Abstract
Background
The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multi-site, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at five years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension.
Methods
722 infants ≤ 60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine RA or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born < 26 weeks’ gestation. Moderate hypotension was defined as mean arterial pressure (MAP) measurement of < 35 mm Hg. Any hypotension was defined as mean arterial pressure (MAP) of <45 mm Hg. Epochs were defined as a 5 minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol (APP).
Results
The relative risk of general anesthesia compared with regional anesthesia predicting any measured hypotension<35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (CI 2.0, 4.1, p value <0.001) by ITT analysis and 4.5 (CI 2.7,7.4, p value <0.001) by APP analysis In the GA group 87% and 49% and in the RA group 41% and 16% exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA vs. RA), weight at the time of surgery and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (Relative Risk 2.8, 95% CI:1.7,4.4 by ITT).
Conclusions
RA reduces the incidence of hypotension and chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.
Keywords: Anesthesia, General, Anesthesia, Spinal, Blood Pressure, Infant
Introduction
It is estimated that over 6 million general anesthetics are administered to young children worldwide annually.(1,2) Several studies have demonstrated an association between surgery in infancy and increased risk of poor neurobehavioral outcome, although the reason for this association is unclear.(3–5) Since many general anesthetics cause neurotoxicity in young animals, there is concern that general anesthetics maybe neurotoxic to infants.(6–8) Apart from neurotoxicity, there may be other modifiable peri-operative factors which impact on long term neurocognitive outcome, among them hypotension.(9)
The General Anesthesia compared to Spinal anesthesia (GAS) study, a prospective randomized equivalence trial, which was designed to determine whether GA and RA have similar long-term effects on the developing brain.(10) In this study, 722 infants undergoing inguinal herniorrhaphy were randomized to regional anesthesia (RA) or general anesthesia (GA). The apnea, interim 2 year neurocognitive and summary blood pressure data have been recently published elsewhere.(10–12) The hypothesis of this study is that moderate hypotension is more common in infants undergoing general anesthesia compared to infants undergoing regional anesthesia as measured by the incidences of moderate hypotension. Secondary aims were to compare duration of hypotension and the incidence of interventions to treat it, and identify factors associated with hypotension.
Methods
This manuscript adheres to the applicable Equator guidelines. The GAS study is registered in Australia and New Zealand at ANZCTR: ID# ACTRN12606000441516 first registered on 16th October 2006, Principal Investigators Andrew Davidson, Mary Ellen McCann and Neil Morton; in the USA at ClinicalTrials.gov: ID#: NCT00756600 first registered on 18th September 2008, Principal Investigators Andrew Davidson, Mary Ellen McCann and Neil Morton; and in UK at UK Clinical Research Network (UKCRN) ID#: 6635 (ISRCTN ID#: 12437565; MREC No: 07/S0709/20) Principal Investigator Neil Morton. A summary of the protocol for the GAS study is available on line.
Study participants
After institutional review board approval from each site and written informed consent from parents or guardians, infants were enrolled. (Table 1) Recruitment began in 2007 and ended in 2013. Eligibility criteria included infants up to 60 weeks’ postmenstrual age (PMA) undergoing inguinal herniorrhaphy (with or without circumcision)born at greater than 26 weeks’ gestation. Exclusion criteria included contraindications for either anesthetic technique, history of heart disease requiring surgery or pharmacotherapy, mechanical ventilation immediately prior to surgery, known chromosomal or congenital abnormalities known to affect neurodevelopment, previous exposure to volatile GA or benzodiazepines as a neonate or in the third trimester in utero, known neurologic injury such as cystic peri-ventricular leukomalacia or grade three or four intra-ventricular hemorrhage, and social or geographic factor or language barriers that made follow up difficult. Eligible infants were identified from operating room schedules and preadmission clinics.
Table 1.
Baseline demographic anesthetic and surgical data.
