Michael E. Nemergut

Anesthetic neurotoxicity: what to tell the parents?

Over the past decade, numerous preclinical and retrospective human studies have reported that the provision of anesthetic and sedative agents to infants and children may be associated with adverse neurodevelopmental outcomes. These data have gained widespread attention from professional and regulatory agencies, including the public at large. As such, pediatric anesthesiologists are being increasingly questioned by parents about the risks of anesthetic agents on their childrens neurocognitive development. To impart a framework from which anesthesiologists may address the apprehensions of parents who actively bring up this issue, we review the data supporting anesthetic neurotoxicity and discuss its strengths and limitations. As many parents are not yet aware and do not actively raise these concerns, we also discuss whether such a conversation should be undertaken as a part of the consent process.

Anesthetic-related neurotoxicity in the young and outcome measures: the devil is in the details.

There are few issues facing the field that are more concerning and contentious than the possible neurotoxic effects of anesthetics on children. While laboratory studies report that virtually all commonly used anesthetics invariably induce neurodegeneration in the developing animal brain, observational studies are less conclusive with some reporting an association between exposure to anesthesia/surgery and adverse neurobehavioral outcome, while others do not (1). Among the many methodologic problems associated with human studies are the outcome measures available to the investigators (1,2). As virtually all of these studies are retrospective, the outcome is not chosen by the investigator and therefore may not provide the most meaningful measure of the cognitive or behavioural effect. Additionally, the various neurocognitive outcomes may or may not be comparable as few studies have reported more than a single endpoint. In this issue of Anesthesiology, Ing et al have attempted to provide a structured comparison of outcome measures representative of those found in most studies of this type (3). Similar to their previous publication (4) data from the Raine Study, a cohort of 2868 children born from 1989 to 1992 in Western Australia, was examined for an association between exposure to anesthesia/surgery in children prior to the age of 3 years and 3 different but closely related outcomes including direct neuropsychological testing, International Classification of Diseases, 9th Revision (ICD-9) coded clinical disorders and a group test of academic achievement. Of the 781 children included, 112 had been exposed to anesthesia/surgery and among those exposed, the risk of deficits in individual language assessments and ICD-9 codes for language or cognitive disorders were increased. In contrast, exposed and unexposed children did not differ with regard to academic achievement. The authors conclude that these data explain some of the variation in the literature and underscore the importance of the outcome measure when interpreting studies of cognitive function. Similar findings have previously been noted in other studies employing more than a single measure of neurodevelopment (5). A cursory review of the literature suggests that the majority of negative studies employ broad measures of academic performance such as group tests of achievement (California Achievement Test, Danish standardized test of achievement) and teacher/parent rating scales very similar to that used in this study (6–9). Studies employing individual tests of cognitive performance have been uniformly positive, commonly in areas of speech and language. The larger studies performed in Europe utilizing group tests (or similar) tend to be negative whereas smaller studies employing individual neurobehavioral tests more frequently are positive. Utilization of ICD-9 codes in epidemiologic research is common as administrative data are widely available and often represent the only source of information related to an outcome of interest. Unfortunately errors in coding are exceedingly common and represent a source of significant bias (10). Attention deficit hyperactivity disorder (ADHD) provides an instructive example alluded to by the authors. Ing and colleagues utilized ICD-9 codes as a means of identifying relevant behavioral or cognitive outcomes including ADHD the diagnosis of which is clearly delineated within the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV). However, in studies of ADHD diagnostic accuracy only a third of children diagnosed with ADHD have been subject to the DSM IV criteria and as many as two thirds of children with ADHD have a diagnosed learning disability that may or may not be identified with by a specific ICD-9 code (11). It is therefore difficult to be certain whether a child has the outcome of interest (ADHD) or has a similar outcome that may confound the relationship (learning disability). In the case of the Ing study the problem of mis-coding was magnified by assigning codes from parental reports of childhood illness, rather than medical records, an additional source of potential bias. Ing and colleagues somewhat inaccurately compares ADHD as an outcome in this study to that of Sprung and colleagues (12). The comparison provides an instructive example of how apparently identical outcome measures may differ in profound ways. In the Sprung study, ADHD was diagnosed by strict DSM IV criteria using a robust medical record and unique access to school records - information unavailable to Ing and colleagues. Additionally Sprung, but not Ing, was able to separate those children with ADHD alone from those with a learning disability and ADHD to examine the effects of these overlapping cognitive disorders separately. Consequently, the methodology in the Ing study almost certainly overestimates the frequency of ADHD, cannot determine whether the observed differences are truly driven by ADHD, or is the result of confounding between ADHD and learning disability. As such these data should be compared to that of the Sprung study with great caution, if at all. The lack of an obvious human phenotype for anesthetic neurotoxicity represents a major obstacle to study design and interpretation. The study by Ing and colleagues is intended in part to identify a robust endpoint for evaluating existing work as well as designing future studies that may be more informative. The unique feature of the data reported by Ing is the extensive neurodevelopmental testing that was performed repeatedly for each of the studied subjects. No other study to date contains as much cognitive outcome data as this and their previous publication using the same data. In addition to studies from the Mayo Clinic, those by Ing and colleagues are the only extant studies that contain data from individually administered tests of cognition. It is striking that these studies are both positive and report disproportionate effects on speech and language. Nonetheless, as mentioned above, caution should also be used when interpreting these data as many of the outcomes are interrelated and the use of multiple tests increases the risk of a Type 1 statistical error. Noteworthy is the observation that 25% of the exposed comprised children undergoing myringotomies – a population notoriously known to suffer from later language and learning problems (13). Ing et al suggest that group tests may lack sufficient sensitivity to detect small differences in performance that may exist between those exposed and those not exposed, but that these minor differences may not be clinically or academically meaningful. They also suggest that studies using large cohorts but insensitive outcomes are likely to be negative and should be interpreted with caution; studies using individually administered tests of cognition may be more likely to be positive and can provide insight into phenotype (i.e. abnormalities in speech and language). However, the value of ICD-9 or other administrative data in this setting as an endpoint is unclear and awaits the results of studies that examine the correlation between such codes and direct testing depending location and time. Moreover, studies using comprehensive cognitive testing are laborious and expensive; therefore the sample size in these studies will invariably be small. If this approach is used more widely in the future a possible consequence is the accumulation of limited powered studies that might overestimate the effects we are looking for (type I error) or fail to detect a difference (type II error) based on limited sample size. Indeed, similar concerns have been raised regarding studies on postoperative cognitive dysfunction (POCD) in the elderly (14, 15). POCD researchers still have no tools available that can reliably assess the presence of POCD and increasing the number of tests used to classify POCD increases the sensitivity to change not only in postoperative patients but also in the controls (14). Ing and colleagues should be congratulated for their contribution to the understanding of the growing concerns related to the effects of exposure to anesthetic agents in young children. However, not all outcome measures are created equally - the devil is truly in the details with regard to not only outcome but also many other aspects of study design and conduct not discussed here. However, the problems with the POCD studies suggest that one must ascertain under what circumstances individual cognitive testing are also meaningful human outcome measures. Indeed, exactly how different are individually administered tests of speech and language and school tests – certainly, good school test scores require adequate speech and learning skills?

