Pediatric Critical Care Medicine:
Pediatric Neurointensive Care: 2008 Update for the Rogers’ Textbook of Pediatric Intensive Care
Kochanek, Patrick M. MD, FCCM, FAAP; Tasker, Robert C. MB, MD, FRCP
From the Department of Critical Care Medicine (PMK), Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA; and Department of Paediatrics (RCT), University of Cambridge Clinical School, Addenbrooke’s Hospital, Cambridge, United Kingdom.
Supported, in part, by grants from NINDS (NS38087, 3730318), the CDC (University of Pittsburgh Center for Injury Research and Control/CIRCL), DARPA, and the United States Army PR-054755 W81× WH-06-1-0247 (to PMK) and from The Evelyn Trust, Cambridge, U.K., and Sparks, U.K. (to RCT).
The authors have not disclosed any potential conflicts of interest.
For information regarding this article, E-mail: firstname.lastname@example.org
Objective: To review important articles, in the field of pediatric neurointensive care, that were published subsequent to the fourth edition of the Rogers’ Textbook of Pediatric Intensive Care.
Data Sources: The U.S. National Library of Medicine (http://www.ncbi.nlm.nih.gov/sites/entrezPubMed) was searched for the term pediatric and the following individual terms, cardiac arrest, asphyxia, traumatic brain injury, status epilepticus, stroke, cerebral ischemia, and cerebral hemorrhage, to generate abstracts of additional citations that were then screened for potential inclusion. The authors were also aware of a number of key recent articles in both pediatric and adult neurointensive care and these were also screened.
Study Selection and Data Extraction: Promising articles were reviewed and the decision as to whether they were included was made at the discretion of the section editors.
Data Synthesis: Articles in four categories were included based on selected chapters in the neurointensive care section of the textbook, using the specific chapter heading in the textbook, namely, head and spinal cord trauma, hypoxic-ischemic encephalopathy, status epilepticus, and cerebrovascular disease and stroke.
Conclusion: Developments in the field and practice of pediatric neurocritical care continue with significant additions to the literature and practice recommendations concerning care following traumatic brain injury, cardiac arrest, status epilepticus, and cerebrovascular events. Importantly, the continued progression in knowledge raises the health services issue of whether, in certain settings of high clinical volume, it is time for specialized pediatric neurointensive care services or units.
This article begins a series of brief, targeted updates to the fourth edition of the Rogers’ Textbook of Pediatric Intensive Care (1). These updates will be written by one or more of the section editors or guest editors and published on a rotating basis, each addressing a specific section of the book. Each update will highlight studies in infants and children; reports on studies in adults may be included if felt to be of special importance. Given the space limitations for such a project in a medical journal that highlights conventional peer-reviewed scientific reports, these targeted updates are not meant to be comprehensive, but will be practical and indicate whether the results may affect changes in practice. These updates will be peer reviewed. Specific book chapter headings are used to help guide the reader back to the relevant original text. In this first installment, we will focus on the topic of pediatric neurointensive care and address the most relevant articles published in 2008. We were aware of a number of pertinent articles in pediatric neurointensive care that were published subsequent to the fourth edition of the Rogers’ textbook, and these were included. In addition, the U.S. National Library of Medicine (http://www.ncbi.nlm.nih.gov/sites/entrezPubMed) was searched for the term pediatric and the following individual terms, cardiac arrest, asphyxia, traumatic brain injury, status epilepticus, stroke, cerebral ischemia, and cerebral hemorrhage, to generate abstracts of additional citations that were then screened for potential inclusion. Promising articles were reviewed and the decision as to whether they were included was made at the discretion of the section editors.
In 2008, the lion’s share of the most valuable publications in pediatric neurointensive care addressed the chapter on Head and spinal cord injury. Thus, this update is weighted toward that topic. However, a number of interesting reports were also published on Hypoxic-ischemic encephalopathy, Status epilepticus, and Cerebrovascular disease and stroke, including two guidelines document on the management of stroke in infants and children (2, 3).