| Demographics | RA arm as intention to treat N=361 |
GA arm as intention to treat N=358 |
RA arm as per protocol N=286 |
|---|---|---|---|
| Male gender | 294 (81.7%) | 306 (85.5%) | 231 (80.8%) |
| Gestational age at birth (days) | 248.3 (28.5) | 248.6 (27.2) | 248.2 (28.7) |
| Chronological age at surgery (days)* | 70.1 (31.8) | 71.0 (31.7) | 68.9 (30.9) |
| Post menstrual age at surgery (days)* | 318.3 (32.6) | 319.5 (32) | 317.1 (32.0) |
| Birth weight (kg) | 2.4 (0.9) | 2.3 (0.9) | 2.3 (0.9) |
| Weight at time of surgery (kg)* | 4.2 (1.1) | 4.3 (1.1) | 4.2 (91.1) |
| Median Apgar at 1 minute | 9 (7–9) | 9 (7–9) | 9 (7–9) |
| Median Apgar at 5 minutes | 9 (9–10) | 9 (9–10) | 9 (9–10) |
| Ever ventilated with a tracheal tube | 47 (13.1%) | 45 (12.6%) | 37 (12.9%) |
| Ever required supplemental oxygen | 95 (26.4%) | 81 (22.6%) | 76 (26.6%) |
| Supplemental oxygen immediately prior to surgery* | 6 (1.7%) | 6 (1.7%) | 4 (1.4%) |
| Electronic monitoring for apnea in previous 24 hr | 17 (4.7%) | 17 (4.8%) | 13 (4.6%) |
| Observed apnea previous 24 hrs * | 6 (1.7%) | 8 (2.2%) | 6 (2.1%) |
| Fasting time (mins)* | 368.2 (146.4) | 367.3 (155.1) | 370.7 (152.6) |
| Pre-operative intravenous fluid* | 46 (12.8%) | 45 (12.6%) | 36 (12.6%) |
| Hemoglobin (g.100ml)* | 10.3 (2.1) | 10.2 (2.0) | 10.3 (2.0) |
| Baseline oxygen saturation | 99 (98–100) | 99 (98–|100) | 99 (98–100) |
| Baseline heart rate | 152.4 (19.7) | 149.9 (16.3) | 153.4 (19.9) |
| Surgical details* | |||
| Bilateral hernia exploration/repair | 162 (45.9%) | 161 (45.4%) | 127 (44.4%) |
| Surgery time: from knife to skin to last stitch (mins) | 28.0 (20–38) | 28 (20–40) | 26.0 (19–35) |
| Anesthesia details* | |||
| Anesthesia time: from start skin prep for regional or induction of GA, to out of operating theatre (mins) | 51.0 (40–69) | 66 (51.5–84.5) | 46.5 (39–61) |
| Suxamethonium | 0 | 1 (0.3%) | 0 |
| Non depolarising neuromuscular blocker | 20 (5.5%) | 125 (34.9%) | 0 |
| Spinal without caudal* | 222 (64%) | 0 | 193 (67%) |
| Caudal without spinal* | 7 (2%) | 332 (93.3%) | 4 (1%) |
| Caudal plus spinal* | 117 (34%) | 0 | 89 (31%) |
| Ilioinguinal block | 3 (0.8%) | 16 (4.5%) | 2 (0.7%) |
| Field block | 51 (14.4%) | 40 (11.2%) | 36 (12.6%) |
| Laryngeal mask airway used | 7 (2.0%) | 60 (16.9%) | 0 |
| Tracheal tube used | 40 (11.3%) | 281 (79.4%) | 0 |
| Minimum systolic blood pressure (mmHg) | 70·7 (15·3) | 54·8 (11·7) | 73·2 (14·3) |
Data presented as mean and standard deviation or median and interquartile range or frequencies and percentage of non-missing data.
Note these data refer to all cases where the listed blocks were attempted before the start of surgery whether the blocks were effective or not. GA as per protocol data are not presented as only two children in the GA arm had surgery cancelled, so the data is very similar to the intention to treat data.
ECG= electrocardiogram; GA= general anesthesia; IQR=interquartile range; RA=regional anesthesia.
Randomization and blinding
A 24-hour web-based randomization was managed by The Data Management & Analysis Centre, Department of Public Health, University of Adelaide, South Australia. Children were randomized with a 1:1 allocation ratio to either RA or GA by random permuted blocks of two or four and stratified by site and gestational age at birth: 26 to 29 weeks and 6 days, 30 to 36 weeks and 6 days, and 37 weeks and more.
Procedures
Patients in the RA arm received regional anesthesia: either spinal, spinal with caudal, spinal with ilioinguinal nerve block, or caudal block. The anesthetic used was bupivacaine or levobupivacaine. Some patients received caudal chloroprocaine intra-operatively to prolong the block. In the RA arm, any sedation or GA given was considered a protocol violation. Oral sucrose drops were permitted in the RA arm and acetaminophen (paracetamol) in both arms. Those in the GA arm received sevoflurane in air/oxygen for induction and maintenance along with neural blockade via caudal or ilioinguinal block with bupivacaine or levobupivacaine. Airway support and use of neuromuscular blocking agents was not standardized. No opioids or nitrous oxide were allowed intra-operatively. Blood pressure, heart rate, oxygen saturation, endtidal CO2 and temperature were recorded every 5 minutes intra-operatively. Because there was no airway management standardization within this study, end tidal CO2 measurements were considered unreliable. These measurements were recorded on the Case Report Forms by a research assistant and in the anesthesia record. A blood glucose measurement was obtained perioperatively.
The pre-specified primary outcome for this analysis was at least one epoch of observed moderate hypotension. Secondary outcomes include observation of at least one epoch of observed any hypotension; at least three epochs of moderate hypotension, at least three epochs of any hypotension and average intraoperative MAP as well as interventions done for blood pressures less than 80% of baseline. Moderate hypotension and any hypotension was defined as single or multiple measures of MAP of <35 mm Hg and MAP of <45 mm Hg, respectively. NIRS and Doppler evidence demonstrates that cerebral blood flow decreases at MAPs <45 mm Hg and cerebral oxygenation decreases at MAPs <35 mm Hg in infants <6 months undergoing sevoflurane anesthesia.(13) An epoch was defined as a single intraoperative measurement representing a 5 minute period. Multiple measures within a 5 minute period were averaged. Mean arterial pressures were calculated from the formula ((systolic BP) +2(diastolic BP))/3. Cuff position (calf vs arm) was not adjusted for because there is less than a 1 mm Hg difference between calf and arm pressures in infants less than 3 months of age.(14,15) Cuff size was determined by choice of a cuff width that was between 2/3 the length of either the humerus, femur or tibia depending on the limb. Baseline blood pressure measurements were the first blood pressure measured in the operating room. Intraoperative and PACU interventions for blood pressure greater than 20% below baseline included lactated Ringer’s bolus of 20 milliliters/kilogram and vasoactive medications at the discretion of the anesthesiologist.
