Abstract
Introduction
Delayed respiratory depression is a feared complication of intrathecal morphine in patients undergoing cesarean delivery. The incidence, timing and risk factors for hypoxia in this population are not known.
Methods
Patients undergoing cesarean delivery under spinal anesthesia at a tertiary care center from October 2012 to March 2016 were included in the study. The Berlin sleep apnea Questionnaire was completed before surgery. Oxygen saturation was recorded every second for 24 hours after the initiation of spinal anesthesia. Desaturation events were defined as a median saturation of <90% (mild) or <85% (severe) across a 30 second period. Multivariable logistic regression was used to determine predictors of a desaturation event.
Results
A total of 721 patients were included in the analysis. Within this cohort, 169 women (23%) experienced at least one mild desaturation event, 91 (13%) experienced two or more mild desaturations, and 26 (4%) suffered a severe desaturation event. After the administration of intrathecal morphine, the median times to first mild or first severe desaturation were 7.4 (IQR 4.1–13.5) h and 12.0 (IQR 5.4–19.6) h, respectively. Patients who screened positive for sleep apnea had increased odds of having a mild desaturation event (OR 2.31, 95% CI: 1.40 to 3.79, P=0.001), as did patients who were obese (OR 1.80, 95% CI 1.05 to 3.09, P=0.033).
Conclusions
Mild hypoxemia occurred frequently in women receiving intrathecal morphine 150 μg for post-cesarean analgesia. Desaturations were observed most frequently 4–8 hours after administration of intrathecal morphine. Obesity and a positive Berlin questionnaire were risk factors for hypoxemic events.
Keywords: Cesarean delivery, Oxygen, pulse oximeter, Oxygen, desaturation, Opioid, intrathecal morphine
Introduction
Intrathecal morphine (ITM) is commonly used for patients undergoing cesarean delivery (CD).1 Although pruritus, urinary retention and nausea are common adverse effects of ITM, delayed respiratory depression is especially concerning, due to its potential for significant morbidity and mortality.2 The incidence of bradypnea associated with ITM for post-cesarean analgesia is reported to be as low as 0–0.26%.3–5 However, the rate estimations provided in these studies may not fully account for the extent of opioid-induced respiratory depression, because respiratory rate was not monitored continuously. In addition, patients may be hypoxic and hypercarbic without exhibiting bradypnea.6
There are limited data on the incidence of hypoxia following ITM in patients undergoing CD because postoperative pulse oximetry is not typically measured. Furthermore, few studies have investigated the impact of patient characteristics, for example obstructive sleep apnea (OSA), on the rate of hypoxia following the administration of neuraxial opioids.7 The physiologic changes of pregnancy may predispose women to OSA.8
Defining populations at risk for hypoxia following ITM may allow for more targeted surveillance through the use of continuous pulse oximetry. The aim of this study was to analyze the timing and incidence of hypoxic events in parturients receiving ITM 150 μg for post-cesarean analgesia, and to identify factors associated with postoperative hypoxia.
Methods
This study was approval by the medical research Ethics Board at Kitasato University School of Medicine (B12-98) and Partners Institutional Review Board, and registered at the UMIN Clinical Trials Registry (UMIN000018487).
Patients undergoing CD under spinal anesthesia at Kitasato University Hospital, a tertiary care center located in Sagamihara, Japan, from October 2012 to March 2016 were considered for inclusion into the study. This included all elective and non-elective cases scheduled between 0745 to 1930 hours. Parturients were included irrespective of gestational age. Women who were American Society of Anesthesiologist’s physical status >2; on supplemental oxygen preoperatively; a non-elective case that prevented obtaining informed consent; undergoing a cesarean hysterectomy or radiological intervention; or administered additional anesthetics or analgesics intraoperatively, other than single-shot spinal anesthesia, were excluded.
Patients were positioned in the right lateral decubitus position and dural puncture was performed at the L3/4 or L4/5 vertebral interspace with a 25- or 27-gauge pencil-point spinal needle. Subsequently, 0.5% hyperbaric bupivacaine 2.4 mL, fentanyl 10 μg and morphine hydrochloride 150 μg were administered. Postoperative pain management was changed during the study time period. From October 2012 to September 2013, a transversus abdominis plane (TAP) block (0.375% ropivacaine 20 mL each side) was performed after surgery unless the patient refused it. At the patient’s request for additional analgesia, flurbiprofen 50 mg (intravenous), diclofenac 50 mg (rectal) and/or pentazocine 15 mg (intramuscular) was administered at the discretion of the obstetrician in charge. From October 2013 to March 2016, a TAP block was performed only when a patient requested it. Acetaminophen 1g (intravenous) and flurbiprofen 50 mg (intravenous) were administered every 8 hours for at least 24 hours after surgery. When the patient requested additional analgesia, flurbiprofen 50 mg (intravenous) and/or pentazocine 15 mg (intravenous) was administered at the discretion of the obstetrician in charge.
Oxygen saturation was recorded every second from the time the patient was transferred to the obstetric ward after surgery until 24 hours after the initiation of spinal anesthesia. The saturation probe was secured with tape on the annular finger of the non-dominant hand. The recording was interrupted when the patient left her bed to see her baby in the neonatal intensive care unit or ambulated on the first postoperative day. Data were recorded and stored in the pulse oximeter (Nellcor Oximax N-600X, Covidien Co. Japan) set at the patient’s bedside and clinicians were able to see these readings. The pulse oximeter was programmed to alarm when the pulse rate was >140 beats/min or <40 beats/min or SatSeconds™ (Covidien Co. Japan) exceeded 50. SatSeconds™ is calculated by (90-SpO2) × time (s). Interventions in the event of low oxygen saturation (SpO2) were not dictated by protocol, but were noted on the medical record. Patients who received supplemental oxygen were excluded from the analysis.
Demographic information collected included patient age, height and weight; and time of operation. The Berlin Questionnaire was administered to patients before surgery. Data extracted from the medical record included past history, a diagnosis of preeclampsia, administration of magnesium or ritodrine, and interventions in the event of low SpO2.
The median oxygen saturation was calculated for overlapping 30-second intervals within the 24 hour period. If the median oxygen saturation was less than 90% in a 30 second window, then the patient was considered to have a mild desaturation event. The duration of a desaturation event was defined as the number of contiguous windows in which the median was less than 90%. Additionally, if the median oxygen saturation was less than 85% in a particular window, then the patient was considered to have a severe desaturation event, with the duration calculated in the same manner. These values were selected based on their use in prior studies.9,10 If more than half of the oxygen saturation measurements were deemed by the machine to be artifact or of poor quality, then the window was excluded from the analysis. The definition and algorithm to determine whether a reading was artifactual is propriety company information, and not publically available.
Unadjusted univariate analysis was undertaken and differences between the groups were tested using t-tests for continuous variables and chi-square tests for categorical variables. Multivariable logistic regression was used to determine predictors of having a hypoxic event. The predictors included in the model were advanced maternal age (defined as age >35, obesity (defined as a body mass index [BMI] >30 kg/m2), afternoon surgery, a positive result on the Berlin Questionnaire, whether the patient had a diagnosis of preeclampsia, and if the patient had received a TAP block, ritodrine or magnesium. Potential predictors were defined prior to analyzing the data and all covariates were included in the model without further selection. Statistical tests were two-tailed and a P value of <0.05 was considered to be significant. All analyses were performed in Stata (version 12; StataCorp, College Station, TX, USA).
Results
Eight-hundred-and-thirty-two of 838 patients consented to participate in the study. Patients were excluded for having a saturation recording failure (n=31) or requiring intraoperative anesthetics or analgesics during surgery (n=33). Interventions for low SpO2 included encouragement of breathing and supplemental oxygen. All patients who were encouraged to breathe were given oxygen. Eighteen patients (six of whom had preeclampsia) received oxygen postoperatively and were excluded from analysis. A patient flowchart is shown in Fig. 1. After exclusions, 721 patients were included in the analysis and their demographic information is presented in Table 1. Within this cohort, 169 women (23%) experienced at least one mild desaturation event, 91 (13%) experienced two or more mild desaturations, and 26 (4%) suffered a severe desaturation event.
Fig. 1.
Flow chart outlining patient inclusion and exclusion criteria
Table 1.
Baseline characteristics and univariate associations with mild desaturation
| No desaturation | At least one mild desaturation | P-value | |
|---|---|---|---|
| n | 552 | 169 | |
| Age, mean (SD) | 34.1 (5.0) | 34.8 (4.9) | 0.098 |
| Advanced maternal age | 277 (50.2%) | 91 (53.8%) | 0.40 |
| Obese | 49 (8.9%) | 34 (20.1%) | <0.001 |
| BMI, mean (SD) | 25.3 (3.7) | 27.0 (4.7) | <0.001 |
| Preeclampsia | 37 (6.7%) | 8 (4.7%) | 0.35 |
| Afternoon delivery | 169 (30.6%) | 52 (30.8%) | 0.97 |
| Positive Berlin Questionnaire | |||
| category 1 | 112 (20.3%) | 65 (38.5%) | <0.001 |
| Positive Berlin Questionnaire | |||
| category 2 | 67 (12.2%) | 34 (20.1%) | 0.009 |
| Positive Berlin Questionnaire | |||
| category 3 | 113 (20.5%) | 46 (27.2%) | 0.066 |
| Positive Berlin Questionnaire | |||
| overall | 68 (12.3%) | 44 (26.0%) | <0.001 |
| TAP block | 472 (85.5%) | 147 (87.0%) | 0.63 |
| Pentazocine | 10 (1.8%) | 1 (0.6%) | 0.26 |
| Ritodrine | 91 (16.5%) | 23 (13.6%) | 0.37 |
| Magnesium | 21 (3.8%) | 10 (5.9%) | 0.24 |
All values displayed as n (%) unless otherwise specified
SD: standard deviation. BMI: body mass index. TAP: transversus abdominis plane.
