Incidence and Associated Factors for Neuraxial Anaesthesia-Related Hypotension in COVID-19 Parturients Undergoing Caesarean Delivery: A Multicenter Case-Control Study

Background: COVID-19 continues to spread globally and results in additional challenges for perioperative management in parturients. The purpose of this study was to determine the incidence and identify associated factors for neuraxial anaesthesia-related hypotension in COVDI-19 parturients during caesarean delivery. Methods: We performed a multicenter case-control study at 3 medical institutions in Hubei province, China form 1th January to 30th May 2020. All ASA Physical Status II full termed pregnant women who received caesarean delivery under neuraxial anaesthesia were eligible for inclusion. The univariate analysis and binary logistic regression analysis were used to identied the independent predictors of neuraxial anaesthesia-related hypotension. Results: Present study included 102 COVID-19 parturients. The incidence of neuraxial anaesthesia-related hypotension was 58%. Maternal abnormal lymphocyte count (OR = 3.41, p = 0.03), full stomach (OR = 3.22, p = 0.04), baseline heart rate (OR = 1.04, p = 0.03), experience of anaesthetist (OR = 0.86, p = 0.02) and surgeon (OR = 0.76, p = 0.03), and combined spinal-epidural anaesthesia technique (OR = 3.27, p = 0.02) were associated with neuraxial anaesthesia-related hypotension. The area under the receiver operating characteristic curve achieved 0.83 which was signicantly higher than 0.5 (p < 0.001). And the sensitivity, specicity and percentage correct were 75%, 79% and 75%, respectively. The Hosmer-Lemeshow test showed a good calibration of the model (H = 2.01, DF = 8, p = 0.98). Conclusions: Maternal abnormal lymphocyte count, full stomach, baseline heart rate, experience of anaesthetist and surgeon, and combined spinal-epidural anaesthesia technique were identied as the independent predictors of neuraxial anaesthesia-related hypotension. Block-surgery Mann-Whitney


Background
With increased levels of testing and effective contact tracing and isolation, coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is no longer uncontrollable. However, COVID-19 continues to spread globally. Furthermore, modelling studies have suggested a second COVID-19 epidemic wave would occur and peak in the end of 2020 or the beginning of 2021 due to gradual relaxing of test-trace-isolate strategy and reopening of public transport (Malki, Atlam et al., 2020;Panovska-Gri ths, Kerr et al., 2020).
Although the clinical characteristics of COVID-19 parturients is similar with non-pregnant COVID-19 patients (Allotey, Stallings et al., 2020), COVID-19 results in additional challenges for perioperative management in parturients (Zheng, Hebert et al., 2020) and the outcomes of maternal and fetal appeared barely satisfactory (Yu, Li et al., 2020). Based on clinical practices and expert opinions, neuraxial anaesthesia in preference to general anaesthesia for caesarean delivery in COVID-19 parturients (Bhatia, Columb et al., 2020). However, more attention should be focused on neuraxial anaesthesia-related hypotension in COVID-19 parturients.

Design and Setting
We conducted a multicenter case-control study at Renmin Hospital of Wuhan University, Union Hospital A liated to Tongji Medical College of Huazhong University of Science and Technology, and Yichang Central People's Hospital from 1th January to 31th May, 2020. The methodology in this study was based on the international guidelines for observational studies according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 2010 statement (von Elm, Altman et al., 2014). The three medical institutions were designated as the diagnosis and treatment center for COVID-19 patients (including pregnant women) in Hubei province, China. SARS-CoV-2 nucleic acid test was used to screen COVID-19 in all parturients. And the chest CT scan was performed on parturients after delivery.
We planned to collect all ASA Physical Status II full termed pregnant women who received caesarean delivery (ICD-10 codes O82.0-O82.9 and O84.2) under neuraxial anaesthesia. Parturients who had a cesarean delivery after failed vaginal delivery were also included. The exclusion criteria included inadequate blockade (requiring the addition of a general anaesthetic administration) or incomplete data.

Anaesthesia Protocol
Neuraxial anaesthesia techniques was according to the established protocol of institutions. All parturients had an intravenous line placed before anaesthesia puncture. And non-invasive blood pressure (BP), electrocardiograph, pulse oximetry was used from anaesthesia commence to surgery nish. Parturients received puncture procedure in the upright position under strict aseptic precaution and then kept in supine left lateral tilt position until the end of surgery. Sensory block height was assessed bilaterally using loss of cold sensitivity to alcohol every 3 to 5 minutes. All BP recordings in this study were performed with the patient in the supine position.

