Perioperative Mortality of the COVID-19 Recovered Patient Compared to a Matched Control: A Multicenter Retrospective Cohort Study.

BACKGROUND: Surgical procedures performed on patients with recent exposure to COVID-19 infection have been associated with increased mortality risk in previous studies. Accordingly, elective surgery is often delayed after infection. The study aimed to compare 30-day hospital mortality and postoperative complications (acute kidney injury, pulmonary complications) of surgical patients with a previous COVID-19 infection to a matched cohort of patients without known previous COVID-19. The authors hypothesized that COVID-19 exposure would be associated with an increased mortality risk. METHODS: In this retrospective observational cohort study, patients presenting for elective inpatient surgery across a multicenter cohort of academic and community hospitals from April 2020 to April 2021 who had previously tested positive for COVID-19 were compared to controls who had received at least one previous COVID-19 test but without a known previous COVID-19-positive test. The cases were matched based on anthropometric data, institution, and comorbidities. Further, the outcomes were analyzed stratified by timing of a positive test result in relation to surgery. RESULTS: Thirty-day mortality occurred in 229 of 4,951 (4.6%) COVID-19-exposed patients and 122 of 4,951 (2.5%) controls. Acute kidney injury was observed in 172 of 1,814 (9.5%) exposed patients and 156 of 1,814 (8.6%) controls. Pulmonary complications were observed in 237 of 1,637 (14%) exposed patients and 164 of 1,637 (10%) controls. COVID-19 exposure was associated with an increased 30-day mortality risk (adjusted odds ratio, 1.63; 95% CI, 1.38 to 1.91) and an increased risk of pulmonary complications (1.60; 1.36 to 1.88), but was not associated with an increased risk of acute kidney injury (1.03; 0.87 to 1.22). Surgery within 2 weeks of infection was associated with a significantly increased risk of mortality and pulmonary complications, but that effect was nonsignificant after 2 weeks. CONCLUSIONS: Patients with a positive test for COVID-19 before elective surgery early in the pandemic have an elevated risk of perioperative mortality and pulmonary complications but not acute kidney injury as compared to matched controls. The span of time from positive test to time of surgery affected the mortality and pulmonary risk, which subsided after 2 weeks.

Early-in-life isoflurane exposure alters resting-state functional connectivity in juvenile non-human primates.

BACKGROUND: Clinical studies suggest that anaesthesia exposure early in life affects neurobehavioural development. We designed a non-human primate (NHP) study to evaluate cognitive, behavioural, and brain functional and structural alterations after isoflurane exposure during infancy. These NHPs displayed decreased close social behaviour and increased astrogliosis in specific brain regions, most notably in the amygdala. Here we hypothesise that resting-state functional connectivity MRI can detect alterations in connectivity of brain areas that relate to these social behaviours and astrogliosis. METHODS: Imaging was performed in 2-yr-old NHPs under light anaesthesia, after early-in-life (postnatal days 6-12) exposure to 5 h of isoflurane either one or three times, or to room air. Brain images were segmented into 82 regions of interest; the amygdala and the posterior cingulate cortex were chosen for a seed-based resting-state functional connectivity MRI analysis. RESULTS: We found differences between groups in resting-state functional connectivity of the amygdala and the auditory cortices, medial premotor cortex, and posterior cingulate cortex. There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula. Relationships were identified between resting-state functional connectivity alterations and the decrease in close social behaviour and increased astrogliosis. CONCLUSIONS: Early-in-life anaesthesia exposure in NHPs is associated with resting-state functional connectivity alterations of the amygdala and the posterior cingulate cortex with other brain regions, evident at the juvenile age of 2 yr. These changes in resting-state functional connectivity correlate with the decrease in close social behaviour and increased astrogliosis. Using resting-state functional connectivity MRI to study the neuronal underpinnings of early-in-life anaesthesia-induced behavioural alterations could facilitate development of a biomarker for anaesthesia-induced developmental neurotoxicity.

Pro-Con Debate: Judicious Benzodiazepine Administration for Preoperative Anxiolysis in Older Patients.