Prolonged hypotension was defined as 3 or more consecutive epochs of MAP <35 mm Hg. Any hypotension and moderate hypotension rates were analyzed in three time periods: anesthesia time: time from the start of the anesthesia to time of leaving the operating room (primary analysis); pre-incision time: time from the start of anesthesia to incision and surgical time: time between knife to skin and last stitch. The level of intervention for intraoperative hypotension was also noted. A significant intervention was defined a-priori as a fluid bolus or the administration of a vasoactive substance.
Statistical Analysis
Analysis populations
The primary analysis is reported as intention to treat (ITT) excluding participants who withdrew consent or were randomized after surgery. A secondary analysis was performed as per-protocol (APP), which excludes cases where surgery was cancelled, and in the RA arm, any child who received any sevoflurane or sedative medication.
Data analysis
For occurrence of moderate and any hypotension, a comparison between GA and RA groups is presented as a relative risk (RR) estimated using the generalized estimating equation (GEE) approach, assuming binomially distributed outcome data, and applying a log link function and robust standard errors in Stata 13 (Stata Corp LP., USA). A fixed effect was fitted for each group and gestational age (treated as a continuous outcome) and an exchangeable correlation was assumed between observations within the same site. It is noted in the results where the GEE approach did not converge, and an alternative, more conservative method was applied.
For average MAP, a comparison between GA and RA groups is presented as a difference in means as estimated from a 3-level random intercept model, where site is the top level, individual is the second level and observation within individual is the third level, using xtmixed with maximum likelihood estimation in Stata 13 (Stata Corp LP., USA). A random intercept is fit to each randomization site and individual, and a fixed effect is fit for each group and gestational age. The residual errors within each individual were assumed to have an autoregressive structure of order 4, to account for the expected autocorrelation between successive blood pressure measurements. An order of 4 was chosen by performing a likelihood ratio test between models fit with successive orders of autogression for observations in the anesthesia time period, and selecting the highest order where p<0.05. All estimates are presented with 95% confidence intervals (CIs) and two-sided p-values As a further secondary analysis we aimed to identify risk factors for prolonged hypotension (3 or more consecutive epochs <35 mm Hg). Prolonged hypotension was chosen instead of any hypotension because the outcomes are likely to be more severe. The following risk factors for prolonged hypotension (3 or more consecutive epochs <35 mm Hg) were identified a-priori: chronological age, gender, weight at time of surgery, postmenstrual age at time of surgery, gestational age at birth, preoperative fasting time, preincisional times, intraoperative temperature (mean and minimum values) and duration of surgery. These risk factors were chosen by previous research and consensus by and clinical expertise of the authors.
To assess the strength of association of each risk factor with prolonged hypotension we present estimates from: a tri-variable model as described in Data Analysis, including allocated study group and gestational age in addition to the risk factor of interest; and a full multivariable model containing all risk factors of interest. Prior to constructing the full multivariable model we assessed the set of risk factors for multicollinearity by visual inspection of two way scatterplots and by calculating the variance inflation factors. We determined that only one factor in the following sets of factors could be estimated in the full model: mean intraoperative temperature and minimum intraoperative temperature; and weight at surgery, PMA at surgery and chronological age at surgery. We selected the factor with the strongest tri-variable association for the full model.
Sample size considerations
The sample size for the GAS study was based on the 5 year neurodevelopmental outcome.(11)
In line with CONSORT recommendations, post-hoc power calculations were not done and instead results are presented with confidence intervals, which capture the uncertainty in our findings that reflect the sample size.
For our sample size of 709, the observed reduction in moderate hypotension from 49% to 16% in the GA and RA arms respectively can be estimated with a 95% confidence interval of 2.4 to 4.1 for relative risk, using an unadjusted two-sample χ2 proportions test. The confidence intervals presented in the Results differ because our analysis accounts for the randomization stratification factors, and non-independence between observations taken within the same site.
Results
722 infants were recruited into the trial (see figure 1). For the ITT analysis 355 were in the RA arm and 356 in the GA arm (figure 1). Baseline, demographic, anesthetic and surgical data are summarized in table 1. There were 394 premature infants and 325 term infants. In the RA arm 70 patients had a protocol violation involving exposure to sevoflurane or sedation; 10 patients were converted to GA with no block attempted, 23 had a partially successful RA but required sedation after incision and 37 had a regional block attempted but were converted to GA before incision. Thus for the APP analysis 286 were in the RA arm and 356 in the GA arm. There was no hypoglycemia noted in any of the infants. There were no infants with patent ductus arteriosus or other conditions known to alter blood pressure at the time of surgery. Most of the GA group also received concurrent caudal blocks for intra and postoperative analgesia. The mean end-expiratory sevoflurane concentration measured in the GA group was 2.6 (0.7) %.