After the administration of ITM, the median times to the first mild and severe desaturations were 7.4 h (IQR 4.1–13.5) and 12.0 h (IQR 5.4–19.6), respectively. Fig. 2 displays a histogram showing the time after anesthesia for the first desaturation. There was a similar time trend when examining all desaturation events, with the number of events peaking 4–8 h after anesthesia (Fig. 3). The median duration of mild and severe desaturation was 52 (IQR 45–70) and 47 (IQR 44–55) s, respectively. Desaturations occurred more frequently in the evening hours (Fig. 4).
Fig. 2.
Histogram demonstrating the distribution of the timing of the first event, for both mild and severe desaturation, after the administration of single-shot spinal anesthesia
Fig. 3.
Histogram showing the distribution of all desaturation events, for both mild and severe desaturation, in relation to the administration of single-shot spinal anesthesia.
Fig. 4.
Histogram displaying the distribution of all desaturation events, for mild and severe desaturation, by the time of day. “00” on the x-axis represents midnight.
In univariate analysis, there were no differences in age or time of day of surgery between patients who did and did not experience a desaturation. However, patients who experienced a mild desaturation had a higher BMI, were more likely to be obese and to screen positive on the Berlin Questionnaire. Patients who experienced a severe desaturation were more likely to be positive on category 1 of the Berlin Questionnaire. Tables 1 and 2 describe the characteristics of the study cohort and the differences between the groups.
Table 2.
Baseline characteristics and univariate associations with severe desaturation
| No desaturation | At least one severe desaturation | P-value | |
|---|---|---|---|
| n | 695 | 26 | |
| Age, mean (SD) | 34.3 (5.0) | 34.5 (5.1) | 0.78 |
| Advanced maternal age | 354 (50.9%) | 14 (53.8%) | 0.77 |
| Obese | 77 (11.1%) | 6 (23.1%) | 0.060 |
| BMI, mean (SD) | 25.7 (4.0) | 27.1 (4.7) | 0.082 |
| Preeclampsia | 44 (6.3%) | 1 (3.8%) | 0.61 |
| Afternoon delivery | 212 (30.5%) | 9 (34.6%) | 0.66 |
| BMI, mean (SD) | 25.7 (4.0) | 27.1 (4.7) | 0.082 |
| Positive Berlin Questionnaire | |||
| category 1 | 164 (23.6%) | 13 (50.0%) | 0.002 |
| Positive Berlin Questionnaire | |||
| category 2 | 95 (13.7%) | 6 (23.1%) | 0.18 |
| Positive Berlin Questionnaire | |||
| category 3 | 154 (22.2%) | 5 (19.2%) | 0.72 |
| Positive Berlin Questionnaire | |||
| overall | 106 (15.3%) | 6 (23.1%) | 0.28 |
| TAP block | 596 (85.8%) | 23 (88.5%) | 0.70 |
| Pentazocine | 11 (1.6%) | 0 (0.0%) | 0.52 |
| Ritodrine | 110 (15.8%) | 4 (15.4%) | 0.95 |
| Magnesium | 30 (4.3%) | 1 (3.8%) | 0.91 |
All values displayed as n, (%) unless otherwise specified. SD: standard deviation. BMI: body mass index. TAP: transversus abdominis plane
In multivariable logistic regression analysis, age and an afternoon CD were not significant predictors of having a mild desaturation. Patients who screened positive for OSA had increased odds of having a mild desaturation event (OR 2.31, 95% CI 1.40 to 3.82, P=0.001). Obese patients had an increased odds of having a mild desaturation event (OR 1.80, 95% CI 1.05 to 3.09, P=0.033). There were no statistically significant predictors of having a severe desaturation event in the setting of relatively few events. The point estimate from this analysis suggested a two-fold increase in severe desaturation associated with obesity. The results from the regression analysis are shown in Table 3.
Table 3.