In this Pro-Con commentary article, we discuss the risks and benefits of administering preoperative benzodiazepines to older patients to decrease preoperative anxiety. The Pro side first focuses on the critical importance of treating preoperative anxiety and that benzodiazepines are the best tool to achieve that goal. The competing argument presented by the Con side is that myriad options exist to treat preoperative anxiety without simultaneously increasing the risk for devastating complications such as postoperative delirium. Both sides call for more high-quality investigations to determine the most effective strategies for decreasing preoperative anxiety in older adults while improving outcomes and reducing morbidity.

Update on Perioperative Delirium.

A strong association between frailty and in-hospital delirium in nonsurgical patients has been shown. Physical and cognitive frailties have been associated with decline and dysfunction in the frontal cognitive domains. Risk factors for frailty are similar to risk factors for postoperative delirium (POD). Frailty can be screened and diagnosed by various tools and instruments. Different anesthetic techniques have been studied to decrease the incidence of POD. However, no anesthetic technique has been conclusively proven to decrease the risk of POD. Patients with dementia develop delirium more often, and delirium is associated with accelerated cognitive decline.

Optimizing Reversal of Neuromuscular Block in Older Adults: Sugammadex or Neostigmine.

Residual neuromuscular paralysis, the presence of clinically significant weakness after administration of pharmacologic neuromuscular blockade reversal, is associated with postoperative pulmonary complications and is more common in older patients. In contemporary anesthesia practice, reversal of neuromuscular blockade is accomplished with neostigmine or sugammadex. Neostigmine, an acetylcholinesterase inhibitor, increases the concentration of acetylcholine at the neuromuscular junction, providing competitive antagonism of neuromuscular blocking drug and facilitating muscle contraction. Sugammadex, a modified gamma-cyclodextrin, antagonizes neuromuscular blockade by encapsulating rocuronium and vecuronium in a one-to-one ratio for renal clearance, a pharmacokinetic property that led to the recommendation that sugammadex not be administered to those with end-stage renal disease. While data are limited, reports suggest sugammadex is efficacious and well tolerated in individuals with reduced renal function. Sugammadex provides a more rapid and complete reversal of neuromuscular blockade than neostigmine. There is also accumulating evidence that sugammadex may provide a protective effect against the development of postoperative pulmonary complications, nausea, and vomiting, and that it may have beneficial effects on the rate of bowel and bladder recovery after surgery. Accordingly, sugammadex administration is beneficial for most older patients undergoing surgery.

Potentially Inappropriate Medication Administration Is Associated With Adverse Postoperative Outcomes in Older Surgical Patients: A Retrospective Cohort Study.

BACKGROUND: The American Geriatrics Society (AGS) Beers Criteria is an explicit list of potentially inappropriate medications (PIMs) best avoided in adults ≥65 years of age. Cognitively impaired and frail surgical patients often experience poor outcomes after surgery, but the impacts of PIMs on these patients are unclear. Our objective was to assess whether perioperative PIM administration was associated with poor outcomes in geriatric surgical patients. We then evaluated the association between PIM administration and postoperative outcomes in subgroups of patients who were frail or cognitively impaired. METHODS: We performed a retrospective cohort study of patients ≥65 years of age who underwent elective inpatient surgery at a large academic medical center from February 2018 to January 2020. Edmonton Frail Scale and Mini-Cog screening tools were administered to all patients at their preoperative clinic visit. A Mini-Cog score of 0 to 2 was considered cognitive impairment, and frailty was defined by an Edmonton Frail Scale score of ≥8. Patients were divided into 2 groups depending on whether they received at least 1 PIM (PIM+), based on the 2019 AGS Beers Criteria, in the perioperative period or none (PIM-). We assessed the association of preoperative frailty, cognitive impairment, and perioperative PIM administration with the length of hospital stay and discharge disposition using multiple regression analyses adjusted for age, sex, ASA physical status, and intensive care unit (ICU) admission. RESULTS: Of the 1627 included patients (mean age, 73.7 years), 69.3% (n = 1128) received at least 1 PIM. A total of 12.7% of patients were frail, and 11.1% of patients were cognitively impaired; 64% of the frail patients and 58% of the cognitively impaired patients received at least 1 PIM. Perioperative PIM administration was associated with longer hospital stay after surgery (PIM-, 3.56 ± 5.2 vs PIM+, 4.93 ± 5.66 days; P < .001; 95% confidence interval [CI], 0.360-0.546). Frail patients who received PIMs had an average length of stay (LOS) that was nearly 2 days longer than frail patients who did not receive PIMs (PIM-, 4.48 ± 5.04 vs PIM+, 6.33 ± 5.89 days; P = .02). Multiple regression analysis revealed no significant association between PIM administration and proportion of patients discharged to a care facility (PIM+, 26.3% vs PIM-, 28.7%; P = .87; 95% CI, -0.046 to 0.054). CONCLUSIONS: Perioperative PIM administration was common in older surgical patients, including cognitively impaired and frail patients. PIM administration was associated with an increased hospital LOS, particularly in frail patients. There was no association found between PIM administration and discharge disposition.

