Juraj Sprung

Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort

Background:Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. The authors studied association between anesthetic exposure before age 4 yr and the development of reading, written language, and math learning disabilities (LD). Methods:This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota, from 1976 to 1982 and who remained in the community at 5 yr of age were reviewed to identify children with LD. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of LD, adjusting for gestational age at birth, sex, and birth weight. Results:Of the 5,357 children in this cohort, 593 received general anesthesia before age 4 yr. Compared with those not receiving anesthesia (n = 4,764), a single exposure to anesthesia (n = 449) was not associated with an increased risk of LD (hazard ratio = 1.0; 95% confidence interval, 0.79–1.27). However, children receiving two anesthetics (n = 100) or three or more anesthetics (n = 44) were at increased risk for LD (hazard ratio = 1.59; 95% confidence interval, 1.06–2.37, and hazard ratio = 2.60; 95% confidence interval, 1.60–4.24, respectively). The risk for LD increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable) (P = 0.016). Conclusion:Exposure to anesthesia was a significant risk factor for the later development of LD in children receiving multiple, but not single anesthetics. These data cannot reveal whether anesthesia itself may contribute to LD or whether the need for anesthesia is a marker for other unidentified factors that contribute to LD.

Cognitive and Behavioral Outcomes After Early Exposure to Anesthesia and Surgery

BACKGROUND: Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests. METHODS: This was a matched cohort study in which children (N = 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n = 350) before the age of 2 were matched to unexposed controls (n = 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of group-administered tests of cognition and achievement were outcomes. RESULTS: Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26–3.54]), even when accounting for health status. A similar pattern was observed for decrements in group-administered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program. CONCLUSIONS: Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.

Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study.

Metabolic acidosis and changes in serum osmolarity are consequences of 0.9% normal saline (NS) solution administration. We sought to determine if these physiologic changes influence patient outcome. Patients undergoing aortic reconstructive surgery were enrolled and were randomly assigned to receive lactated Ringer’s (LR) solution (n = 33) or NS (n = 33) in a double-blinded fashion. Anesthetic and fluid management were standardized. Multiple measures of outcome were monitored. The NS patients developed a hyperchloremic acidosis and received more bicarbonate therapy (30 ± 62 mL in the NS group versus 4 ± 16 mL in the LR group; mean ± sd), which was given if the base deficit was greater than −5 mEq/L. The NS patients also received a larger volume of platelet transfusion (478 ± 302 mL in the NS group versus 223 ± 24 mL in the LR group; mean ± sd). When all blood products were summed, the NS group received significantly more blood products (P = 0.02). There were no differences in duration of mechanical ventilation, intensive care unit stay, hospital stay, and incidence of complications. When NS was used as the primary intraoperative solution, significantly more acidosis was seen on completion of surgery. This acidosis resulted in no apparent change in outcome but required larger amounts of bicarbonate to achieve predetermined measurements of base deficit and was associated with the use of larger amounts of blood products. These changes should be considered when choosing fluids for surgical procedures involving extensive blood loss and requiring extensive fluid administration.

Attention-Deficit/Hyperactivity Disorder After Early Exposure to Procedures Requiring General Anesthesia