The Use of ECMO in HIV/AIDS with Pneumocystis jirovecii Pneumonia: A Case Report and Review of the Literature

There are few reports of extracorporeal membrane oxygenation (ECMO) therapy for respiratory failure because of Pneumocystis jirovecii pneumonia (PJP) in patients with acquired immunodeficiency syndrome (AIDS). None of the cases reported involvement of immune reconstitution inflammatory syndrome (IRIS), a paradoxical clinical worsening after the initiation of antiretroviral therapy (ART) in ART-naïve patients because of an exaggerated systemic inflammation with cell count recovery. We present a patient with newly diagnosed AIDS and PJP pneumonia that progressed to acute respiratory distress syndrome (ARDS) secondary to probable IRIS for which veno-venous ECMO was initiated. He transitioned to conventional ventilator after 57 days of ECMO therapy. However, he did not survive to hospital discharge. Combined with four previously reported cases of ARDS in human immunodeficiency virus patients secondary to PJP treated with ECMO, three of the five patients survived to ECMO decannulation. Extracorporeal membrane oxygenation is considered an accepted modality for adult patients with respiratory and/or cardiac failure refractory to maximal medical therapy. As ECMO becomes increasingly utilized in clinical practice, there is ongoing controversy regarding the appropriate selection of patients. In the past, contraindications to ECMO included immunocompromised states and conditions with known poor prognosis. The cases herein suggest the indications and contraindications warrant further discussion and research.