HEAD AND SPINAL CORD TRAUMA
The most important pediatric study since publication of the Roger’s textbook is the report by Hutchison et al (4) on the randomized controlled trial (RCT) of therapeutic hypothermia after severe traumatic brain injury (TBI) in children from the Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group in the New England Journal of Medicine. A total of 225 children were randomized to hypothermia (surface cooling) vs. normothermia for 24 hours. The protocol produced mean esophageal temperatures of 33.1°C ± 1.2°C vs. 36.9°C ± 0.5°C, respectively. Mean time to initiation of cooling was 6.3 hours after the injury, mean time to target temperature was 3.9 hours after onset of cooling, and mean duration of rewarming was 18.8 hours. There was no benefit of hypothermia on either 6-month Pediatric Cerebral Performance Category score or mortality; trends toward worse outcome and higher mortality were seen with hypothermia. More hypotension was observed and more vasoactive agents were given in the group treated with hypothermia vs. normothermia, but fewer patients required hypertonic saline in the hypothermia group. The results were disappointing, in light of the positive trials of hypothermia in adults with cardiac arrest (5, 6) and newborns with hypoxic-ischemic encephalopathy (HIE) (7). Given that mild therapeutic hypothermia is also beneficial in experimental TBI, several explanations have been postulated to explain this discrepancy including 1) the prolonged time from injury to target temperature (∼10.2 hours), 2) the short duration of hypothermia (rewarming on day 2—as brain edema is peaking), 3) the occurrence of side effects of hypothermia, and 4) the fact that the control group was not promptly rewarmed as was the case in either the study by Marion et al (8) or in the aforementioned cardiac arrest trials. Alternatively, unlike cardiac arrest or HIE, given the many brain-oriented treatments that are already used for severe TBI, hypothermia may not be added sufficiently to our therapeutic armamentarium and its use may simply result in trading of therapies in TBI—as suggested by the reduced need for hypertonic saline in the hypothermia group. Similarly, phenytoin was administered to all patients in the Hutchison trial (4), and it may confer some neuroprotection by shared mechanisms with hypothermia. Finally, some have also argued that rather than responding to hypotension it should have been prevented. The Cool Kids trial currently underway in the United States may help address some of these questions based on its more rapid induction and longer duration of hypothermia. Nevertheless, based on this important work of Hutchison et al (4), routine use of hypothermia cannot be recommended after severe TBI in children. However, there is considerable evidence that mild therapeutic hypothermia reduces intracranial hypertension in children with severe TBI (9, 10) and this study did not address its use as a second tier therapy for refractory intracranial hypertension—as recommended at the option level in the TBI guidelines (11). That is particularly true since rewarming was initiated ∼30 hours after injury. Many questions about nuances related to the application of hypothermia remain unanswered such as optimal management of blood gases (12) and effects on drug metabolism and dosing (13). Given its beneficial effect in cardiac arrest and HIE, its potential use in children with TBI and cardiac arrest deserves further examination.
In another study on TBI published in 2008, Samant et al (14) provided a descriptive report on the impact of hypotension after severe TBI in children, presenting findings from a single experience in 146 cases. Detailed reports on the impact of secondary insults in pediatric TBI are scarce. A highly significant association for poor outcome from systolic blood pressure less than fifth percentile (relative risk 1.3-3.3) was observed, and the initial 6 hour after injury was defined as the critical period. This study suggests the need for meticulous blood pressure control early after severe TBI in children, embellishing on the work of Chambers et al (15) who previously identified age-related values for cerebral perfusion pressure in children in the initial 6 hours after injury in a multicentered study from the United Kingdom. Although neither of these reports directly answers the question as to whether improving low-blood pressure or cerebral perfusion pressure values will improve outcome, taken together, they reinforce recommendations that it is important to prevent or treat promptly hypotension early after injury. These studies also raise questions as to whether the blood pressure threshold of less than fifth percentile is inadequate as a therapeutic target. This was an issue that was challenging to address in the initial guidelines and undoubtedly will be readdressed when the guidelines are updated. Finally, it is tempting to extrapolate that these two studies also suggest that early interventions may be critical to improving outcomes, given the powerful associations seen with data from the initial 6 hours after injury, a lesson that may be very relevant to future clinical trials.
Curry et al (16) provided interesting insight into the possible contribution of another secondary insult to poor outcome after severe TBI in children, namely severe hypocarbia—defined as a Paco2 <30 mm Hg. In this single-center experience in 375 patients, an occurrence rate of 52%-60% was seen in the initial 48 hours after injury (often despite intracranial pressure [ICP] <20 mm Hg). Severe hypocarbia was most common in the initial 2 hours after TBI and associated with mortality. The remarkable frequency of severe hypocarbia again mirrors the findings published by Morris et al (17) in the United Kingdom, where moderate to severe hyperventilation was still found to be used with surprising frequency. Hutchison et al (4), in the Canadian Hypothermia Trial, reported that 44% of patients in the hypothermia group were treated with hyperventilation that resulted in Paco2 <30 mm Hg, a fact that also drew criticism (18). It seems that despite guidelines recommendations and mounting evidence in the neurointensive care literature that hyperventilation is potentially detrimental (19–21), this therapy seems to remain entrenched in pediatric neurointensive care. Is it time to set the “alarm” threshold for Paco2 in TBI or for a practice bundle in TBI including this facet of care?