OBJECTIVE To study the association between exposure to procedures performed under general anesthesia before age 2 years and development of attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS Study patients included all children born between January 1, 1976, and December 31, 1982, in Rochester, MN, who remained in Rochester after age 5. Cases of ADHD diagnosed before age 19 years were identified by applying stringent research criteria. Cox proportional hazards regression assessed exposure to procedures requiring general anesthesia (none, 1, 2 or more) as a predictor of ADHD using a stratified analysis with strata based on a propensity score including comorbid health conditions. RESULTS Among the 5357 children analyzed, 341 ADHD cases were identified (estimated cumulative incidence, 7.6%; 95% confidence interval [CI], 6.8%-8.4%). For children with no postnatal exposure to procedures requiring anesthesia before the age of 2 years, the cumulative incidence of ADHD at age 19 years was 7.3% (95% CI, 6.5%-8.1%). For single and 2 or more exposures, the estimates were 10.7% ( 95% CI, 6.8%-14.4%) and 17.9% ( 95% CI, 7.2%-27.4%), respectively. After adjusting for gestational age, sex, birth weight, and comorbid health conditions, exposure to multiple (hazard ratio, 1.95; 95% CI, 1.03-3.71), but not single (hazard ratio,1.18; 95% CI, 0.79-1.77), procedures requiring general anesthesia was associated with an increased risk for ADHD. CONCLUSION Children repeatedly exposed to procedures requiring general anesthesia before age 2 years are at increased risk for the later development of ADHD even after adjusting for comorbidities.

Angiotensin system inhibitors in a general surgical population.

We studied the relationship between the timing of discontinuing chronic angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor subtype 1 antagonists (ARA) and hypotension after the induction of general anesthesia in a general surgical population. We retrospectively studied 267 hypertensive patients receiving chronic ACEI/ARA therapy undergoing elective noncardiac surgery under general anesthesia. During preoperative visits, patients were asked to either take their last ACEI/ARA therapy on the morning of surgery or withhold it up to 24 h before surgery. The number of hours from the last ACEI/ARA dose to surgery was recorded during the preoperative interview. Electronic medical and anesthesia records were reviewed for comorbidities, type and dose of anesthetics used, intraoperative hemodynamics, IV fluids, perioperative vasopressor administration, and rate of severe postoperative complications. Arterial blood pressure (BP) and heart rate were recorded during the 60-min postinduction period, and hypotension was classified as moderate (systolic BP ≤85 mm Hg) and severe (systolic BP ≤65 mm Hg). We analyzed all variables separately for patients who took their last ACEI/ARA therapy <10 h and ≥10 h before surgery. During the first 30 min after anesthetic induction, moderate hypotension was more frequent in patients whose most recent ACEI/ARA therapy was taken <10 h (60%) compared with those who stopped it ≥10 h (46%) before induction (P = 0.02). The adjusted odds ratio for moderate hypotension was 1.74 (95% confidence interval, 1.03–2.93) for those who took their ACEI/ARA therapy <10 h before surgery (P = 0.04). There were no differences between groups in the incidence of severe hypotension, nor was there a difference in the use of vasopressors. During the 31–60 min after induction, the incidence of either moderate (P = 0.43) or severe (P = 0.97) hypotension was similar in the two groups. No differences in postoperative complications were found between groups. In conclusion, discontinuation of ACEI/ARA therapy at least 10 h before anesthesia was associated with a reduced risk of immediate postinduction hypotension.

Perioperative cardiac arrests in children between 1988 and 2005 at a tertiary referral center: A study of 92,881 patients

Background:The objective of this study was to determine the incidence and outcome of perioperative cardiac arrest (CA) in children younger than 18 yr undergoing anesthesia for noncardiac and cardiac procedures at a tertiary care center. Methods:After institutional review board approval (Mayo Clinic, Rochester, Minnesota), all patients younger than 18 yr who had perioperative CA between November 1, 1988, and June 30, 2005, were identified. Perioperative CA was defined as a need for cardiopulmonary resuscitation or death during anesthesia care. A cardiac procedure was defined as a surgical procedure involving the heart or great vessels requiring an incision. Results:A total of 92,881 anesthetics were administered during the study period, of which 4,242 (5%) were for the repair of congenital heart malformations. The incidence of perioperative CA during noncardiac procedures was 2.9 per 10,000, and the incidence during cardiac procedures was 127 per 10,000. The incidence of perioperative CA attributable to anesthesia was 0.65 per 10,000 anesthetics, representing 7.5% of the 80 perioperative CAs. Both CA incidence and mortality were highest among neonates (0–30 days of life) undergoing cardiac procedures (incidence: 435 per 10,000; mortality: 389 per 10,000). Regardless of procedure type, most patients who experienced perioperative CA (88%) had congenital heart disease. Conclusion:The majority of perioperative CAs were caused by factors not attributed to anesthesia, in distinction to some recent reports. The incidence of perioperative CA is many-fold higher in children undergoing cardiac procedures, suggesting that definition of case mix is necessary to accurately interpret epidemiologic studies of perioperative CA in children.