Results of the multivariable logistic regression predicting a desaturation event
| Mild desaturation | Severe desaturation | |||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |
| Advanced maternal age | 1.14 | (0.80 to 1.63) | 0.47 | 1.11 | (0.50 to 2.46) | 0.79 |
| Obese | 1.80 | (1.05 to 3.09) | 0.033 | 2.16 | (0.72 to 6.45) | 0.17 |
| Preeclampsia | 0.43 | (0.19 to 1.01) | 0.053 | 0.51 | (0.06 to 4.08) | 0.53 |
| Afternoon delivery | 0.98 | (0.67 to 1.44) | 0.92 | 1.22 | (0.53 to 2.81) | 0.64 |
| Positive Berlin | 2.31 | (1.40 to 3.82) | 0.001 | 1.31 | (0.43 to 4.00) | 0.62 |
| Questionnaire overall | ||||||
| TAP block | 1.25 | (0.74 to 2.11) | 0.41 | 1.37 | (0.40 to 4.68) | 0.98 |
| Pentazocine | 0.28 | (0.04 to 2.25) | 0.23 | – | ||
| Ritodrine | 0.72 | (0.42 to 1.26) | 0.25 | 0.98 | (0.31 to 3.13) | 0.87 |
| Magnesium | 1.89 | (0.80 to 4.49) | 0.15 | 0.84 | (0.10 to 7.17) | 0.53 |
OR: odds ratio. CI: confidence interval. TAP: transversus abdominis plane
Discussion
In this prospective study of postoperative oxygen saturation, 23% and 4% of parturients undergoing CD with spinal anesthesia containing morphine 150 μg experienced mild and severe desaturation episodes, respectively. Obese and OSA-screen positive patients were more likely to have mild desaturation episodes. No factors were associated with severe desaturation episodes, although the study power for this was limited. Desaturation episodes generally occurred several hours after the administration of ITM and occurred more frequently in the evening hours.
The incidence of desaturation episodes was significantly greater than that reported by Dalchow et al., who found no episodes of desaturation after intrathecal diamorphine 300 μg in women undergoing CD.11 However, their study looked for a sustained desaturation of SpO2 <90% for more than two minutes. In our study, the incidence of desaturation episodes was greater than the number of bradypnea episodes previously described after ITM.3–5 We attribute this to the enhanced detection of episodes due to continuous pulse oximetry, with respiratory rate being a less sensitive measure of respiratory depression than hypoxia and hypercarbia. Our findings are consistent with the 32% incidence of hypercapnic events (transcutaneous CO2 >50 mmHg for ≥2 min) in post-cesarean delivery patients who had received ITM 150 μg.12 Our results are also consistent with other studies in which delayed respiratory depression occurred 4 to 12 hours after the administration of ITM.13,14
Obesity and a positive Berlin Questionnaire were both predictors of having a mild desaturation event. The Berlin Questionnaire, a validated screening tool to detect OSA, consists of three parts related to snoring (category 1), day-time somnolence and fatigue (category 2), and hypertension and obesity (category 3).15 While no factor was associated with severe desaturation, the number of total severe events was likely too low for the number of possible predictors in the regression model. It may be reasonable to infer that those at risk of having a mild desaturation episode are also at increased risk of having a severe desaturation episode, given the point estimate for a severe desaturation episode associated with obesity.
Because desaturation can occur during normal pregnancy, the additional contribution of ITM 150 μg is unclear. The prevalence of OSA (defined as an apnea-hypopnea index ≥5) during the third trimester of pregnancy has been estimated to be 19.7%,16 but the actual prevalence in our population is unknown and may differ by ethnicity and race, which would be relevant to the current study. There have been no investigations, to our knowledge, of post-cesarean desaturation in women not receiving ITM.
While pulse oximeter probe misalignments or desaturation artifacts can occur clinically, we believe these effects to be minimal in our study for several reasons. These include the method of saturation probe attachment, the exclusion of unreliable SpO2 measurements by signal interference and pulse loss indicators, and critical review and adjudication of the medical record.
Our study has several limitations inherent to its design that should be considered when interpreting the results. Firstly, because the pulse oximeter alarmed with patient desaturation, either the sound or a care provider may have aroused the patient, thus reducing the duration and magnitude of hypoxia. Secondly, medical staff was not blinded to oximetry readings and could intervene if oxygen saturation was low. We excluded the 2.5% of patients who were given supplemental oxygen, as this would have interfered with subsequent desaturation episodes. This likely resulted in an underestimation of the incidence of desaturation. Thirdly, this study was performed at a single institution in Japan and therefore the results may not be generalizable to other centers or patient populations. The prevalence of obesity17, OSA, and even sensitivity to ITM may differ in other populations.
The results of this study demonstrate that hypoxia after CD under spinal anesthesia with morphine 150 μg is common. Patients who are obese and screen positive for OSA by the Berlin Questionnaire are at increased risk. The risk of hypoxia seems to be increased several hours after the administration of ITM and during evening hours. Our findings provide some guidance for defining which parturients are at high risk for desaturation and when these patients should be more closely monitored.
Highlights.
In this study, mild desaturation after 150 μg intrathecal morphine was common
Desaturation occurred most frequently 4–8 hours after intrathecal morphine
Obesity and a positive Berlin questionnaire were predictive of mild desaturation
Acknowledgments
Funding
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Footnotes
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