Figure 1. Consort flow diagram.
Of the 70 protocol violations in the RA arm, 10 infants had a full GA with no awake regional attempted, 37 had a full GA after complete block failure, and 23 infants had a partly successful block requiring a short period of GA or sedation. Participants who withdrew consent (n=1) or were randomized after surgery (n=2) were excluded from the intention-to-treat analyses. GA=general anesthesia, RA =regional anesthesia.
MAP was not measured in 14% of epochs in the RA group and 15% in the GA group. The missing data occurred mostly at the beginning and end of cases. MAP was missing for 32% of the first three epochs after the start of anesthesia in both the GA and RA groups, while in the last epoch 33% of GA and 23% of RA cases were missing MAP. Furthermore, in 71% of GA cases the first MAP measurement was taken in the 10 minutes after the start of anesthesia, compared to 51% of RA cases. The initial baseline MAP for the GA group was 59 mm Hg and 62 mm Hg for the RA group by ITT and 61 mm Hg for the RA group by APP.
The relative risk of general anesthesia compared with regional anesthesia predicting any measured hypotension <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (CI 2.0, 4.1, p value <0.001) by ITT analysis and 4.5 (CI 2.7,7.4, p value <0.001) by APP (Table 4). The percentages of infants in the GA group who exhibited any epochs of any and moderate hypotension were 87% and 49% respectively. In the RA group the percentages of infants exhibiting any epochs of any and moderate epochs of hypotension were 41% and 16 % by ITT and 34% and 9% by APP, respectively (Table 2). In the GA group, 15% (54 infants) experienced 5–9 epochs and 8% (28 infants) experienced 10 or more epochs of moderate hypotension with three infants experiencing 15 or more epochs. In the RA group on APP analysis, 8% (22 infants) experienced 1–4 epochs and 2% (5 infants) experienced 5–9 epochs of moderate hypotension. These epochs could be consecutive or nonconsecutive. In the GA group, 18% (63 infants) had prolonged hypotension (3 or more consecutive measurements<35 mm Hg) and in the RA group, 3% (11 infants) by ITT and 0% (1 infant) by APP had prolonged hypotension.
Table 4.
Relative Risks for Hypotension-related outcomes General Anesthesia compared with Regional Anesthesia
| Intention to Treat | As Per Protocol | |||||
|---|---|---|---|---|---|---|
| Outcome | Relative Risk (95% CI) |
P value | Relative Risk (95% CI) |
P value | ||
| Anesthesia Time | AnyHypoten sion | MAP<45 mm Hg (single epoch) a | 2.1 [1.8,2.4] | <0.001 | 2.5 [2.1, 3.0] | <0.001 |
| MAP<45 mm Hg (triple epoch) | 3.5 [2.7,4.4] | <0.001 | 6.8 [4.5, 10.1] | <0.001 | ||
| Moderate Hypotension | MAP<35 mm Hg (single epoch) | 2.8 [2.0, 4.1] | <0.001 | 4.5 [2.7, 7.4] | <0.001 | |
| MAP<35 mm Hg (triple epoch) | 5.1 [2.7,10.1] | <0.001 | 44.7 [6.9,290.1 ] | <0.001 | ||
| Any Intervention for Blood Pressureb | 2.8 [1.7,4.4] | <0.001 | 2.8 [1.7, 4.9] | <0.001 | ||
| Preincision Time | AnyHypoten sion | MAP<45 mm Hg (single epoch) | 2.8 [2.1, 3.6] | <0.001 | 3.6 [2.4, 5.3] | <0.001 |
| MAP<45 mm Hg (triple epoch) | 12.3 [4.8,31.4] | <0.001 | NA | |||
| Moderate Hypotension | MAP<35 mm Hg (single epoch) | 3.4 [2.3, 5.0] | <0.001 | 5.5 [3.1,9.9] | <0.001 | |
| MAP<35 mm Hg (triple epoch) | NA | NA | ||||
| Surgical Time | Any Hypotension | MAP<45 mm Hg (single epoch)a | 2.1 [1.8, 2.5] | <0.001 | 2.6 [2.2,3.1] | <0.001 |
| MAP<45 mm Hg (triple epoch) | 3.0 [2.3, 4.1] | <0.001 | 6.6 [4.4, 9.8] | <0.001 | ||
| Moderate Hypotension | MAP<35 mm Hg | 3.2 [2.2, 4.7] | <0.001 | 5.6 [3.5, 8.9] | <0.001 | |
| MAP<35 mm Hg (triple epoch) | 5.2 [2.4, 11.1] | <0.001 | NA | |||
Estimates of difference between groups presented as relative risk and 95% confidence intervals (95% CI).
Estimate not adjusted for gestational age.
