In December 2019 a novel Coronavirus, SARS-COV-2, was identified as the cause of a severe acute respiratory syndrome, label COVID-19 [1]. COVID-19 could range from asymptomatic infection to severe viral pneumonia with respiratory failure.

Pregnant women are usually more susceptible to infection due to typical physiological and mechanical changes, such as increased heart rate, stroke volume and pulmonary residual capacity [2]. Fever, cough, and dyspnea are the most common symptoms of COVID-19 in pregnant women [3, 4, 5]. They are more predisposed to superimposed bacterial infections due to direct mucosal injury and dysregulation of immune responses after viral pneumonia [6, 7, 8]. The evidence of physiological and mechanical changes during pregnancy may influence anesthetic management in women undergoing cesarean delivery while positive at SARS-COV-2.

The aim of this study was to evaluate an innovative anesthesiologic opioid-free management protocol in pregnant women with SARS-COV-2 undergoing cesarean delivery.

During the study period, 40 pregnant women with one or more symptoms and supplemental oxygen (FiO2 35–40%) who underwent cesarean delivery were included in the study. Out of the 40 included women, 30 had planned cesarean delivery for prior cesarean delivery, 5 had cesarean delivery for breech presentation, 4 had cesarean delivery for placenta previa, and one had cesarean delivery for maternal request. No women were on anticoagulation at the time of delivery.

All pregnant women had VAS $\le$3, and no pregnant women required rescue dose. Adverse effects, such as nausea, vomiting, shivering, or pruritus were not recorded in any case. After a mean of 2.5 hours from the spinal anesthesia, all the included women had a complete motility of the lower limbs and were able to mobilize independently within 12 hours after delivery. Mean time to first flatus was about 8 hours after delivery.

This study aimed to evaluate an innovative anesthesiologic management protocol in pregnant women with COVID-19 undergoing cesarean delivery. We opted for an opioid free management to avoid opioid-related side effects that may worse the symptoms of COVID-19. Opioids induce alterations in immune function at level of lymphocyte and phagocytic cell and increase susceptibility to infections [9].

We chose to inject dexamethasone 4 mg due to a powerful anti-inflammatory action. Intrathecal dexamethasone administration may influence intraspinal prostaglandin synthesis by inhibiting cytosolic phospholipase A2 (cPLA2) in laminae I and II after peripheral tissue injury and the expression of cyclo-oxygenase 2 reducing the peripheral inflammatory state, postoperative pain and analgesic requirements [10, 11, 12]. Epidural dexamethasone plus levobupivacaine prolongs the duration of spinal analgesia during combined spinal-epidural for management of labor pain, with hemodynamic stability and limited maternal and neonatal adverse effects [13]. Some study revealed that epidural bupivacaine—dexamethasone admixture had the same analgesic potency as bupivacaine—fentanyl with opioid sparing and antiemetic effects [14].

In COVID-19 patients with established moderate-to-severe ARDS dexamethasone down-regulates pulmonary and systemic inflammation improving medical condition [15].

All of glucocorticoids have anti-inflammatory effect but we opted to administrate dexamethasone because it is 20–30 times more potent than the natural hormone cortisol and 4–5 times than prednisone, moreover dexamethasone had a long half-life of 36–54 hours [15, 16].

Dexmedetomidine is a highly selective a-2 adrenergic agonist used like adjuvant in anesthesia. There were different possible mechanisms to explain the enhanced anesthetic efficiency. According to some researchers the action of $\alpha$2-agonism of dexmedetomidine, induces vasoconstriction, which might contribute to prolonging the period of analgesia. Also dexmedetomidine potentiates the spinal block via a synergistic interaction between $\alpha$2 receptors and sodium channels, resulting in a reduction in the dose of the local anesthetics required for achieving effective spinal anaesthesia for certain surgical procedures [17].

Dexmedetomidine 10 mcg was administrated in spinal anesthesia in order to enhance the anesthetic effect in local anesthesia. Dexmedetomidine together with bupivacaine can increase the duration of anesthesia with shorter sensory and motor block onset compared with bupivacaine alone andit guarantee hemodynamic stability, consumption of rescue dose of analgesic drug reduce [18]. Intrathecal dexmedetomidine significantly reduced the occurrence of shivering during cesarean section, it inhibit the body’s thermoregulatory center by the block of the transmission of body temperature information at the level of the spinal cord. It is important because shivering increase oxygen consumption and carbon dioxide production, with a certain impact on maternal physio logical function. Dexmedetomidine can reduce the use of opioids during cesarean delivery reducing the risk of nausea and vomiting. Also in the postoperative period it have an opioid sparing effect reducing rescue dose of opioid and analgesic [19]. Intrathecal dexmedetomidine during cesarean section appears safe both for the mother and for the fetus. Dexmedetomidine is not easily transferred through the placenta due to their fat-soluble characteristics so it does not increase neonatal adverse reactions during cesarean section. No significant differences in neonatal 1- and 5-min Apgar scores or cord blood gas parameters are observed. Also, it did not increase the incidence of adverse reactions such as maternal bradycardia and hypotension [20]. No abnormal symptoms or signs in the nervous system were found, which suggest that dexmedetomidine is a safe intrathecal adjuvant.

In summary, pregnant women in COVID-19 can safely receive intrathecal dexamethasone and dexmedetomidine during planned cesarean delivery.

CDA, GS, AC, CP, EG and MV conceived and designed the study; CDA, CP, EG and GiuS analyzed the data; MI, LG, GC, AnnM, GiuS and AlfM contributed reagents and materials; AC, AnnM, MV, GS, MI, LG, GC and AlfM wrote the paper.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the approval for this study (Ethical Committee N${}^{\circ }$ 145/20) was provided by the Ethical Committee of Federico II University of Naples, Italy, (Prof Domenico Del Forno) on 3 April 2020. IRB approval: 145/20 (University of Naples Federico II).

Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest.