In this large, multi-center database, we found that hypertonic saline and mannitol for pediatric TBI are used more often in older children, those with skull fractures and non-epidural intracranial hemorrhages, and those with more severe head injuries; however, substantial variation between hospitals was present. In addition, the 2003 guidelines for the care of children with severe TBI appear to have impacted practice, with increased hypertonic saline use and decreased mannitol use after their publication.
To our knowledge, associations of osmolar therapy use with head injury severity and age have not been previously reported. It seems logical that osmolar agents are used more often in patients with more severe head injuries, as these patients are more likely to have intracranial hypertension. Osmolar therapy was also much more common in children with ICP monitors, likely the more severely injured patients. Interestingly, approximately one-quarter of the sustained (≥ 2–3 days in the first week) osmolar therapy we found was in children without ICP monitoring. In infants, approximately half of the sustained osmolar therapy was without ICP monitoring. Morris et al also found that first-tier ICP-targeted therapy (CSF drainage, osmolar therapy, or mild hyperventilation) was common (35%) in children with severe TBI and no ICP monitor.[24
The association of osmolar therapy use with age after adjustment for the effect of the published guidelines, between-hospital variation, and injury severity suggests that providers are treating infants as if they are at lower risk for intracranial hypertension, despite a clear statement in the 2003 guidelines that “[t]he presence of open fontanels and/or sutures in an infant with severe TBI does not preclude the development of intracranial hypertension...”[25
] This effect persisted when the analysis was restricted to patients with ICP monitors.
It is impossible to determine which factors caused the changes in hypertonic saline and mannitol use at approximately the time of guideline publication, but interrupted time series analysis is among the most rigorous available quasi-experimental methods to study interventions at a particular time in the past.[23
] Although chosen a priori
, cluster adjustment for variation across hospitals was necessary given the substantial hospital-level variation we found. Our interrupted time series models, as is typical, did not include patient-level covariates because of the low likelihood that, for example, injury type, changed in July, 2003 at the time of guideline publication.[23
The peak of osmolar therapy use on the second day of admission fit with our understanding of the mechanisms and timing of cerebral edema and intracranial hypertension in children with TBI. However, we were surprised at the relatively constant rate of hypertonic saline use across the first week of hospital care. Prolonged tapers of hypertonic saline to avoid hyponatremia or malignant intracranial hypertension may explain this finding. It is possible that the mannitol use for only one day in patients with EDH reflects rapid medical stabilization prior to operative intervention or adoption in the pediatric community of adult recommendations for high-dose emergency department mannitol use based on now-retracted papers by Cruz et al.[30
Hypertonic saline may be given to treat hyponatremia from cerebral salt wasting (CSW). We analyzed the diagnosis of hyponatremia (there is no ICD-9-CM diagnosis code for CSW) over the same time period, because increased awareness of CSW might increase the use of hypertonic saline. Hyponatremia was diagnosed at a relatively constant rate, and had a slightly decreasing trend after TBI guideline publication, making it unlikely that the increase in hypertonic saline use was due to treatment of hyponatremia. This may also mean that increasing hypertonic saline use has not resulted in an increase in rebound hyponatremia.
Post-resuscitation Glasgow Coma Scale (GCS) score, pupillary exam, and CT results, the most predictive measures of TBI severity, are not present in the PHIS database. We restricted our analysis using head/neck AIS scores and mechanical ventilation and ICU billing codes as proxies for severity, but they may not completely represent GCS-based severity of TBI. ICDMAP-90, the software package we used to calculate AIS and ISS scores from ICD-9-CM diagnosis codes, has been validated overall[33
] and in children[34
] for its ability to determine injury severity, and has been successfully used in several studies of children with TBI, including one using the PHIS database.[35
] Coates et al and Di Gennaro et al also defined their study populations using head AIS scores (≥3) in analyses of children with TBI.[38
Despite the absence of GCS scores, pupillary exam, and CT results in our dataset, our patients were similar to those in other studies. The in-hospital mortality of our study population (18.8%) compared well with published single-center estimates (22–24%) and with a multicenter trial without an apparent treatment effect (16.4%, with 8.9% of patients lost to follow-up).[40
] Some older studies reported higher mortality[44
], and a recently published study reported lower mortality.[45
] The rates of skull fracture (55% versus 52%) and intracranial hematoma (71% versus 69%) in our sample compared well with those reported by Hutchison et al.[43
] The median ISS in our sample was lower (16 versus 25) than in the work of Coates et al and Zebrack et al.[38
] Hutchison et al reported higher rates of hypertonic saline and mannitol use (50–60% for both osmolar agents), but the “usual care” arm of clinical trials may be different than usual care in other settings.[43
There are several other potential limitations to this study, primarily related to our use of an existing database. The PHIS database has advantages over a strictly administrative database, but pharmacy and clinical billing data are only available by day of service, and not, for example, by hour. In addition, the available ICD-9-CM diagnosis codes for TBI do not allow ideal categorization of injury type, and those diagnosis codes were used to derive both injury scores (AIS, ISS) and specific injury types (SDH, EDH, etc).
In conclusion, hypertonic saline and mannitol use in pediatric TBI is higher in older children, those with skull fractures and intracranial hemorrhage, and those with more severe head injuries, with substantial variation between hospitals. The patient-level and hospital-level variation and the significant amount of sustained osmolar therapy without an ICP monitor, particularly in infants, suggest opportunities to improve the quality of pediatric TBI care. The apparent effect of published guidelines on clinical practice in this area suggests that, with limited available high-quality evidence on how to use hypertonic saline and mannitol in children with TBI, providers attempt to follow expert guidelines.