We report on 6 infants who underwent elective surgery and developed postoperative encephalopathy, which had features most consistent with intraoperative cerebral hypoperfusion. All infants were <48 weeks’ postmenstrual age and underwent procedures lasting 120 to 185 minutes. Intraoperative records revealed that most of the measured systolic blood pressure (SBP) values were <60 mm Hg (the threshold for hypotension in awake infants according to the Pediatric Advanced Life Support guidelines) but that only 11% of the measured SBP values were <1 SD of the mean definition of hypotension (<45 mm Hg) as reported in a survey of members of the Society for Pediatric Anesthesia in 2009. Four infants also exhibited prolonged periods of mild hypocapnia (<35 mm Hg). One infant did not receive intraoperative dextrose. All infants developed new-onset seizures within 25 hours of administration of the anesthetic, with a predominant cerebral pathology of supratentorial watershed infarction in the border zone between the anterior, middle, and posterior cerebral arteries. Follow-up of these infants found that 1 died, 1 had profound developmental delays, 1 had minor motor delays, 2 were normal, and 1 was lost to follow-up. Although the precise cause of encephalopathy cannot be determined, it is important to consider the role that SBP hypotension (as well as hypoglycemia, hyperthermia, hyperoxia, and hypocapnia) plays during general anesthesia in young infants in the development of infantile postoperative encephalopathy. Our observations highlight the lack of evidence-based recommendations for the lower limits of adequate SBP and end-tidal carbon dioxide in anesthetized infants.
- BP —
- blood pressure
- ETCO2 —
- end-tidal carbon dioxide
- PALS —
- Pediatric Advanced Life Support
- SBP —
- systolic blood pressure
- SPA —
- Society for Pediatric Anesthesia
General anesthesia early in life has a higher immediate morbidity and mortality rate than at any other period during childhood.1 The purpose of the current report was to highlight the potential problem of perioperative cerebral hypoperfusion that we identified after reviewing the management of 6 infants treated at 4 academic medical centers (see the supplemental information). All 6 infants developed encephalopathy within 25 hours of administration of a general anesthetic.
We undertook the case series review after receiving approval from Boston Children’s Hospital Committee on Clinical Investigation.
Table 1 summarizes demographic, surgical, and anesthetic information. All infants were considered hemodynamically and neurologically stable before surgery, and they underwent anesthesia with sevoflurane with no episodes of hypoxia or arrhythmia. None of the infants had cardiac disease, hypertension, or preoperative seizures. Baseline blood pressure (BP) readings, based on a single value, were available for 5 of 6 infants; elevated baseline BP for infant 6 was likely obtained while he was crying. Intraoperatively, infants 1 and 2 received supplemental narcotics and infants 1, 2, 4, and 5 received adjunctive local anesthesia with bupivacaine or ropivacaine in low doses. All infants were intubated on the first or second attempt with no pulse oximetry (Spo2) desaturations. Infant 1 was intubated fiberoptically; the others were intubated by using direct laryngoscopy. Infants 1 and 2 were brought to the NICU intubated and ventilated with stable vital signs. Infant 3 had an episode of laryngospasm lasting 1 minute; her lowest Spo2 was 86%. Infants 4 through 6 were extubated uneventfully and were awake, alert, and feeding in the pediatric anesthetic care unit. There were no episodes of hypoxemia or hypotension in the pediatric anesthetic care unit or NICU postoperatively. Infants 3 and 4 required endotracheal reintubation after seizure treatment postoperatively. Infant 1, with Pierre Robin sequence, had several episodes of airway obstruction without major Spo2 desaturations before her procedure. She developed right-sided focal seizures, which progressed to status epilepticus at 21 hours’ postoperatively. Her seizures were controlled with phenobarbital, midazolam, levetiracetam, and phenytoin. Infant 2 had biliary atresia and a chromosomal deletion 22q11.1, which is not typically associated with seizures. He developed right-sided focal and then several generalized seizures 19 hours’ postoperatively. Infant 3 was born at 900 g and developed hydrocephalus. Cranial computed tomography scans just before her procedure revealed only hydrocephalus. She developed right-sided focal and then sporadic generalized seizures 25 hours’ postoperatively and was successfully treated with phenobarbital and phenytoin. Infant 4 was born at 26 weeks’ postmenstrual age and had a grade 1 intraventricular hemorrhage before surgery and grade 2 intraventricular hemorrhage before uneventful surgeries for necrotizing enterocolitis. Twelve hours’ postoperatively, the patient developed myoclonic activity and apnea. He was treated with phenobarbital. Infants 5 and 6 were born premature but had no evidence of previous neurologic injury. Twenty-five hours’ postoperatively, infant 5 developed generalized seizures treated with phenobarbital and fosphenytoin. Twenty-four hours’ postoperatively, infant 6 developed left-sided focal seizures, which responded to phenobarbital and lorazepam. All of the infants had a normal blood glucose level at the time of their first seizure, and all of the infants except patient 5 received dextrose intraoperatively. In addition, interviews with the anesthesiologists who performed the anesthetics (cases 3–6) revealed no intraoperative concerns. Figure 1 shows the serial systolic blood pressure (SBP) recordings in all 6 infants according to the Society for Pediatric Anesthesia (SPA) membership survey and the Pediatric Advanced Life Support (PALS) definition of hypotension. Figure 2 shows the serial end-tidal carbon dioxide (ETCO2) measurements for all 6 infants.