An interesting descriptive, report of 96 pediatric patients managed at the University of Virginia with severe TBI, raised ICP (>20 mm Hg), and 2-year follow-up was published by Jagannathan et al (22). Three management strategies were described including medical management, ventriculostomy, or surgery. In the setting of mass lesion, surgery was used to control ICP. In the absence of a mass lesion, when medical management failed, surgical decompression or ventriculostomy followed, depending on factors such as patient stability. In this center, which favors the use of early decompressive craniectomy, control of ICP was important to patient survival and was achieved in 85% of patients, but the modality used for ICP control did not yield an outcome difference. The mean time to peak ICP in this series was 69 hours after TBI and in some cases peak ICP was not seen until as late as 196 hours. Given selection bias for the various interventions in this study, it is difficult to infer with any confidence the benefits of medical management vs. craniectomy in pediatric TBI. However, this study aptly quantifies the sustained nature of raised ICP after TBI in children and provides data that may be useful to the design of an RCT on decompressive craniectomy in pediatric TBI.
Finally, additional insight into the importance of ICP in pediatric TBI and clinical trial design targeting raised ICP can be gleaned from the report of Forsyth et al (23) who interrogated the U.K. multicentered database of 501 children admitted to the intensive care unit for the management of TBI. Multivariate logistic regression confirmed independent association with death before discharge for both raised ICP (>20 mm Hg on more than one hourly recording) and, interestingly, the lack of ICP monitoring. Raised ICP was documented in 49% (98 of 199) of the cases in which it was measured. The authors thus suggest “errors” of both omission and commission for ICP monitoring. A simple decision tree predicted raised ICP with reasonable sensitivity and specificity (Fig. 1) and based on the data in this study, a clinical trial to determine the effect of an ICP management strategy on mortality would require enrollment of 320 children to detect a reduction in mortality rate from 24% (baseline) to 15% with 80% power. This study could be valuable to future trial design, particularly if a therapy such as surgical decompression is tested. On the adult side, in addition to surgical decompression, two promising therapies that are either in or on track for RCTs are progesterone (24) and cyclosporine A (25).
In addition to therapeutic hypothermia, another area of emerging interest is the use of extracorporeal membrane oxygenation as a rescue therapy in failed cardiopulmonary resuscitation (CPR)-known as ECPR. Huang et al (26) described the use of ECPR after in-hospital cardiac arrest in 26 patients, across a variety of diagnoses, in a single center in Taiwan. A 40.7% survival rate was reported despite generally prolonged durations of CPR and neurologic outcome was good in 10 of the 11 survivors. A shorter activating time for extracorporeal membrane oxygenation (5 vs. 12.5 minutes) was associated with survival, and a dramatic learning curve was observed for ECPR. From the practical standpoint, this result emphasizes the need for a very rapid decision to activate extracorporeal membrane oxygenation (<5 minutes) after onset of CPR. Learning curves are well described for extracorporeal membrane oxygenation, but they may be particularly important with its use in the complex setting of cardiac arrest. The authors argue that the learning involved patient selection with postoperative cardiac patients being the best candidates. Renal failure and a high lactate (14 mmol/L) were associated with mortality. This report adds to an expanding body of work on this approach, and although it does not prove its efficacy, ECPR has a number of desirable features including the ability to control blood flow and temperature in the periresuscitation period, and the ability to administer therapies that might not otherwise be hemodynamically tolerated.
Rafaat et al (27) reviewed cranial computed tomographic (CT) findings of the San Diego Children’s Hospital group in the largest series of children with drowning ever reported—a total of 961 drowning victims over an 18-year period in which 156 received CT scans. All of the 28 patients who required CPR and had an abnormal initial CT died. Twenty-three of 24 patients who required CPR and had a normal initial CT, but an abnormal follow-up CT (mean of 2.8 days later) either died or were in persistent vegetative state. One patient in that group had good outcome. The authors also pointed out that none of the patients in this large series of asphyxial cardiac arrest had either hemorrhage or unilateral findings and suggested important differences from CT findings in inflicted childhood neurotrauma. This study provides the intensivist with helpful prognostic and diagnostic information from a large series, a valuable enhancement to the information in the textbook, and may have implications for future trial design in the setting of asphyxial cardiac arrest.