Estimate obtained from generalised linear model using a log-link assuming outcome data follows a binomial distribution and robust standard errors allowing for observations within sites to be clustered.
Table 2.
Outcomes: Frequency of Hypotensive Events during Anesthesia Time and Blood Pressure Estimates by Time Period. Outcome measures are reported in percentage of total patients from each treatment group who exhibited outcome and comparison between RA and GA groups are presented as relative risk (RR) with 95% confidence interval (CI) and p-value. RA number for ITT is 354 rather than 361 because of missing outcome data; there were 5 cancelled surgeries and 1 withdrawal of consent and 1 RA case where no outcome data was collected. GA number for ITT is 355 rather than 358 because there were 2 cancelled surgeries and 1 GA case with missing hemodynamic data.
| Intention to Treat | |||||
|---|---|---|---|---|---|
| Outcome by frequency and by time period |
GA (355) | RA (354) | As per Protocol- RA (286) |
RA to Supplemental GA/Sedation (23) |
RA to Full GA (37) |
| Number of Epochs of Hypotension <35 mm Hg | |||||
| Any Epoch < 35 mm Hg | 49% (175) | 16%(56) | 9% (27) | 22% (5) | 51% (19) |
| 0 | 51% (180) | 84% (298) | 91% (259) | 78% (18) | 49% (18) |
| 1–4 | 26% (93) | 11% (39) | 8% (22) | 17% (4) | 30% (11) |
| 5–9 | 15% (54) | 3% (12) | 2% (5) | 4% (1) | 11% (4) |
| 10–15 | 7% (25) | 1% (3) | 0% (0) | 0% (0) | 5% (2) |
| 15–19 | 1% (3) | 0% (1) | 0% (0) | 0% (0) | 3% (1) |
| 20 or > | 0% (0) | 0% (1) | 0% (0) | 0% (0) | 3% (1) |
| Number of Epochs of Hypotension <45 mm Hg | |||||
| Any Epoch < 45 mm Hg | 87% (309) | 41%(145) | 34% (98) | 52% (12) | 76% (28) |
| 0 | 13% (46) | 59% (209) | 66% (188) | 48% (11) | 24% (9) |
| 1–4 | 20% (72) | 22% (79) | 23% (65) | 17% (4) | 24% (9) |
| 5–9 | 36% (128) | 14% (49) | 10% (29) | 26% (6) | 32% (12) |
| 10–14 | 23% (82) | 4% (13) | 1% (4) | 9% (2) | 14% (5) |
| 15–19 | 6% (20) | 1% (2) | 0% (0) | 0% (0) | 0% (0) |
| 20 or > | 2% (7) | 1% (2) | 0% (0) | 0% (0) | 5% (2) |
Estimate not adjusted for gestational age.
There was strong evidence that the mean MAP for the GA group was 10 mm Hg below the mean MAP for the RA group in each time period (preincision, surgical time, anesthesia time) and type of analysis (ITT, APP)(Table 3). There was strong evidence for increased risk of any hypotension during the anesthesia time period in the GA group in both the ITT population (RR = 2.1, 95% CI:1.8 – 2.4, p <0.001 ), and the APP population (RR = 2.5, 95% CI:2.1 – 3.0, p <0.001 ), and similarly for moderate hypotension (ITT, RR = 4.8, 95% CI:2.0 – 4.1, p <0.001 ; APP, RR = 4.5, 95% CI:2.7 – 7.4, p <0.001) (table 4).
Table 3.
Time period data presented as mean and standard deviation in mm Hg
| Estimates of MAP and HR | |||||
|---|---|---|---|---|---|
| Time Period | GA Mean (SD) |
RA Mean (SD) |
As per Protocol- RA Mean (SD) (286) |
Estimate Difference GA- RA (ITT) |
95% CI |
| Preincision MAP | 43.7 (10.5) | 55.8 (13.7) | 58.2 (13.1) | −12.9 | [−14.5, −11.3]* |
| Preincision HR | 144.6 (15.2) | 159.3 (21.8) | 160.6 (22.1) | −15.4 | [−17.6, −13.2]* |
| Surgical MAP | 40.9 (9.3) | 52.1 (11.6) | 54.2 (10.5) | −12.2 | [−13.6, −10.8]* |
| Surgical HR | 138.3 (14.7) | 146.8 (19.0) | 147.3 (19.2) | −8.9 | [−11.1, −6.7]* |
| Anesthesia MAP | 42.4 (10.2 | 53.0 (12.2) | 55.2 (11.3) | −11.3 | [−12.7, −10.0]* |
| Anesthesia HR | 141.9 (16.3) | 150.9 (20.8) | 151.6 (21.1) | −10.3 | [−12.2, −8.3]* |
ITT=intention to treat, APP= as per protocol,MAP=mean arterial pressure, GA= general anesthesia, RA=regional anesthesia, SD=standard deviation. CI = Confidence Interval.
P value <0.001 Values are unadjusted for gestational age at birth.