Intraoperative Physiologic Monitoring and Definitions
SBP and diastolic BP measurements were extracted from the anesthetic records. The cuff width-to-arm-circumference ratio was 0.5 in accordance with pediatric guidelines, and BP readings were obtained by using an automated oscillometric method in 5 patients (invasive BP monitoring in patient 2). All anesthetic records were independently reviewed by 2 anesthesiologists. Five-minute interval mean BP values were either extracted from the electronic anesthesia records (patients 1–3) or calculated from the written anesthesia records by using the formula SBP + (2 × diastolic BP)/3 (Table 2). We also extracted simultaneous recordings of ETCO2, end-tidal sevoflurane concentration, and fraction of inspired oxygen, Spo2, heart rate, and temperature. All infants were intubated; controlled ventilation was accomplished with a pediatric circle anesthesia breathing circuit, and capnography was measured by proximal sampling.
All 6 infants underwent brain imaging within 4 days of general anesthesia. Standard clinical techniques were used for computed tomography and MRI scans. The imaging is presented in summary format to give an indication of the underlying pathophysiology. A pediatric neuroradiologist and pediatric neurologist, who were blinded to the infants’ clinical course, reviewed all of the studies.
Table 3 summarizes the features of the postoperative encephalopathy. All patients responded to single or multidrug anticonvulsant therapy, and protracted status epilepticus was not evident in patients 2 through 6. Supportive care was withdrawn from infant 1, who died within 3 weeks. The autopsy showed massive damage to both occipital lobes, with decreased volume of white matter and extensive loss of neurons in the cortex of both occipital lobes. In the 5 survivors, early brain imaging studies (within 4 days of presentation) showed supratentorial watershed infarction as the predominant finding (ie, in the border zone between the anterior, middle, and posterior cerebral arteries).
Figure 3 shows brain MRI findings from 3 survivors. The images show abnormalities in the anterior and posterior watershed with sparing of the central gray matter. In case 3, the border zone abnormality is bilateral anteriorly and posteriorly. In case 5, the abnormality is greater on the left, more posterior, and includes the splenium. In case 6, the border zone abnormality is symmetric anteriorly and posteriorly and also includes the splenium. These changes are consistent with hypoxic-ischemic events occurring in the previous 48 to 96 hours, which would include the perioperative period.
Patient 2 was discharged from the hospital 47 days after surgery, and there were profound neurodevelopmental delays at follow-up. Patient 3 was discharged from the hospital after 23 days and had a normal 6-month physical examination. Patient 4 was discharged on day 14 without follow-up data available. Patient 5 was discharged on day 7 and had a normal Bayley III cognitive composite score (95 adjusted for prematurity) with abnormal motor score (76 adjusted for prematurity) at 18 months. Patient 6 was discharged from the hospital on day 5 and had a normal examination at 6 months.
We undertook the current review to determine potential etiologies of unexplained postoperative seizures. Infantile seizures after general anesthesia is extremely rare, with only 7 cases reported in the literature that were unrelated to local anesthetic toxicity or not occurring in infants undergoing cardiac or major neurosurgery.2–5 In our cases, causes such as local anesthesia toxicity or paradoxical venous air embolism are unlikely because of the time course of the seizures. Mechanisms of neurologic injury in infants undergoing cardiac surgery include hypoxic-ischemia, emboli, reactive oxygen species, and inflammatory microvasculopathy.6 Although the mechanisms of central nervous system injury in infants having noncardiac surgery have not been well characterized, it is plausible that they are similar. In our group of patients, who were deemed hemodynamically and neurologically stable by their caregivers, all spent time in NICUs before surgery (patients 1 and 2 because of underlying disease and patients 3–6 because of prematurity and/or underlying disease). Although there were no preoperative resuscitations or adverse events in these patients, there may have been episodes of instability that caused subtle, undetected neurologic abnormalities either perinatally or preoperatively that predisposed them to perioperative neurologic injury. However, the radiology and features of the encephalopathy point to a period of cerebral hypoperfusion occurring in the perioperative period. The watershed pattern of injury seen is typically thought to follow “prolonged partial asphyxia” rather than “acute near-total asphyxia.”7,8 This same injury pattern is associated with episodes of hypotension, infection, and hypoglycemia.9,10 This presumed pathophysiology is consistent with the observations described in our infants. Although the neuroimaging findings are concerning, long-term follow-up is necessary in this group of patients. Several of the infants had preoperative neurologic issues (isolated hydrocephalus in patient 3 and grade 1 intraventricular hemorrhage in patient 4). Review of the literature reveals that normative data on hemodynamic and chemical parameters for young infants undergoing general anesthesia are not established at this time.