Anesthetic-related neurotoxicity in young children: an update

Purpose of review This review examines the recent data, animal and human, reporting an association between early anesthetic exposure, neuronal cell death, and adverse neurocognitive and behavioral outcomes. Recent findings Numerous studies have demonstrated that essentially all commonly used anesthetics, when used alone or in combination, enhance neuroapoptosis in developing rodent brains with resultant impairment in learning, memory, and cognition. Recently, these data have been extended to include studies of nonhuman primates also demonstrating neuroapoptosis and long-term cognitive deficits in response to anesthetic exposure. Of additional concern are several retrospective cohort studies of humans that suggest an association between early anesthetic exposure and neurocognitive deficits. Prospective data in humans are lacking and, as such, a causal relationship between anesthetic exposure and developmental outcome remains speculative. Summary Although the evidence from nonhuman primates and humans is overtly concerning, it lacks clinical verification. There are, at present, no data that would dictate a change in clinical practice in the anesthetic management of infants and children.

Sedation and Analgesia to Facilitate Mechanical Ventilation

Regardless of age, health care professionals have a professional and ethical obligation to provide safe and effective analgesia to patients undergoing painful procedures. Historically, newborns, particularly premature and sick infants, have been undertreated for pain. Intubation of the trachea and mechanical ventilation are ubiquitous painful procedures in the neonatal intensive care unit that are poorly assessed and treated. The authors review the use of sedation and analgesia to facilitate endotracheal tube placement and mechanical ventilation. Controversies regarding possible adverse neurodevelopmental outcomes after sedative and anesthetic exposure and in the failure to treat pain is also discussed.

Anesthetic-Related Neurotoxicity and Neuroimaging in Children: A Call for Conversation

Each year millions of young children undergo procedures requiring sedation or general anesthesia. An increasing proportion of the anesthetics used are provided to optimize diagnostic imaging studies such as magnetic resonance imaging. Concern regarding the neurotoxicity of sedatives and anesthetics has prompted the US Food and Drug Administration to change labeling of anesthetics and sedative agents warning against repeated or prolonged exposure in young children. This review aims to summarize the risk of anesthesia in children with an emphasis on anesthetic-related neurotoxicity, acknowledge the value of pediatric neuroimaging, and address this call for conversation.