Two other noteworthy studies were published in 2008 in the area of HIE in term infants who are relevant to pediatric neurointensive care. Laptook et al (28) carried out a secondary analysis of the control group (n = 99) in the National Institutes of Child Health and Human Development-funded Neonatal Network multicentered hypothermia trial for the treatment of HIE and assessed the impact of elevated temperature in the initial 72 hours on outcome (assessed at 18-22 months). The odds of death or disability were increased 3.6- or 4.0-fold for each 1°C greater than 37.5°C or 38.0°C, respectively. Studies in experimental animal models across central nervous system insults have shown marked detrimental effects of postinsult hyperthermia, and hyperthermia after cardiac arrest and resuscitation in children are commonly seen with standard treatment (29). This study provides important confirmatory evidence that even mild hyperthermia is associated with morbidity and mortality. Although it does not prove that preventing or reducing increased body temperature after the insult would improve outcome, it likely comes as close as possible to addressing this question, given that including a hyperthermic group in a clinical trial would be unethical. It seems prudent to prevent even small increases in body temperature after hypoxic-ischemic insults in infants and children. Rigorous prevention of hyperthermia represents another care item that should be considered for a pediatric TBI or neurointensive care practice bundle.
Burns et al (30) studied 35 term infants and assessed the patterns of cerebral injury and neurodevelopmental outcomes after symptomatic hypoglycemia (<2.6 mmol/L [47.3 mg/dL]) but without evidence of HIE. Remarkably, severe white matter abnormalities were seen on magnetic resonance imaging (assessed at <6 weeks) in 43% of these infants, and 51% and 40% had cortical and basal ganglia/thalamic lesions, respectively. Sixty-five percent of the infants showed impairments in outcome at 18 months. It is always difficult to tease out the relative contribution of hypoglycemia vs. other confounders in these types of studies; i.e., curiously, 43% of these infants required at least some resuscitation at birth and 6% required a major resuscitation. Nevertheless, this study builds on prior work refreshing our knowledge of the potential detrimental impact of hypoglycemia—knowledge that may be timely given the surge of interest in tight glucose control in pediatric critical care (31–33), and potential detrimental impact of that approach in neonates (34) and injured adult brain (35).
Although representing a study in adult neurocritical care, and published late in 2007, likely the most important study published on status epilepticus subsequent to the Rogers’ textbook is a report by Vespa et al (36) on the impact of nonconvulsive seizures using continuous electroencephalography monitoring and cerebral microdialysis for 7 days after severe TBI. Studying ten patients, and a matched cohort, posttraumatic subclinical seizures or status epilepticus were associated with episodic clinically relevant increases in ICP. In addition, brain interstitial levels of lactate/pyruvate ratio were greater in the seizure group and remained increased for >100 hours. Although a small study, the University of California, Los Angeles group is known for high quality and sophisticated multimodal monitoring and imaging of critically injured patients. Often, subclinical status epilepticus is neither diagnosed nor treated in the pediatric intensive care unit (PICU), and this report provides important evidence that it is likely a key target in neurointensive care for improving patient outcomes. Continuous electroencephalography monitoring in pediatric TBI has generally only been performed in some of the major TBI research centers (37). Studying its use in that application and in the broader context of pediatric neurointensive care represents an important research priority.
Three studies are noteworthy regarding status epilepticus in children in the continuum of care from prehospital to the PICU. First, Tobias and Berkenbosch (38) reviewed pre-PICU evaluation and treatment of 100 patients with status epilepticus and found that compliance with current guidelines was poor. Second, a practice evaluation from Japan (39) reviewed the national experience of lidocaine infusion for status epilepticus and found that it was being used in a significant numbers of patients; 279 children aged between 1 month and 15 years. However, it did not seem to show efficacy in patients with status epilepticus with an underlying infectious etiology. Finally, the Cochrane reviewers provided an update on “Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children” (40). The main conclusion of the update, which is a change from previous findings, was that intravenous lorazepam is at least as effective as intravenous diazepam and is associated with fewer adverse events in the treatment of acute tonic-clonic convulsions.