Anesthesia for Cesarean Delivery and Learning Disabilities in a Population-Based Birth Cohort

Background:Anesthetics administered to immature brains may cause histopathological changes and long-term behavioral abnormalities. The association between perinatal exposure to anesthetics during Cesarean delivery (CD) and development of learning disabilities (LD) was determined in a population-based birth cohort. Methods:The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976–1982 and remaining in the community at age 5 were reviewed to identify those with LDs. Cox proportional hazards regression was used to compare rates of LD between children delivered vaginally and via CD (with general or regional anesthesia). Results:Of the 5,320 children in this cohort, 497 were delivered via CD (under general anesthesia n = 193, and regional anesthesia n = 304). The incidence of LD depended on mode of delivery (P = 0.050, adjusted for sex, birth weight, gestational age, exposure to anesthesia before age 4 yr, and maternal education). LD risk was similar in children delivered by vagina or CD with general anesthesia, but was reduced in children receiving CD with regional anesthesia (hazard ratio = 0.64, 95% confidence interval 0.44 to 0.92; P = 0.017 for comparison of CD under regional anesthesia compared to vaginal delivery). Conclusion:Children exposed to general or regional anesthesia during CD are not more likely to develop LD compared to children delivered vaginally, suggesting that brief perinatal exposure to anesthetic drugs does not adversely affect long-term neurodevelopmental outcomes. The risk of LD may be lower in children delivered by CD whose mothers received regional anesthesia.

Predictors of survival following Cardiac arrest in patients undergoing noncardiac surgery: A study of 518,294 patients at a tertiary referral center

Background The authors determined the incidence of cardiac arrest and predictors of survival following perioperative cardiac arrest in a large population of patients at a tertiary referral center. Methods Medical records of patients who experienced cardiac arrest in the perioperative period surrounding noncardiac surgery between January 1, 1990, and December 31, 2000, were reviewed. Logistic regression identified characteristics associated with immediate (≥ 1 h) and hospital survival, with P ≤ 0.01 considered statistically significant. Results Cardiac arrest occurred in 223 of 518,294 anesthetics (4.3 per 10,000) during the study period. Frequency of arrest for patients receiving general anesthesia decreased over time (7.8 per 10,000 during 1990–1992; 3.2 per 10,000 during 1998–2000). The frequency of arrest during regional anesthesia (1.5 per 10,000) and monitored anesthesia care (0.7 per 10,000) remained consistent. Immediate survival after arrest was 46.6%, and hospital survival was 34.5%. Twenty-four patients (0.5 per 10,000) had cardiac arrest related primarily to anesthesia. From multivariate analysis, patients who experienced arrest due to bleeding were less likely to survive hospitalization (P = 0.001). Survival was also lower for patients who experienced arrest during nonstandard working hours (P = 0.006) and for patients who had protracted hypotension before arrest (P < 0.001). Conclusions The overall frequency of arrest for patients receiving anesthesia decreased during the study period. Most arrests were not due to anesthesia-related causes, and most patients experiencing anesthesia-related arrest survived to hospital discharge. Although many factors determining survival may not be amenable to modification, the fact that arrests during nonregular working hours had worse outcomes may indicate that the availability of human resources influences survival.