Cognitive Outcomes After Infant Spinal Anesthesia: The Other Side of the Coin

Few issues in pediatric anesthesia have garnered more attention from the research, clinical, and regulatory communities than the possibility that adverse neurocognitive outcomes result from the administration of general anesthetics to young children. While preclinical studies are nearly uniformly positive, data from human studies are far less consistent. Virtually all human studies conducted thus far have been retrospective, rely on a database not designed to study the outcome of interest, and exhibit profound differences with regard to the specific outcome measured.1,2 Criticisms of these studies are numerous, appropriate, and frequently center on two fundamental issues: confounding secondary to comorbidity and the coincidence of anesthetic exposure with a surgical procedure. In essence, do these studies truly measure the effects of anesthesia or are they simply studies of cognitive outcome among those needing surgery or the effect of the surgical procedure itself? Several studies from the Mayo Clinic, Columbia University Medical Center, and elsewhere have attempted to control for co-morbidity.3–6 These studies suggest, but by no means prove, that medical comorbidity is inadequate as an explanation for the decrement in cognitive performance observed especially in those with multiple anesthetic and surgical exposures. If one accepts that co-morbidity can be accounted for through adjustment or matching, the major known confounder remaining is that attributed to the effects of the surgical procedure. Like opposite sides of the same coin, the effects of anesthetic and surgical exposure are extremely difficult to separate, particularly in a retrospective study. However, in this month’s issue of Anesthesia & Analgesia, Williams and colleagues have attempted to do just that and in so doing provide insight into one of the primary criticisms of the extant clinical literature.7 The Williams et al. study is the first to specifically examine whether a surgical procedure devoid of exposure to general anesthetics would produce the same cognitive effects as those procedures with general anesthetic exposure. The fundamental assumption of the study is, of course, that exposure to local anesthetics placed in the subarachnoid space would not be associated with subsequent neurodevelopmental injury. This assumption, while supported by preclinical data, has not been rigorously studied in the clinical setting and, as such, is plausible but still conjectural.8,9 In their study, Williams and colleagues sought to isolate the effect of surgery from that of general anesthesia by retrospectively comparing the cognitive outcomes of a cohort of infants who had undergone a brief surgical procedure under spinal anesthesia to normative data for the population of Vermont.7 The authors queried the Vermont Infant Spinal Registry database, a unique database composed of children who have undergone surgery by spinal anesthesia since 1979. They found 265 children who had received a solitary exposure to spinal anesthesia for one of three surgical procedures: circumcision, pyloromyotomy, or inguinal herniorrhaphy. These children were matched by age, gender, need for a free/reduced school lunch, and year of examination to unexposed children. Borrowing from the recent study by Block et al., the primary outcome was children with very poor academic achievement (VPAA) defined as scoring below the 5th percentile on a group-administered test of achievement.10 Reading and math scores, as well as need for an individualized educational program, were evaluated as secondary outcomes. They found that children who had received a single exposure to spinal anesthetics during infancy did not differ significantly to unexposed children with regard to VPAA or need for an individualized educational program. Furthermore, standardized test scores were not negatively correlated with duration of surgery. These findings are in direct contrast to those of Block et al., who found in a similarly designed study of exposure to general anesthetics and surgery an increase in VPAA among those exposed as compared to the population at large.10 From these data Williams and colleagues concluded that the provision of a single spinal anesthetic was not associated with VPAA and that there was no link between the duration of surgery and academic achievement scores. The obvious implications of the Williams et al. study are that the observed decrement in performance associated with surgical/anesthetic in prior studies cannot be attributed to the surgery but must result from some other factor. Whether that factor is N-methyl-D-aspartate receptor and/or γ-aminobutyric acid receptor active agents that comprise virtually all of our anesthetics remains to be determined. Interestingly, as the Williams et al. and Block et al. studies together loosely resemble a retrospective version of the GAS (General Anesthesia Spinal Anesthesia) study now underway at several United States and international sites, it is tempting to ponder whether these two studies may foreshadow the results of the GAS study…or not. Indeed, while past editorials have cautioned against equating the relationship between general anesthesia and neurologic outcome as causal,2 we find ourselves stressing the opposite side of that coin. While Williams and colleagues did not find significant differences between exposed and unexposed children in their study, we caution against concluding that no difference exists. Studies evaluating single anesthetic/surgical exposures as well as those utilizing group-administered tests of achievement as outcome measures have commonly not shown differences in cognitive outcome in exposed children.5,6,11–14 The absence of a positive control (such as a group with exposure to general anesthesia) and the observation that the upper-bound for the confidence intervals for VPPA for math and reading in this study (2.68 and 2.1, respectively) are similar to that reported from larger, positive studies,2 suggest that the current study lacked the statistical power necessary to discriminate between exposed and unexposed children unless their cognitive differences were relatively large, likely larger than that reported in prior studies that evaluated children with multiple exposures to general anesthesia. As such, one must strongly caution against using the current data as justification for prematurely flipping the general/regional anesthetic coin in favor of regional techniques, the risks of which were not quantified in this study. Therefore, the critical difference between this study, Block et al.’s and other retrospective studies and the GAS study is that the GAS study is the only truly randomized controlled trial underway to evaluate the cognitive effects of general and spinal anesthesia. That study will for the most part be free of the confounding and bias that plagues this study and all others published to date. The authors are to be commended for their contribution in assessing whether a surgical procedure may contribute to adverse cognitive outcome later in childhood. The PANDA (Columbia) and MASK (Mayo) studies, although not randomized controlled trials, will augment the insights gained from GAS. None however will report definitive outcomes for at least 2 or 3 years. In the meantime, we must content ourselves with very important but severely limited studies such as that published by Williams et al. in this issue of Anesthesia & Analgesia.7 He and his colleagues have provided us with a glimpse at the previously unseen flip side of the anesthesia-surgery coin.

Anesthetic Outcomes of Children with Arthrogryposis Syndromes: No Evidence of Hyperthermia

BACKGROUND: Arthrogryposis syndromes are a heterogeneous group of disorders characterized by congenital joint contractures often requiring multiple surgeries during childhood to address skeletal and visceral abnormalities. Previous reports suggest that these children have increased perioperative risk, including hypermetabolic events discrete from malignant hyperthermia, difficult airway management, isolated hyperthermia, and difficult IV line placement. We sought to compare children with arthrogryposis multiplex congenita (AMC) versus the less severe, distal arthrogryposis syndromes (DAS) and to evaluate possible intraoperative hyperthermia of patients with AMC. We hypothesized that children with AMC had a greater incidence of intraoperative hyperthermia and more difficulty with airway management and IV access. METHODS: Children aged 0 to 25 years with arthrogryposis syndromes who underwent anesthesia from 1972 to 2013 were identified. The medical records were reviewed for demographics, arthrogryposis type, and anesthetic complications. AMC subjects were compared with DAS subjects. To evaluate the probability of hyperthermia and hypermetabolic responses of patients with AMC, we performed a post hoc case–control analysis. Patients with AMC were matched in a 1:2 ratio to patients without arthrogryposis to evaluate the primary outcome of maximum intraoperative temperature. RESULTS: Forty-five patients with AMC and 16 patients with DAS underwent 264 and 105 unique anesthetics, respectively. There was no significant difference in intraoperative hyperthermia or hypermetabolic events (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.36–2.47; P = .90). Children with AMC were more likely to have difficult IV access (OR, 7.1; 95% CI, 1.81–27.90; P = .005). Additional evidence suggested that difficult airway management (OR, 4.06; 95% CI, 1.01–16.39; P = .049) and hemodynamic instability (OR, 4.22; 95% CI, 1.03–17.26; P = .045) were more likely in children with AMC. From post hoc case–control analysis, there was no significant difference in the mean maximum intraoperative temperature (estimated difference +0.04°C; 95% CI, −0.14 to +0.22; P = .64) or odds of intraoperative hyperthermia (OR, 1.49; 95% CI, 0.78–2.82; P = .223) for patients with AMC compared with control subjects. CONCLUSIONS: Children with arthrogryposis syndromes present challenges to the anesthesia and surgical teams, including greater neuromuscular disease burden and challenging peripheral IV placement, with additional evidence suggesting difficult airway management and intraoperative hemodynamic instability. Although more definitive studies are warranted, we did not find evidence of increased odds of intraoperative hyperthermia or hypermetabolic responses.