In a multivariable prediction model (N=609, 69 events with complete data) the risk of prolonged hypotension was significantly associated with assignment to the GA group (GA RR = 4.63, 95% CI:2.23 – 9.66, p <0.001), lower weight at time of surgery (per kg RR =0.56, 95% CI :0.47 −0.67, p <0.001) and minimum intraoperative temperature (per deg C RR =0.78, 95% CI:0.65 – 0.95, p =0.011). There was no evidence for an association between fasting time, surgical time, and gender (table 5). We note that mean intraoperative temperature and minimum intraoperative temperature; and weight at time of surgery, PMA and chronological age at surgery, were highly associated with each other. As a result, the full model can only estimate the association between one of these factors with prolonged hypotension. The alternative factors provided almost the same strength of association with prolonged hypotension. Each factor may be independently important, but the sample size was too small to estimate these associations reliably.
Table 5.
Relative risk of 3 consecutive epochs of MAP <35 mm trivariable and multivariable model during anesthesia time (time in the room).
| Predictor | Relative risk tri* |
95% CI | P value | Relative risk multi N=609 |
95% CI | P value |
|---|---|---|---|---|---|---|
| General Anesthesia vs Regional Anesthesiaa | 5.62 | 2.60,12.1 | <0.001 | 4.64 | 2.23,9.66 | <0.001 |
| Gestational birth age (days)a | 0.94 | .90,0.98 | 0.009 | 1.01 | 0.97,1.06 | 0.533 |
| Weight at surgery (kg) | 0.60 | 0.49,0.72 | <0.001 | 0.56 | 0.47,0.67 | <0.001 |
| Log Fasting time (1–2.7, 2.7–7.4, 7.4–20 hrs) | 0.95 | 0.65,1.40 | 0.808 | 0.94 | 0.67,1.32 | 0.711 |
| Log Surgery time (1–2.7, 2.7–7.4, 7.4–20 hrs) | 1.27 | 0.78,2.07 | 0.331 | 1.43 | 0.87,2.36 | 0.161 |
| Sex male vs female | 1.05 | 0.59,1.85 | 0.873 | 0.96 | 0.56,1.63 | 0.870 |
| Chronologic Age at surgery (weeks)b | 0.92 | 0.86,0.97 | 0.003 | - | - | - |
| PMA at surgery (weeks)b | 0.92 | 0.86,0.97 | 0.003 | - | - | - |
| Mean Temperature (degrees Celsius)c | 0.73 | 0.51,1.03 | 0.073 | - | - | - |
| Minimum Temperature (degrees Celsius) | 0.74 | 0.60,0.90 | 0.003 | 0.78 | 0.65,0.95 | 0.011 |
Estimates of difference between groups presented as relative risk and 95% confidence intervals (95% CI). Relative risk tri is the ratio of risk for factor of interest plus randomized anesthetic group and gestational age, and includes all non-missing observations. Relative risk multi is the ratio of risk found in a multivariable model.
Bivariable model containing group and gestational age as predictors
Factors were strongly associated with weight at surgery and therefore not included in full model.
Factor was strongly associated with mean temperature and therefore not included in full model. PMA means post menstrual age.
Interventions for hypotension occurred more commonly in the GA group compared with the RA group (19.2% vs 7.3% by ITT and 19.2% vs 6.6% by APP). The most common intervention was a fluid bolus, which accounted for 75% or more of the interventions (Table 6). The relative risk for GA compared to RA predicting an intervention for hypotension were 2.8 (95% CI:1.7 −4.4) by ITT and 2.8 (95% CI:1.7 – 4.9) by APP.
Table 6.
Interventions for Hypotension
| Intervention | GA | RA (ITT) | RA (APP) |
|---|---|---|---|
| Bolus only | 14.4% (51) | 5.6% (20) | 5.2% (15) |
| Vasoactive only | 2.8% (10) | 1.4% (5) | 1.4% (4) |
| Both | 2.0% (7) | 0.3% (1) | 0 (0) |
| Total | 19.2% (68) | 7.3% (26) | 6.6% (19) |
Data presented as percentage of group that was treated. Parentheses represent actual number of patients treated. ITT=intention to treat, APP= as per protocol. GA=general anesthesia, RA=regional anesthesia.
Discussion
In this analysis we found more frequent hypotension in the GA group compared with the RA group. The GA group was more likely to demonstrate any and moderate hypotension for both single measurements and 3 or more consecutive measurements.
There are many different working definitions of hypotension for awake premature and term infants but the acceptable lower limits of blood pressures in neonates and young infants undergoing general anesthesia have not been established.(16,17) Normative data from preterm and term infants reveal a steady increase in blood pressure over the first month of life.(15,18–20) In term infants, the systolic blood pressure at birth averages 62 mm Hg but by one month of age it is >80 mm Hg, representing an increase of almost 30%. (19) The slope for the rise in blood pressure for preterm infants is similar.(20) The rise in calculated MAP over the first month of life is approximately 15% from a mean calculated MAP of 52 mm Hg on day 1 to 61 mm Hg on day 30.(18,19) It is also important to note that the blood pressures of infants born prematurely are higher than those of term infants at 41 weeks post menstrual age.(20) The reasons for this are unclear but may have to do with the inflammatory stress that premature infants endure while developing. These expected blood pressure differences between term and expremature infants highlight the importance of obtaining accurate baseline blood pressures in all infants and neonates before anesthesia.