COVID-19 in the perioperative setting: A review of the literature and the clinical landscape.

The COVID-19 pandemic has dramatically affected societies and healthcare systems around the globe. The perioperative care continuum has also been under significant strain due to the pandemic-tasked with simultaneously addressing surgical strains and backlogs, infection prevention strategies, and emerging data regarding significantly higher perioperative risk for COVID-19 patients and survivors. Many uncertainties persist regarding the perioperative risk, assessment, and management of COVID-19 survivors-and the energy to catch up on surgical backlogs must be tempered with strategies to continue to mitigate COVID-19 related perioperative risk. Here, we review the available data for COVID-19-related perioperative risk, discuss areas of persistent uncertainty, and empower the perioperative teams to pursue evidence-based strategies for high quality, patient-centered, team-based care as we enter the third year of the COVID-19 pandemic.

Diagnosis and Management of Obesity Hypoventilation Syndrome during Labor.

Obesity hypoventilation syndrome (OHS) is a disorder in which patients with a body mass index ≥30 kg/m2 develop awake hypercapnia with a partial pressure of carbon dioxide ≥45 mm Hg, in the absence of other diseases that may produce alveolar hypoventilation. Additional clinical features include sleep disordered breathing, restrictive lung disease, polycythemia, hypoxemia, and an increased serum bicarbonate concentration (≥27 mEq/L). Anesthesia providers should be familiar with OHS because it is often undiagnosed, it is associated with a higher mortality rate than obstructive sleep apnea, and it is projected to increase in prevalence along with the obesity epidemic. In this case, a 33-year-old obese woman with presumed OHS developed respiratory acidosis during induction of labor. Continuous positive airway pressure treatment was initiated, but the patient continued to have hypercapnia. A cesarean delivery was recommended. The patient had baseline orthopnea due to her body habitus; thus, despite adequate labor analgesia, a cesarean delivery was completed with general endotracheal anesthesia. We believe this patient had OHS despite a serum bicarbonate <27 mEq/L, a partial pressure of oxygen >70 mm Hg, and a hemoglobin <16 g/dL, which would typically rule out OHS. Pregnant women experience a decrease in serum bicarbonate concentration due to progesterone-mediated hyperventilation, an increase in arterial oxygenation from increased minute ventilation and higher cardiac output, and a decrease in hemoglobin due to the physiologic anemia of pregnancy. Thus, OHS may be defined differently in pregnant than in non-pregnant patients.

Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice.

BACKGROUND: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. OBJECTIVE: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. METHODS: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. RESULTS: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer's disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. CONCLUSION: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

Prevention of postoperative delirium through the avoidance of potentially inappropriate medications in a geriatric surgical patient.