Hypotension: Definitions in Young Infants and Occurrence With Anesthesia
There any many definitions of intraoperative hypotension, including those using mean BPs and those using SBP, but a mean BP of 20% to 30% less than baseline is often considered the lower acceptable limit.11 A recent survey of members of the SPA and the Association of Pediatric Anaesthetists of Great Britain and Ireland12 identified an SBP threshold value for neonates as 45.5 ± 8.5 mm Hg and 49.6 ± 8.4 mm Hg, respectively. This value is 20% to 25% below the definition of hypotension used in the PALS for awake neonates and represents a 40% to 46% drop in expected normative SBP for awake healthy neonates aged >1 week and awake preterm infants that are aged >70 days.13–15 Other authors have suggested a more conservative definition of intraoperative hypotension in neonates. Davis et al16 defined a hypotensive response to anesthesia in neonates as an SBP <60 mm Hg for 1 minute on 2 consecutive readings in a multicenter trial comparing remifentanil with halothane anesthesia for pyloromyotomy patients. The numerous nonevidence-based definitions used to identify intraoperative hypotension in neonates and infants reveal that more research is needed to define the acceptable lower limits and the acceptable duration for hypotension and to determine whether SBP or mean BP is more important in determining outcomes.
Hypocapnia: Definitions in Young Infants and Occurrence With Anesthesia
There are also no standard definitions for degrees of hypocapnia. Pediatric critical care specialists have defined hypocapnia for traumatic brain injury as the following: mild (ETCO2 30–35 mm Hg), moderate (ETCO2 between 25 and 30 mm Hg), and severe (ETCO2 <25 mm Hg).17,18 The significance of hypocapnia in healthy awake or anesthetized infants is unknown but even mild hypocapnia in nonanesthethized neonates with previous hypoxic-ischemic injury is associated with poor neurologic outcomes.19 A limitation of using ETCO2 rather than arterial partial pressure of carbon dioxide is that there can be inaccuracies secondary to anesthetic gas flows, uncuffed endotracheal tubes, and ETCO2 measurements.20
Hypoglycemia, Hyperoxia, and Hyperthermia
There is a paucity of literature examining the effects of hyperthermia on neonates undergoing surgery, but even a modest increase in core temperature will increase the cerebral metabolic rate. A modest elevation in maternal temperature before delivery will increase the risk of hypoxic-ischemic injury to the newborn.21 Mild hypoxia-ischemia in newborn primates who experience prolonged, severe hypoglycemia or mild hypoglycemia (blood glucose <45 mg dL) leads to cerebral injury.22 Hyperoxia, even for short periods, has also been found to exacerbate cerebral injury in neonates and neonatal animals who have suffered partial asphyxia.23,24 There are few data about safe limits for temperature, glucose control, and oxygen levels in neonates undergoing anesthesia for noncardiac procedures.
The caregivers for these infants were left with the conundrum that all were considered neurologically stable before their general anesthetic and yet within 25 hours of the anesthetic each patient developed an encephalopathy heralded by seizures. In all cases, most of the intraoperative BP readings were lower than the level suggested for infants according to the PALS guidelines and the British Working Group on Perinatology, which recommends using the infant’s gestational age in weeks as the lower limit of mean BP.13–15 However, most readings were not lower than the lower limits of SBP suggested by members of the SPA or the Association of Paediatric Anaesthetists for infants undergoing general anesthesia.
The retrospective nature of this case series makes it difficult to assign a specific etiology to these infants’ encephalopathy. However, these cases illustrate, most importantly, what is unknown about safely managing pediatric anesthesia for young infants. The acceptable lower limits of BP, ETCO2, and blood glucose levels and the acceptable upper limits of the fraction of inspired oxygen and core temperatures have not been determined for these fragile patients. The preoperative risk factors, which may in rare circumstances predispose some infants to perioperative neurologic injury, also need to be further elucidated in patients undergoing noncardiac procedures.
- Accepted August 2, 2013.
- Address correspondence to Mary Ellen McCann, MD, MPH, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail:
Drs McCann, Schouten, and Tasker contributed substantially to the interpretation and analysis of the data. All authors substantially contributed to the acquisition of data, the drafting and revisions of the article, and had final approval of the version to be published.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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