevation to mild BG elevation. The prevalence of hyperglycemia in our study depended on the definition applied. Our data are consistent with past reports of hyperglycemia among head-injured children. Other studies defined hyperglycemia as a BG measurement more than 200 mg/dL (11 mmol/L), but it differed on duration of BG measurements or patients studied. Melo et al (26) used only the initial BG measurement and reported 34% of patients with severe TBI had hyperglycemia, whereas Sharma et al (28) evaluated children with TBI and emergency surgery and reported that 45% had hyperglycemia, and Smith et al (25) included all BG values for 2 days after injury and reported that 61% of severe TBI patients had hyperglycemia. An important observation in our study is the relatively short period of hyperglycemia. In most cases, average glucose over 200 mg/dL (11 mmol/L) persisted only 12–16 hours, and average glucose over 150 mg/dL (8 mmol/L) persisted less than 24 hours. The fall in glucose concentration followed a sigmoid shape with a relatively rapid initial fall. Thus, the window for potential therapy to lessen pathologic effects of severe hyperglycemia is brief. Other studies also examined the period of hyperglycemia but reported less detail. Melo et al (26) reported that 75% normalized in 2 days but did not describe changes. Smith et al (25) compared early versus late hyperglycemia, www.pccmjournal.org
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Table 2. Demographic, Clinical Features, and Outcomes of Head-Injured Children by Glucose Groupsa Normal Glycemia BG, 80–109 mg/dL (n = 19)
Variable
Age
4.6 (1.2, 10.9)
< 2 yr
Mild Hyperglycemia BG, 110–160 mg/dL (n = 132)
Moderate Hyperglycemia BG, 161–200 mg/dL (n = 66)
6.8 (3.1, 12.0)
8.5 (3.5, 12.0)
Severe Hyperglycemia BG, > 200 mg/dL (n = 53)
6.1 (1.9, 10.5)
6 (32)
19 (14)
8 (12)
13 (25)
11 (58)
80 (61)
43 (65)
35 (66)
Nonaccidental trauma
4 (21)
11 (8)
4 (6)
10 (19)
Motorized
6 (32)
48 (36)
35 (53)
29 (55)
Nonmotorized
9 (47)
73 (55)
27 (41)
14 (26)
Prehospital hypoxia/apnea
7 (37)
39 (30)b
27 (41)c
35 (66)
Prehospital hypotension
9 (47)
34 (26)
20 (30)
28 (53)
Cardiac arrest
1 (5)
3 (2)
0
1 (2)
Moderate traumatic brain injury
5 (26)
Male Mechanism of injury
b
Severity of injury
25 (17, 27)
Isolated head injury
11 (60)
c
31 (24)
d
Injury Severity Score (median IQR) pH in emergency department (median IQR)
b
15 (23)
b
25 (16, 29)
b
7.36 (7.33, 7.47)
25 (16, 34)
29 (25, 35)
40 (61)
32 (60)
c
66 (50) d
2 (4)
c
7.35 (7.30, 7.39)
b
7.29 (7.24, 7.35)
7.24 (7.15, 7.38)
Rotterdam scorec 1
1 (6)
5 (4)
4 (6)
1 (2)
2
9 (47)
70 (53)
29 (44)
11 (21)
3
7 (37)
41 (31)
19 (29)
10 (19)
4
1 (5)
12 (9)
13 (20)
15 (28)
5
1 (5)
4 (3)
1 (2)
15 (28)
6
0
0
0
1 (2)
b
c
Intracranial pressure monitors Fiber optic
6 (32)
21 (16)
7 (11)
9 (17)
External ventricular drain
2 (11)
4 (3)
8 (12)
10 (19)
Both
1 (5)
24 (18)
12 (18)
12 (23)
10 (53)
83 (63)
39 (59)
22 (42)
0
8 (6)
1 (2)
1 (2)
Any neurosurgery
5 (26)
30 (23)
23 (35)
11 (21)
Insulin
1 (6)b
10 (8)c
10 (15)
16 (31)
0c
17 (32)
Not monitored Surgery in first 12 hr
Death in 24 hr
0d
b
2 (2)b
Outcomes PICU length of stay (days: median IQR)
5 (1, 8)
2 (1, 6)
3 (1, 8)
1 (1, 7)
(Continued)
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Table 2. (Continued). Demographic, Clinical Features, and Outcomes of Head-Injured Children by Glucose Groupsa Normal Glycemia BG, 80–109 mg/dL (n = 19)
Mild Hyperglycemia BG, 110–160 mg/dL (n = 132)
14 (74)
103 (78)
49 (74)
13 (25)
Rehabilitation or nursing home
4 (21)
19 (14)
15 (23)
10 (19)
Death
1 (5)
10 (8)
2 (3)c
30 (57)
Poor Glasgow Outcome Scorec
5 (26)d
17 (13)b
8 (12)c
36 (68)
Variable
Moderate Hyperglycemia BG, 161–200 mg/dL (n = 66)
Severe Hyperglycemia BG, > 200 mg/dL (n = 53)
Disposition Home
BG = blood glucose, IQR = interquartile range. a One toddler < 80 mg/dL excluded from group analysis expired from nonaccidental trauma. b BG 110–160 mg/dL (6–9 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017. c BG 161–200 mg/dL (9–11 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017. d BG 80–109 mg/dL (4–6 mmol/L) differs from BG > 200 mg/dL (11 mmol/L), p < 0.017.