The Use of Bovine Hemoglobin Glutamer-250 (hemopure®) in Surgical Patients: Results of a Multicenter, Randomized, Single-blinded Trial

Hemoglobin-based oxygen carrier-201 (HBOC-201, hemoglobin glutamer-250 [bovine], Hemopure®; Biopure Corporation, Cambridge, MA) is polymerized hemoglobin of bovine origin being developed as an oxygen therapeutic. In this study, we evaluated the tolerability of a single intraoperative dose of HBOC-201 in surgical patients. In a single-blinded, multicenter study, 81 patients were randomized to receive either a single infusion of HBOC-201 (55 patients) or an equivalent volume of lactated Ringer’s solution (26 patients). Forty-two patients originally assigned to the HBOC-201 group received the entire planned treatment of only one of the following doses: 0.6, 0.9, 1.2, 1.5, 2.0, or 2.5 g/kg of body weight. Thirteen of the 55 patients in the HBOC-201-assigned group did not reach the trigger point for transfusion administration, and they were not included in the analysis. We studied clinical outcomes and compared hematologic findings, blood chemistry values, and blood use in the two treatment groups. There were no patient deaths in this study. No pattern of clinically significant laboratory abnormalities could be attributed to exposure to HBOC-201. In the HBOC-201 group, 2 patients had a transient increased concentration of serum transaminases and 6 had transient skin discoloration. One patient in the HBOC-201 group had mast cell degranulation with hypotension. Postoperatively, methemoglobin plasma concentrations increased in the HBOC-201 group in a dose-dependent manner, reaching maximal values of 3.7% ± 3.2% (average of all doses given) on postoperative day 3. There was no difference in the mean number of allogeneic blood units transfused in the 2 groups (3.3 ± 1.8 and 3.7 ± 4.1 for the lactated Ringer’s solution and HBOC-201 groups, respectively) over the course of hospitalization. The intraoperative administration of HBOC-201, up to a maximum of 245 g, was generally well tolerated. There was no relationship between HBOC-201 use and the number of allogeneic blood units transfused over the entire hospitalization course. The administration of HBOC-201 was associated with a delayed (third postoperative day) dose-dependent increase in the plasma methemoglobin concentration. We conclude that the intraoperative use of HBOC-201 was generally well tolerated.

The Impact of Morbid Obesity, Pneumoperitoneum, and Posture on Respiratory System Mechanics and Oxygenation During Laparoscopy

We studied the effect of morbid obesity, 20 mm Hg pneumoperitoneum, and body posture (30° head down and 30° head up) on respiratory system mechanics, oxygenation, and ventilation during laparoscopy. We hypothesized that insufflation of the abdomen with CO2 during laparoscopy would produce more impairment of respiratory system mechanics and gas exchange in the morbidly obese than in patients of normal weight. The static respiratory system compliance and inspiratory resistance were computed by using a Servo Screen pulmonary monitor. A continuous blood gas monitor was used to monitor real-time Paco2 and Pao2, and the ETco2 was recorded by mass spectrometry. Static compliance was 30% lower and inspiratory resistance 68% higher in morbidly obese supine anesthetized patients compared with normal-weight patients. Whereas body posture (head down and head up) did not induce additional large alterations in respiratory mechanics, pneumoperitoneum caused a significant decrease in static respiratory system compliance and an increase in inspiratory resistance. These changes in the mechanics of breathing were not associated with changes in the alveolar-to-arterial oxygen tension difference, which was larger in morbidly obese patients. Before pneumoperitoneum, morbidly obese patients had a larger ventilatory requirement than the normal-weight patients to maintain normocapnia (6.3 ± 1.4 L/min versus 5.4 ± 1.9 L/min, respectively;P = 0.02). During pneumoperitoneum, morbidly obese, supine, anesthetized patients had less efficient ventilation: a 100-mL increase of tidal volume reduced Paco2 on average by 5.3 mm Hg in normal-weight patients and by 3.6 mm Hg in morbidly obese patients (P = 0.02). In conclusion, respiratory mechanics during laparoscopy are affected by obesity and pneumoperitoneum but vary little with body position. The Pao2 was adversely affected only by increased body weight.