We demonstrate the utility of risk stratification for postoperative delirium in geriatric patients and show that postoperative delirium can be prevented in high-risk patients when potentially inappropriate medications (PIMs) (medications that are best avoided in older adults) are avoided. In this case, a 65-year-old woman underwent two debridement procedures with similar presurgical risk for postoperative delirium. There was no risk stratification or preoperative cognitive assessment in the first procedure, she received PIMs and developed postoperative delirium. In the second procedure, PIMs were intentionally avoided and postoperative delirium did not occur. This case supports recent recommendations from the European Society of Anaesthesiology, the American Society of Anesthesiologists and the American Geriatrics Society that providers assess a patient's cognitive function and delirium risk profile preoperatively to appropriately guide perioperative management.

Preparing previously COVID-19-positive patients for elective surgery: a framework for preoperative evaluation.

The preoperative evaluation and risk assessment has always been a critical aspect of safe surgical practice, and in the midst of the SARS-CoV-2 pandemic, it has become even more crucial to patient safety. Emerging data show that surgical procedures in patients who test positive for coronavirus disease (COVID) are associated with worse clinical outcomes and increased postoperative complications and mortality. In addition to personal protective equipment (PPE) management, isolation protocols, preoperative SARS-CoV-2 screening, and steps to ensure clinician safety, determining how to deem patients who have recovered from COVID-19 safe to proceed is an added challenge. We present a preoperative protocol for evaluation of previously COVID-positive patients for elective surgery.

Agreement Between the Mini-Cog in the Preoperative Clinic and on the Day of Surgery and Association With Postanesthesia Care Unit Delirium: A Cohort Study of Cognitive Screening in Older Adults.

BACKGROUND: Cognitive impairment is common in older surgical patients and is associated with postoperative delirium. However, cognitive function is inconsistently assessed preoperatively, leading to missed opportunities to recognize vulnerable patients. We designed a prospective cohort study to assess the agreement of the Mini-Cog screening tool administered in the preoperative clinic (clinic-day test) or immediately before surgery (surgery-day test) and to determine whether a positive screening for cognitive dysfunction in the surgery-day test is associated with postoperative delirium in the postanesthesia care unit (PACU). METHODS: This was a cohort study of patients aged 65-89 years, scheduled for elective, inpatient surgery under general anesthesia between June 20, 2018 and August 3, 2018. Mini-Cog test scores were obtained during a clinic-day test and surgery-day test. The Short Confusion Assessment Method was performed in the PACU. Agreement between Mini-Cog clinic-day and surgery-day test scores was estimated using an ordinally weighted kappa statistic, κ. Multivariable logistic regression was used to determine whether there was an association between a positive screen for cognitive impairment and PACU delirium. Odds ratio analysis was performed to determine whether the Mini-Cog score was associated with PACU delirium. RESULTS: Of 128 patients meeting eligibility criteria, 80 patients were enrolled. Ten had cognitive impairment based on the Mini-Cog clinic-day test score, while 70 did not. Age, sex, race, education level, subjective memory impairment, and American Society of Anesthesiologists (ASA) physical status were equivalent in the 2 groups. The mean number of days between the clinic-day score and the surgery-day score was 8.4 days (standard deviation [SD] = 6.9). Mini-Cog clinic-day and surgery-day scores had high agreement (κ = 0.78; 95% confidence interval [CI], 0.69-0.87; P < .001), and both scores were highly predictive of PACU delirium. Patients with Mini-Cog surgery-day scores compatible with cognitive impairment (Mini-Cog scores ≤2) had an estimated 12.8 times higher odds of PACU delirium compared to patients with normal cognitive function or Mini-Cog scores >2 (odds ratio [OR] = 12.8; 95% CI, 2.6-63.8, P = .002). Similarly, patients with Mini-Cog clinic-day test scores compatible with cognitive impairment had an estimated 29 times higher odds of PACU delirium compared to patients with normal cognitive function (OR = 29.0; 95% CI, 2.6-63.8, P < .001). CONCLUSIONS: These data support the approach of using the Mini-Cog on the day of surgery to screen for cognitive impairment in older patients. Importantly, Mini-Cog surgery-day test scores compatible with cognitive impairment (≤2) were strongly associated with PACU delirium.

Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates.

BACKGROUND: Clinical studies show that children exposed to anaesthetics for short times at young age perform normally on intelligence tests, but display altered social behaviours. In non-human primates (NHPs), infant anaesthesia exposure for several hours causes neurobehavioural impairments, including delayed motor reflex development and increased anxiety-related behaviours assessed by provoked response testing. However, the effects of anaesthesia on spontaneous social behaviours in juvenile NHPs have not been investigated. We hypothesised that multiple, but not single, 5 h isoflurane exposures in infant NHPs are associated with impairments in specific cognitive domains and altered social behaviours at juvenile age. METHODS: Eight Rhesus macaques per group were anaesthetised for 5 h using isoflurane one (1×) or three (3×) times between postnatal days 6 and 12 or were exposed to room air (control). Cognitive testing, behavioural assessments in the home environment, and provoked response testing were performed during the first 2 yr of life. RESULTS: The cognitive functions tested did not differ amongst groups. However, compared to controls, NHPs in the 3× group showed less close social behaviour (P=0.016), and NHPs in the 1× group displayed increased anxiety-related behaviours (P=0.038) and were more inhibited towards novel objects (P<0.001). CONCLUSIONS: 5 h exposures of NHPs to isoflurane during infancy are associated with decreased close social behaviour after multiple exposures and more anxiety-related behaviours and increased behavioural inhibition after single exposure, but they do not affect the cognitive domains tested. Our findings are consistent with behavioural alterations in social settings reported in clinical studies, which may guide future research.

State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018.

Cognitive recovery after anaesthesia and surgery is a concern for older adults, their families, and caregivers. Reports of patients who were 'never the same' prompted a scientific inquiry into the nature of what patients have experienced. In June 2018, the ASA Brain Health Initiative held a summit to discuss the state of the science on perioperative cognition, and to create an implementation plan for patients and providers leveraging the current evidence. This group included representatives from the AARP (formerly the American Association of Retired Persons), American College of Surgeons, American Heart Association, and Alzheimer's Association Perioperative Cognition and Delirium Professional Interest Area. This paper summarises the state of the relevant clinical science, including risk factors, identification and diagnosis, prognosis, disparities, outcomes, and treatment of perioperative neurocognitive disorders. Finally, we discuss gaps in current knowledge with suggestions for future directions and opportunities for clinical and translational projects.

Sex and genetic differences in postoperative cognitive dysfunction: a longitudinal cohort analysis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common postoperative complication experienced by patients aged 65 years and older, and these older adults comprise more than one third of the surgical patients in the USA. Because not everyone with a history of exposure to surgery and anesthesia develops POCD, there are likely major biological risk factors involved. There are important gaps in our knowledge regarding whether genetic makeup, biological sex, or other Alzheimer's disease risk factors predispose older adults to developing POCD. We set out to determine whether biological sex and Apolipoprotein E-ε4 (APOE4) carrier status increase the risk of developing POCD in older adults. METHODS: We performed a cohort analysis of 1033 participants of prospective longitudinal aging studies. Participants underwent regular cognitive test batteries and we compared the annual rate of change over time in various cognitive measures in the women exposed to surgery and general anesthesia compared to the men exposed to surgery and general anesthesia. Mixed-effects statistical models were used to assess the relationship between biological sex, APOE4 carrier status, surgery and anesthesia exposure, and the rate of change in cognitive test scores. RESULTS: When comparing all men (n = 89) and women (n = 164) who had surgery, there were no significant sex differences in postoperative cognitive outcomes. However, men with an APOE4 allele performed significantly worse on cognitive testing following surgery and anesthesia than women APOE4 carriers, even after adjusting for age, education level, and comorbidities. CONCLUSIONS: Older men with APOE4 allele may be more vulnerable to postoperative cognitive dysfunction than older women with APOE4 allele.

A prospective study of the pathophysiology of carcinoid crisis.

BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.

Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group.

As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in-person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed.

Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain.

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7-8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.