using a cutoff of 48 hours. Sharma et al (28) showed that peak glucose more than 200 mg/dL (11 mmol/L) was persistent in only 17% of patients from preoperative through postoperative measurements, while 28% had transient hyperglycemia.
Multivariable Analysis for Factors Independently Associated With Poor Glasgow Outcome Table 3.
Factor
Adjusted Odds Ratio
95% CI
12 hr after injury mean glucose groupa Normal
1.3
0.3–5.6
Mild
1
Moderate
0.6
0.2–1.8
Severe
3.5
1.2–10.3
Reference group
Traumatic brain injury severity Moderate
1
Reference group
Severe
0.5
0.1–2.4
Rotterdam score
2.8
1.8–4.4
Hypotension prehospital
3.6
1.5–8.5
Hypoxia prehospital
3.2
1.3–7.9
Injury Severity Score
1.1
1.0–1.1
Nonaccidental trauma
8.7
2.5–30.3
Motorized mechanism
0.9
0.3–2.5
Nonmotorized
1
Mechanism of injury
Reference group
Excludes one child with hypoglycemia. Poor Glasgow outcome as 1 (dead), 2 (vegetative), or 3 (severely disabled) versus “favorable” outcome as 4 (moderate disability) or 5 (good recovery). Normal, 80–109 mg/dL (4–6 mmol/L); mild hyperglycemia, 110–160 mg/ dL (6–9 mmol/L); moderate hyperglycemia, 161–200 mg/dL (9–11 mmol/L); severe hyperglycemia, > 200 mg/dL (11 mmol/L).
a
Pediatric Critical Care Medicine
In this study, we found an unadjusted mortality of 57% among those with persistent severe BG elevation using the 12-hour window after TBI. This is slightly lower than reported by Melo et al (26) (70%) in a cohort restricted to only severe TBI. Sharma et al (28) reported an unadjusted mortality of 26%. However, this study was limited to surgical patients, and not all patients had severe TBI (mean GCS, 8.8). Michaud et al (29) reported that 30% of pediatric patients with severe TBI had a poor outcome defined as either death or vegetative survival. Like previous studies, we found a persistent association between severe BG elevation with poor outcome and death after adjustment for severity of illness. The magnitude of the association with death was 4.5-fold, which is less than the adjusted odds of death (6.1) reported by Melo et al (26). In addition to physiological markers of injury severity and cardiorespiratory instability (ISS, hypotension, hypoxia, and mechanism of injury), we also adjusted for radiographic severity of injury on the initial cranial CT using Rotterdam scores. Despite consistent confirmation of an association between hyperglycemia and death or poor outcome (7–12, 25, 26, 28, 29), a causal relationship cannot be concluded from these retrospective analyses. We explored multiple definitions for hyperglycemia exposure and reasoned that a time frame of 6 hours after injury was more reasonable to qualify potential subject exposure to allow for injury evaluation and intervention initiation. In similar randomized controlled trials of therapeutic hypothermia for pediatric TBI, 6-hour (30, 31) or 8-hour windows (32) were used. Similarly, a 6-hour window was also used for hypothermia in asphyxiated neonates with hypoxic ischemic encephalopathy (33). Even shorter time frames, with treatment initiation within 2 hours, were used to study hypothermia after cardiac arrest in children (34) and adults (35). We found that when using either lower concentrations of BG or a single qualifying measurement, more patients would qualify to be eligible for potential treatment. The very high rate of good outcome predicted by 12-hour average definition suggests that these may have low potential for treatment benefit, but they do have potential for harm as www.pccmjournal.org
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Table 4. Classifications of Hyperglycemia 6 Hours After Injury: Prevalence, Association With Poor Outcome,a and Test Characteristics
Hyperglycemic
Poor Outcome
Positive Predictive Value (%)
Negative Predictive Value (%)
Positive Likelihood Ratio
Sensitivity (%)
Two blood glucose > 200 mg/dL (11 mmol/L)
68/239b (28)
34/55 (62)
50
88
2.3
62
82
Any > 200 mg/dL (11 mmol/L)
96/240 (40)
42/56 (75)
44
90
2.0
85
77
Any > 160 mg/dL (9 mmol/L)
146/240 (60)
47/56 (84)
32
90
1.6
84
46
All > 140 mg/dL (8 mmol/L)
119/240 (50)
41/56 (73)
34
87
1.7
73
57
Hyperglycemia Definition