It is generally believed that maintaining blood pressure within the limits of cerebral autoregulation is optimal for cerebral protection. Several studies have shown that the lower limit of cerebral autoregulation for some infants is indeed fairly close to the definition of MAP hypotension using the infant’s age in postmenstrual weeks, although there is also evidence that some premature infants are able to demonstrate cerebral autoregulation at a MAP level considerably lower than their gestational age in weeks.(21,22) A retrospective analysis of infants less than 6 months of age undergoing sevoflurane anesthesia found that the lower limit of autoregulation was 45 mm Hg but cerebral oxygenation did not decrease until the MAP was less than 35 mm Hg.(13)
Although it is known that hypotension can lead to decreased cerebral perfusion and thus to hypoxic ischemic injury to the brain, there are many unknowns to consider in infants undergoing general anesthesia. First the duration of hypotension that puts infants at risk is unknown. In a small case series of infants less than 3 months of age undergoing general anesthesia between 120 and 180 minutes who did show evidence of perioperative hypoxic ischemic injury, 5 of the 6 patients had a mean intraoperative MAP of less than 35 mm Hg for the entire procedure.(23) It is important to note as previously published, no neurocognitive differences were found in the 2 year interim neurocognitive evaluations between the GA and RA group even though the lowest mean single systolic blood pressures noted in the GA group were below the American Heart Association guidelines for hypotension in neonates at 55 mm Hg.(24,25) Also, studies have shown that a MAP below 35 mm Hg can lead to decreased cerebral perfusion and cerebral oximetry values but there has been no established link between these factors intraoperatively and later neurocognitive outcomes.(13,26) Risk factors for poor neurocognitive outcomes including hypotension and duration of hypotension will be analyzed when the final 5 year neurocognitive outcome assessments are completed.
Other risk factors that were associated with moderate prolonged hypotension were weight at the time of surgery and minimal temperature recorded during the procedure but these effects sizes were small. Weight was a stronger predictor of moderate hypotension than chronological age, postmenstrual age or gestational age at birth. Speculatively, weight might be a proxy for overall health as well as age.
Criteria for either the timing or type of intervention for hypotension in young infants have not yet been developed. In our study, a fluid bolus was administered in approximately 75% of hypotensive episodes; vasoactive agents were the sole therapy in approximately 15% of interventions in the GA group and 21% in the RA group.
Study Limitations
There are several limitations to this study that warrant discussion. The blood pressure values were missing in 14% of our study data, most commonly at the very beginning or end of the case. However, sensitivity analysis of these missing values to include additional hypotensive measurements for the missing values did not alter the direction of the values. The initial measured blood pressures in the RA group occurred later than the initial blood pressure measurements in the GA group, which might have introduced a bias.
Another limitation is that location (calf vs arm) and sizes were not standardized as part of the protocol. Pediatric anesthesiologists conventionally use the rule of 2/3rds; the cuff width should be 2/3 the length of the underlying bone of the limb measured. However, this is not the most accurate method of sizing blood pressure cuffs. Measuring the limb circumference at midpoint and choosing a blood pressure cuff width that is 40% of this circumference is more accurate.(27,28) This may have introduced some nonsystematic bias into the data since the participants are likely to follow the same rule in all patients. The cuff position among patients in the RA group was predominantly the lower limbs. We chose not to adjust for limb placement because there is very little difference in limb blood pressure measurements in infants. However, leg blood pressures are usually slightly lower than arm blood pressures so any bias in our measurements would result in underestimates of the true blood pressure in the regional group. There also was no standardization of the noninvasive blood pressure monitoring systems across the sites however both these factors should have been accounted for by randomization.
Another limitation is that the definitions of hypotension in infants undergoing general anesthesia are not really developed. The blood pressures we considered to indicate hypotension may in fact have been adequate blood pressures for some or all of the infants who exhibited them. In addition, the risks of hypotension to neurodevelopment are presumably duration dependent and “at risk” duration is not known. We arbitrarily chose 3 or more consecutive epochs of moderate hypotension to be important.
In conclusion, a substantial percentage of our patients had calculated mean arterial blood pressures less than 35 mm Hg at some point during their anesthetic and the incidence was much higher for those who received sevoflurane anesthesia. The importance and consequences, particularly on neurodevelopment, of transient intraoperative hypotension during anesthesia in infancy are unknown. The potential for interplay between hypotension and the putative direct effects of general anesthetics on neurodevelopment are especially intriguing. Further consideration and investigation of this issue is warranted.