Comparison of staff and family perceptions of causes of noise pollution in the Pediatric Intensive Care Unit and suggested intervention strategies.

Noise and excessive, unwanted sound in the Pediatric Intensive Care Unit (PICU) is common and has a major impact on patients′ sleep and recovery. Previous research has focused mostly on absolute noise levels or included only staff as respondents to acknowledge the causes of noise and to plan for its reduction. Thus far, the suggested interventions have not ameliorated noise, and it continues to serve as a barrier to recovery. In addition to surveying PICU providers through internet-based software, patients′ families were evaluated through in-person interviews utilizing a pretested instrument over 3 months. Families of patients admitted for more than 24 h were considered eligible for evaluation. Participants were asked to rank causes of noise from 1 to 8, with eight being highest, and identified potential interventions as effective or ineffective. In total, 50 families from 251 admissions and 65 staff completed the survey. Medical alarms were rated highest (mean ± standard deviation [SD], 4.9 ± 2.1 [2.8-7.0]), followed by noise from medical equipment (mean ± SD, 4.7 ± 2.1 [2.5-6.8]). This response was consistent among PICU providers and families. Suggested interventions to reduce noise included keeping a patient′s room door closed, considered effective by 93% of respondents (98% of staff; 88% of families), and designated quiet times, considered effective by 82% (80% of staff; 84% of families). Keeping the patient′s door closed was the most effective strategy among survey respondents. Most families and staff considered medical alarms an important contributor to noise level. Because decreasing the volume of alarms such that it cannot be heard is inappropriate, alternative strategies to alert staff of changes in vital signs should be explored.

PROPER: Development of an Early Pediatric Intensive Care Unit Readmission Risk Prediction Tool

Objective: No risk prediction model is currently available to measure patient’s probability for readmission to the pediatric intensive care unit (PICU). This retrospective case–control study was designed to assess the applicability of an adult risk prediction score (Stability and Workload Index for Transfer [SWIFT]) and to create a pediatric version (PRediction Of PICU Early Readmissions [PROPER]). Design: Eighty-six unplanned early (<48 hours) PICU readmissions from January 07, 2007, to June 30, 2014, were compared with 170 random controls. Patient- and disease-specific data and PICU workload factors were compared across the 2 groups. Factors statistically significant on multivariate analysis were included in the creation of the risk prediction model. The SWIFT scores were calculated for cases and controls and compared for validation. Results: Readmitted patients were younger, weighed less, and were more likely to be admitted from the emergency department. There were no differences in gender, race, or admission Pediatric Index of Mortality scores. A higher proportion of patients in the readmission group had a Pediatric Cerebral Performance Category in the moderate to severe disability category. Cases and controls did not differ with respect to staff workload at discharge or discharge day of the week; there was a much higher proportion of patients on supplemental oxygen in the readmission group. Only 2 of 5 categories in the SWIFT model were significantly different, and although the median SWIFT score was significantly higher in the readmissions group, the model discriminated poorly between cases and controls (area under the curve: 0.613). A 7-category PROPER score was created based on a multiple logistic regression model. Sensitivity of this model (score ≥12) for the detection of readmission was 81% with a positive predictive value of 0.50. Conclusion: We have created a preliminary model for predicting patients at risk of early readmissions to the PICU from the hospital floor. The SWIFT score is not applicable for predicting the risk for pediatric population.