Data And De nition
The data were independently collected from the electronic medical records using a prefabricated table, and crossed-check by two investigators in each institution. The table mainly addressed maternal variables: age, BMI, gravidity, delivery times, preoperative laboratory parameters (the count of white blood cell and lymphocyte, the concentration of hemoglobin (Hb), C-reactive protein (CRP) and fasting glucose), the count of COVID-19 signs and symptoms, and neonatal weight. anaesthetic and surgical variables were also included: urgency of surgery (emergency or elective), full stomach, baseline heart rate, systolic blood pressure (SBP) and MAP, antiemetic, vasoconstrictor oxytocin and calcium preparation utilization, infusion volume, experience of surgeon and anaesthetist. The other variables were neuraxial anaesthesia technique (epidural anaesthesia (EA), spinal anaesthesia (SA) or combined spinal-epidural anaesthesia (CSE)), site, approach frequency and local complications of anaesthesia puncture, local anaesthetic dose, block-surgery time and sensory block height.
Hypotension was de ned as the SBP below 100 mmHg, the MAP below 80% of the baseline value (the mean of repeated measurements before commencing anaesthesia). Infusion volume over 1000 ml or vasoconstrictor utilization were also considered as the presence of hypotension. Neuraxial anaesthesiarelated hypotension was based on a single episode of de ned hypotension from the time of local anaesthetic injection until 15 minutes after delivery of the newborn. Block-surgery time was de ned as the interval between local anaesthetic injection and skin incision. Experience of surgeon and anaesthetist were de ned as the length of employment.

Statistics
The data was imported to IBM SPSS Statistics 25 for analysis. Outliers of continuous variables were replaced by the value of speci c percentile (5% or 95%) value. Univariate analysis was conducted by the t test, Mann-Whitney U-test, χ 2 test or Fisher's exact test as appropriate. The variables at a two-tailed pvalue ≤ 0.20 in univariate analysis were identi ed and entered into binary logistic regression model by backward elimination (likelihood ratio) method after collinearity test by linear regression with enter method. The model's discriminative power was checked with a receiver operating characteristic (ROC) curve according to the probabilities obtained from binary logistic regression analysis. The goodness model was tested by Hosmer-Lemeshow test. The variables at a two-tailed p-value < 0.05 in the binary logistic regression analysis were considered as the independent associated factors for hypotension in this study.

Results
During the study period, 102 ASA Physical Status II full termed COVID-19 parturients without preoperative comorbidities (such as chronic hypertension and hypertensive disorders of pregnancy) were available ( Fig. 1). Among of them, SBP lower than 100 mmHg was found in 27 parturients and MAP lower than 80% of the baseline value was found in 4 parturients. Twelve parturients received volume infusions more than 1000 ml and 38 parturients were treated with vasoconstrictor. The incidence of neuraxial anaesthesia-related hypotension was 59 (58%) in present study (Table 1). Table 1 The de nition and incidence of neuraxial anaesthesia-related hypotension in COVID-19 parturients undergoing caesarean delivery. Values are presented as number (proportion).

De nition Count
SBP 100 mmHg --- Infusion volume > 1000 ml SBP, systolic blood pressure; MAP, mean arterial blood pressure; baseline value, the mean of repeated measurements before commencing anaesthesia.
All of COVID-19 parturients with neuraxial anaesthesia-related hypotension were employed as case group (n = 59). The others were employed as control group (n = 43). Parturients in case group had a relatively lower age (p = 0.10) than that in control group. Singleton pregnancy occurred in all parturients. Most of COVID-19 parturients had a history of cesarean delivery, followed by primigravida. There were relatively higher abnormal rate of lymphocyte count (p = 0.02) and more parturients present signs and symptoms of COVID-19 (p = 0.16) in case group. However, statistically signi cant differences were not observed between two groups regarding the others maternal variables and the neonatal weight (Table 2). There were relatively higher rate of emergency surgery (54% vs 35%, p = 0.05), full stomach (41% vs 21%, p = 0.04) and second puncture (32% vs 19%, p = 0.12), higher baseline heart rate (p = 0.04), more experience of surgeon (p = 0.02) and anaesthetist (p = 0.03) in case group than those in control group. There were no signi cant differences in baseline SBP and MAP, the rate of oxytocin and calcium preparation utilization and the infusion volume in two groups. All COVID-19 parturients received dexamethasone. Over 70% parturients were treated with metoclopramide, however, fewer than half of parturients had 5-HT 3 receptor antagonist intervention. The commonly used vasoconstrictor was methoxamine followed by phenylephrine, metaraminol and noradrenaline (Table 3). Contrast with control group, the majority of anaesthetic technique was CES (40% vs 63%) but not EA (61% vs 37%) in case group (p = 0.02). The case group had a relative higher dose of lidocaine (p = 0.11) and ropivacaine (p = 0.05) than those in control group. And, there were signi cant differences in the site (p = 0.14), but not in approach and local complications of anaesthesia puncture, block-surgery time and sensory block height in two groups. All CES were performed through the median approach and no additional local anaesthetic were applied epidurally until the end of the surgical procedure (Table 4). Based on these results and clinical practice, maternal age, count of COVID-19 signs and symptoms, lymphocyte count, urgency of surgery, full stomach, baseline heart rate, frequency of anaesthesia puncture, experience of surgeon and anaesthetist and neuraxial anaesthesia technique were identi ed as candidate variables. After collinearity test, no signi cant collinearity was found among those candidate variables (Table 5). Binary logistic regression analysis revealed that abnormal lymphocyte count (OR (95% CI) = 3.41 (1.17 to 9.94), p = 0.03), full stomach (OR (95% CI) = 3.22 (1.06 to 9.84), p = 0.04), baseline heart rate (OR (95% CI) = 1.04 (1.01 to 1.08), p = 0.03), experience of anaesthetist (OR (95% CI) = 0.85 (0.75 to 0.97), p = 0.02) and surgeon (OR (95% CI) = 0.76 (0.60 to 0.97), p = 0.03), and combined spinalepidural anaesthesia technique (OR (95% CI) = 3.27 (1.17 to 9.13), p = 0.02) were signi cantly associated with neuraxial anaesthesia-related hypotension ( Table 6). The area under the ROC curve was 0.83 and the asymptotic 95% CI was 0.79 to 0.91 (p < 0.001). And the threshold of 59% showed the best relationship between sensitivity (75%) and speci city (79%) for predicted probability (  Count of COVID-19 signs and symptoms, fever (body temperature more than 37.3℃), cough, fatigue, chest distress, dyspnoea and diarrhea. Baseline value, the mean of repeated measurements before commencing anaesthesia; Experience, the length of employment. The variables at tolerance < 0.1 and variance in ation factor ≥ 10 were identi ed the presence of collinearity.  Count of COVID-19 signs and symptoms, fever (body temperature more than 37.3℃), cough, fatigue, chest distress, dyspnoea and diarrhea. Baseline value, the mean of repeated measurements before commencing anaesthesia; Experience, the length of employment. * p-value < 0.05.