Acknowledgments
We would like to acknowledge all of these collaborators for their assistance and advice with the GAS study: Mark Fajgman MBBS, FANZCA Department of Anaesthesia, Monash Medical Centre, Melbourne, Australia; Daniela Tronconi RN Department of Anaesthesia, Istituto Giannina Gaslini, Genoa, Italy; David C van der Zee MD, PhD Department of Pediatric Surgery, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, The Netherlands; Jan BF Hulscher MD, PhD Department of Surgery, University Medical Center Groningen, Groningen University, Groningen, The Netherlands; Rob Spanjersberg RN Department of Anaesthesiology, University Medical Center Groningen, Groningen University, Groningen, The Netherlands; Michael J Rivkin MD Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; Michelle Sadler-Greever RN Department of a and Pain Medicine, University of Washington, Seattle, Washington and Department of Anaesthesia and Pain Medicine, Seattle Children's Hospital, Seattle, Washington; Debra Faulk MD Department of Anaesthesiology, Children's Hospital Colorado, Denver, Colorado and Department of Anaesthesiology, University of Colorado School of Medicine, Denver, Colorado; Danai Udomtecha MD, Sarah Titler MD, Susan Stringham RN, Pamela Jacobs RN and Alicia Manning AND Department of Anaesthesia, The University of Iowa Hospital and Clinics, Iowa City, Iowa; Roxana Ploski BS and Alan Farrow-Gillespie MD Department of Anaesthesiology, Children’s Medical Center Dallas, Dallas, Texas and Department of Anaesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas and Dallas and Children's Medical Center at Dallas and Outcome Research Consortium, Dallas, Texas; Timothy Cooper MA, PsyD Division of Developmental Medicine & the Center for Child Development, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, Tennessee; Elizabeth Card MSN, APRN, RN, FNP-BC, CPAN, CCRP Perioperative Clinical Research Institute, Vanderbilt University Medical Center, Nashville, Tennessee; Wendy A Boardman BA Department of Anaesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Theodora K Goebel RN, BSN, CCRC Department of Anaesthesiology and Critical Care Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Funding Institutions:
All hospitals and centers were generously supported by anaesthesiology departmental funding. In addition to this funding, specific grants received for this study are as follows:
Australia and New Zealand: The Australian National Health & Medical Research Council, Canberra, Australian Capital Territory, Australia; Australian and New Zealand College of Anaesthetists, Melbourne, Victoria, Australia; Murdoch Children’s Research Institute, Melbourne, Victoria, Australia. This study was supported by the Victorian Government’s Operational Infrastructure Support Program in Melbourne, Victoria, Australia; Department of Anaesthesia and Pain Management, Royal Children’s Hospital, Melbourne, Victoria, Australia; Department of Anaesthesia, Monash Medical Centre, Melbourne, Victoria, Australia; Department of Anaesthesia and Pain Management, Princess Margaret Hospital Foundation, Perth, Western Australia, Australia; Department of Paediatric Anaesthesia, Women's Children's Hospital, Adelaide, South Australia, Australia and Department of Paediatric Anaesthesia and Operating Rooms, Starship Children's Hospital, Auckland, New Zealand. United States: National Institute of Health, Bethesda, Maryland, United States; Food and Drug Administration, Silver Spring, Maryland, United States; Department of Anaesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Anaesthesia and Pain Medicine, Seattle Children's Hospital, Seattle, Washington, United States; Department of Anaesthesiology, Children's Hospital Colorado, Denver, Colorado, United States; Department of Anaesthesia, University of Iowa Hospital, Iowa City, Iowa, United States; Department of Anaesthesiology, Children's Medical Center Dallas, Dallas, Texas, United States; Department of Pediatric Anaesthesiology, Anne and Robert H. Lurie Children's Memorial Hospital, Chicago, Illinois, United States; Department of Anaesthesiology, Dartmouth Hitchcock Medical Center.
Footnotes
Author’s Contribution:
MEM was involved in study design and concept, conduct, data coordination, contribution to statistical analysis plan, data interpretation, writing and coordinating drafts of the report and revising it critically, and approving of the version to be published. DW was involved in study design and conduct, data acquisition and coordination, data interpretation and revising the report critically. SJA was involved in the development of the statistical analysis plan, data interpretation and revising the report critically, AJD was involved in study design and concept, conduct, data coordination, contribution to statistical analysis plan, data interpretation, writing and coordinating drafts of the report and revising it critically. ND, GF, NSM, GB, DMP, ARA, BS vUS, FI, PS, VY, SS, JCdG were involved in study design and conduct, data acquisition and coordination, data interpretation and revising the report critically. DCB, RWH were involved in study design and conduct, data interpretation and revising the report critically. AL was involved in study conduct, data acquisition and interpretation and revising the report critically.
Disclosure of Funding:
Declaration of Interests:
The authors declare no competing interests.
Conflicts of Interest: None
Trial Registry Number:
The GAS study is registered in Australia and New Zealand at ANZCTR: ID# ACTRN12606000441516 first registered on 16th October 2006, Principal Investigators Andrew Davidson, Mary Ellen McCann and Neil Morton; in the USA at ClinicalTrials.gov: ID#: NCT00756600 first registered on 18th September 2008, Principal Investigators Andrew Davidson, Mary Ellen McCann and Neil Morton; and in UK at UK Clinical Research Network (UKCRN) ID#: 6635 (ISRCTN ID#: 12437565; MREC No: 07/S0709/20) Principal Investigator Neil Morton. The protocol for the GAS study has been previously published by The Lancet.13
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