Three other small case series are worth briefly mentioning—all addressing the frustrating problem of refractory status epilepticus or intractable seizures in infants and children in the PICU. Success in some refractory intensive care unit-relevant cases was observed with continuous lidocaine infusion, vagal nerve stimulation, or urgent resective surgery by Shany et al (41), Zamponi et al (42), and Schrader et al (43), respectively. Refractory status epilepticus in the PICU is a condition that is unlikely to ever be addressed with an RCT, and it is wise to be familiar with the latest literature related to all potential therapeutic options.
CEREBROVASCULAR DISEASE AND STROKE
Consistent with the potential deleterious consequences of hyperthermia, Greer et al (44) undertook a meta-analysis of 1139 citations involving 14,431 subjects (the vast majority of whom where adults) who had either stroke or one of a number of other neurologic injuries and showed that fever was consistently associated with worse outcome. This was shown across a number of relevant outcomes such as mortality, Glasgow outcome scale, and ICU length of stay.
Finally, guidelines for the Management of Stroke in Infants and Children and Antithrombotic Therapy in Neonates and Children were published by the American Heart Association and the American College of Chest Physicians, in the journals Stroke and Chest, respectively (2, 3). Germane to pediatric critical care, these richly referenced documents provide evidence-based recommendations on ischemic, hemorrhagic, and perinatal stroke, along with cerebral sinovenous thrombosis in infants and children. A wonderful overview of these guidelines by DeVeber and Kirkham (45) was promptly published in Lancet Neurology and tersely compares both of these 2008 guidelines documents with the 2004 pediatric guidelines of the Royal College of Physicians. Table 1 in that article compares the acute management guidelines across these documents and identifies several differences, specifically with regard to use of aspirin vs. unfractionated or low-molecular weight heparin across etiologies. The overview article also acknowledges “the rather flimsy evidence base which is mainly … consensus” and that none of the evidence is based on RCTs. It also points out that in adults, one of the most effective interventions to improve outcome in stroke is reorganization of services into specialty stroke units, but recognizes that small numbers of cases in children make this difficult.
There have been a remarkable number of valuable reports in the field of pediatric neurointensive care that have included publication of a major RCT in TBI, several descriptive studies in TBI, HIE, and status epilepticus, along with important guidelines documents in pediatric stroke. In addition, multicentered reports of the national experiences on TBI in the United Kingdom and status epilepticus in Japan are beginning to provide additional experience in the current pediatric neurointensive care practice, and their findings are being confirmed and expanded. Finally, an important broader message from the success of “stroke units” in adult neurointensive care, as raised by DeVeber and Kirkham, is that the time may have arrived for specialized pediatric neurointensive care services or units, as suggested recently by Bell et al (46).
* Routine use of hypothermia cannot be recommended after severe TBI in children. However, there is evidence that mild hypothermia reduces ICP in children with severe TBI as recommended at the option level in the TBI guidelines. Care should be taken to prevent hypotension during rewarming if hypothermia is used.
* It is important to prevent or treat promptly hypotension early after injury. It is also unclear as to whether the TBI guideline-recommended blood pressure threshold of the <5th percentile is inadequate as a therapeutic target.
* Despite the recommendations of the TBI guidelines and mounting evidence in the literature that hyperventilation is potentially detrimental, it remains entrenched in pediatric neurointensive care. Is it time to set the “alarm” threshold for Paco2 in TBI and/or for a practice bundle in TBI including this facet of care?
* Decompressive craniectomy is a therapy that merits an RCT in pediatric TBI.
* Studies suggest that if ECPR is used in pediatric resuscitation, maximal benefit can be derived from a rapid decision to implement it after onset of CPR.
* It seems prudent to prevent even small increases in body temperature after hypoxic-ischemic insults in comatose infants and children. Prevention of hyperthermia is a care item that should be considered for a pediatric neurointensive care practice “bundle.”
* Often, subclinical status epilepticus is neither diagnosed nor treated in the PICU, and may be a target in neurointensive care for improving patient outcomes. Use of continuous EEG monitoring represents an important research priority.
* Intravenous lorazepam is at least as effective as intravenous diazepam and is associated with fewer adverse events in the treatment of acute tonic-clonic convulsions.
* One of the most effective interventions in adult neurointensive care to improve outcome in stroke is reorganization of services into specialty stroke units. The time may have arrived for specialized pediatric neurointensive care services or units.
We thank Marci Provins for her editorial assistance.
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traumatic brain injury; cardiac arrest; asphyxia; hypoxic ischemic encephalopathy; stroke; status epilepticus; children; infant; hypothermia
©2009The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
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