Discussion
Hypotension is the most commonly complication of neuraxial anaesthesia in parturients undergoing caesarean delivery. Investigating factors associated with neuraxial anaesthesia-related hypotension is a valuable strategy to reduce the incidence of it. Current study reported that the incidence of neuraxial anaesthesia-related hypotension in COVID-19 parturients undergoing caesarean delivery was 58% and abnormal lymphocyte count, full stomach, baseline heart rate, experience of anaesthetist and surgeon, CSE technique were the independent predictors of it.
Latest meta-analysis showed that vasoconstrictor (such as metaraminol, norepinephrine and phenylephrine) intervention was effective and safe in preventing and treating neuraxial anaesthesiarelated hypotension in healthy parturients. Leg compression and uid load might be also helpful (Pereira, Grando et al., 2011;Chooi, Cox et al., 2020;Singh, Singh et al., 2020). Present study also reported similar intervention of vasoconstrictor and uids in COVID-19 parturients. Thus, vasoconstrictor utilization and extra infusion volume were considered as the presence of hypotension in COVID-19 parturients.
Prior studies found that maternal age (Bishop, Cairns et al., 2017;Fakherpour, Ghaem et al., 2018), emergency surgery (Hartmann, Junger et al., 2002), baseline heart rate (Bishop, Cairns et al., 2017;Fakherpour, Ghaem et al., 2018) and experience of anaesthetist (Shitemaw, Jemal et al., 2020), but not BMI (Bishop, Cairns et al., 2017;Bishop, Cairns et al., 2017) and preoperative haemoglobin concentration (Bishop, Cairns et al., 2017), were linked with neuraxial anaesthesia-related hypotension in parturients receiving caesarean delivery. Consistent results were observed in COVID-19 parturients. In emergency parturients, SA or CES seems to be the more common anaesthetic regimens due to the simplicity of implementation and the speed of onset. Yet, those advantages of SA or CES allow a higher incidence of hypotension, when compared with EA. Additionally, in emergency medical scenarios, inadequate preoperative preparation, full stomach, sympathetic hyperactivity would increase the risk of hemodynamic instability. Although signi cant collinearity was not been found between anaesthetic technique and urgency of surgery in present study, the effects of COVID-19 epidemic on urgency of surgery and the choice of anaesthetic technique should be taken into account.
A higher baseline heart rate always means a higher activation of sympathicus that will result in a relatively greater reduction in sympathetic resistance induced by neuraxial anaesthesia. However, baseline heart rate remain controversial in predicting neuraxial anaesthesia-related hypotension. Lowfrequency/high-frequency ratio of heart rate might be another applicable method (Bishop, Cairns et al., 2017) .
As reported, maternal BMI was a risk factor of neuraxial anaesthesia-related hypotension (Hartmann, Junger et al., 2002;Fakherpour, Ghaem et al., 2018;Shitemaw, Jemal et al., 2020). Moreover, a higher incidence of hypotension occurred in obese parturients during neuraxial anaesthesia, which partly contributed to vascular compression by hypertrophic uterus (Nani and Torres, 2011). Yet, a recent study declared that the hemodynamic parameters derived from a noninvasive cardiac output monitoring system were not statistically different between the left-tilt and supine position (Tsai, Yeh et al., 2019).
More researches should be focused on the effects of position and BMI on hemodynamic stability in parturients.
The second wave of COVID-19 has been widely concerned. We have to pay more attention to the experience of clinical practice during COVID-19 pandemic to cope with unexpected medical scenarios. Present study provided available information on neuraxial anaesthesia-related hypotension in COVID-19 parturients undergoing caesarean delivery, although historical study design and small sample size were the limitation. More evidences derived from a larger sample size and randomized controlled trails are also needed to validate these associated factors.