Specificity (%)
Poor outcome: 1 (dead), 2 (vegetative), or 3 (severely disabled) at discharge from hospital. b One patient with blood glucose (BG) > 200 mg/dL only had one BG measurement and was excluded. a
severe hypoglycemia is greater among pediatric patients treated with insulin for tight control (14, 16). We found that over 90% of children with average BG concentration between 110 and 200 mg/dL (6–11 mmol/L) by 12 hours after injury survived and 87% had a good outcome at discharge. Other important findings were that few children admitted to ICU after TBI had normal BG concentrations during the first 12 hours compared with children with mild to moderate BG elevations; however, they tended to have worse unadjusted poor GOS compared with the those with mild or moderate BG elevation. Finally, infants and toddlers with NAT had over eight-fold increased adjusted odds of poor outcome, and these factors would need to be evaluated separately in future studies that seek to evaluate benefit from hyperglycemia treatment. Study limitations should be emphasized. This was a retrospective analysis of glucose measurements collected for routine care. Although measurements were frequent, there was no regularity to measurements and patients with marked elevation had more measurements. Our analysis using patient averages in time blocks prevented individual patients to unduly influence the results due to more measurements, but averaging patient averages to determine group values decreased measurement variability and is not comparable to the time weighted averages reported by Agus et al (15). Administration of neither dextrose nor insulin was standardized, and although hypoglycemia (BG < 80 mg/dL) was uncommon in the first days after injury, recent studies of brain metabolism in adults with TBI have raised concern that glucose concentrations in the lower “normal” range may be harmful. Thus, treatment with insulin which was most common in the severe BG elevation group might have been harmful. Although normal saline administration is routinely used for fluid administration, some providers add dextrose when caring for infants and young toddlers; likewise treatment of hyperglycemia with insulin was infrequent and not standardized in our study. Furthermore, because treatment of hyperglycemia in children is less common than in adults, accepted thresholds for treatment initiation and cessation remain unclear currently (35, 36). The changes in glucose concentration for a given patient may have been affected by stress associated with TBI and other factors including administration of glucose and catecholamines to raise cerebral perfusion 630
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pressure. The definitions for BG groups were retrospectively defined. The assessment of outcome was at hospital discharge, and we used a grouped outcome which prevented assessment of either recovery or finer cognitive evaluation. Treatment with insulin was more common in the severe hyperglycemia. Finally, this is a single-center report with both obvious factors such as serving a large catchment area, which affects admission time in relation to time from injury, and less obvious care features, such as routine use of norepinephrine rather than phenylephrine to raise cerebral perfusion pressure (37). In conclusion, we found that severe BG elevation during the initial 12 hours was independently associated with both poor outcome and mortality in children after TBI. If patients dying during the first day after injury were excluded, an independent association with poor outcome was no longer statistically significant. Averaged BG elevations less than 200 mg/dL during the initial 12 hours after injury had no demonstrable association with mortality, but the majority of children with severe TBI did not have normal BG values during this time frame. Nevertheless the duration of severe hyperglycemia is relatively short (< 24 hr), and over 90% of children whose averaged BG measurements during the initial 12 hours after injury were less than 200 mg/dL survived.
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