Cesarean section is one of the most commonly performed surgical procedures; approximately 80-90% of elective cesarean sections are conducted using spinal anesthesia [1]. Spinal anesthesia is the preferred technique for Cesarean Section (CS) due to its simplicity, reliability, low rates of airway complications, facilitation of postoperative analgesia, less neonatal exposure to potentially depressant drugs, to awake mother at the time of the birth of the child that establishes maternal-infant bonding and successful breastfeeding, and due to its low cost as compared to the general anesthesia [2]. Maternal hypotension is a frequent side effect of spinal anesthesia for cesarean delivery and it causes dangerous maternal and fetal effects [3, 4].

Maternal hypotension decreases uteroplacental circulation and it results in nausea, vomiting, bradycardia and different systems dysfunction particularly in the presence of other diseases as renal, hepatic, cardiac and neurological [5, 6]. Anesthesiologists should not allow hypotension to continue, this often requires the use of vasopressors to maintain blood pressure as ephedrine, phenylephrine and norepinephrine [7, 8].

Ketamine, is a non- competitive antagonist at the N-Methyl-D-Aspartic Acid (NMDA) receptor [9], stimulating the cardiovascular system with high blood pressure, heart rate, and cardiac output. These changes are not related to the dose of ketamine [10]. The mechanism by which ketamine stimulates the cardiovascular system seems to be the central reason rather than peripheral. Ketamine attenuates the baroreceptor effect by blocking the NMDA receptors in the nucleus tractus solitarius. This effect results in a centrally mediated sympathetic response [11].

This study was performed to evaluate the effect of sub-anesthetic dose of ketamine to prevent maternal hypotension after spinal anesthesia in cesarean section.

This double-blinded randomized controlled study was conducted between February 2018 till May of the same year in Ain Shams University hospital after approval of the research ethical committee (clinical trials ID is 03624166, Ethical number is FAMUS R 38/2018) and obtaining written informed consent from all participants. It included 80 patients admitted for elective cesarean section, all were term pregnant and of ASA physical status grade І or П. Parturients who had pre-eclampsia, chronic hypertension, cardiovascular troubles, any contraindication to regional anesthesia such as local infection or bleeding disorders or any hypersensitivity to ketamine were excluded from the study (Fig. 1).

All the parturients were randomly allocated into two groups using computer-generated random numbers list and opaque sealed envelopes. Study drugs were prepared by an anesthesiologist independent of the study.

An Intravenous (IV) infusion of lactated Ringer's solution at 5-7 ml/kg prior to the subarachnoid block was started in the operating room in all participants. Standard anesthesia monitoring was applied. Spinal anesthesia was performed with patients in the sitting position in the midline approach at the L2-3 or L3-4 level, with a 25G Quincke needle, local anesthesia of 1.5 ml of 2% lidocaine and then intrathecal bupivacaine 10 mg was injected. All the patients were then placed supine with the table tilted 15⁰ left lateral tilt. The parturients were then divided into two groups; ketamine group (n = 40) received a sub-anesthetic dose of ketamine of 0.5 mg/kg IV bolus in 3 ml of normal saline and the control group (n = 40) received the same volume of normal saline IV bolus. All the parturients received 2 mg midazolam IV directly after delivery of the fetus.

Heart Rate (HR) and Mean Arterial Blood Pressure (MAP) were recorded at baseline 5 minutes prior to the intrathecal injection and 5 minutes, 10 minutes, 15 minutes, and 20 minutes after the injection and then every 15 minutes till the end of the operation. Incidence of hypotension was recorded which was defined as MAP less than 20% below the baseline or was ≤ 65 mmHg. Incidence of severe hypotension ≤ 50 mmHg was recorded. On the occurrence of hypotension, ephedrine 5 mg was then administered intravenously, repeated if needed and total dose of ephedrine was recorded. Also, if HR was < 50 beats/minute, atropine sulfate 0.5 mg was administered intravenously.

Ramsay sedation scale was used to evaluate the sedation effect at baseline in both groups then, at 5, 10, 15, 30, 45 minutes after intrathecal injection and then at the end of the operation (Table 1).

Fig (1). Flow chart of the studied cases.

Incidence of hypotension and total dose of ephedrine used in both the groups were considered the primary outcomes. APGAR scores of neonates were measured at first and fifth minutes after childbirth together with umbilical artery ABG.

No significant difference between the studied groups regarding baseline characteristics (Table 2).

Sedation score was significantly higher among the ketamine group at 5, 10 and 15 minutes compared to the control group (Table 3).

No significant difference between the studied groups regarding umbilical artery ABG findings and APGAR scores at 1 and 5 minutes (Table 4).

Fig (2). MBP (mmHg) characteristics.

MAP was significantly higher among the ketamine group compared to control at 5, 10, 15, and 20 minutes. Total ephedrine dose was significantly lower among the ketamine group compared to control (Fig. 2) and (Table 5).

Heart rate was significantly higher among the ketamine group at 5, 10, 15, and 20 minutes (Fig. 3) and (Table 6).

Fig (3). Heart rate among the studied cases.

Mild hypotension and severe hypotension were significantly less frequent among the ketamine group. Diplopia, nystagmus and hallucination were non-significant between both the groups. Nausea and vomiting were non-significant between both the groups (Table 7).

This study showed that sedation score was significantly higher among the ketamine group with greater hemodynamic stability regarding MAP and HR with less frequent attacks of mild hypotension and no attacks of severe hypotension, with lower total ephedrine dose compared to control group. No difference between both the groups was observed regarding the incidence of other complications or regarding umbilical artery ABG findings and APGAR scores.

Regional anesthesia is performed now in 95% of scheduled CS delivery, as it avoids the risks of pulmonary aspiration, esophageal intubation that may occur with general anesthesia, and it allows the mother to be awake and interact immediately with her baby [13]. The commonest complication due to spinal anesthesia is hypotension with a reported incidence more than 80%, which may have detrimental effects on decreasing uterine blood flow, affecting the fetal well-being and ultimately neonatal outcome measured by umbilical artery pH and Apgar scores [14].

Hypotension that occurs in spinal anesthesia is due to sympathetic nervous system blockade in addition to inferior vena cava and aorta compression in a parturient. It is usually easily treated with left lateral tilt, intravenous fluid, and sympathomimetic drugs such as ephedrine. A lot of techniques have been described in the hope of eliminating hypotension in parturients during spinal anesthesia, but an effective method is yet to be described. These techniques include intravenous fluid prehydration [15] and cohydration [16], sympathomimetic drugs [17], physical methods such as leg bindings and compression stockings [18].

Ketamine is a unique drug that has stood the test of time since being introduced in 1970 with a wide variety of uses including sedation, analgesia, bronchodilation, and sympathetic nervous system stimulation [19]. Since ketamine increases the release and inhibits the reuptake of catecholamines in circulation, thus helps preserve vascular resistance and arterial Blood Pressure (BP), all these have made it an optimal anesthetic agent in hypotensive patients. In a study, ketamine in a dose of 0.7 mg/kg before spinal anesthesia, then 0.35 mg/kg 15 and 30 min after the first dose for osteosynthesis of hip fractures kept the patients hemodynamically stable than fentanyl given in a dose of 1.5 µg/kg before anesthesia [20]. These criteria can help in using ketamine to prevent hypotension that commonly occurs after spinal anesthesia during CS in parturients, as proven by our study, an alternative method that proved to be effective.

Previous animal and human studies have suggested that the fetus adapts to decreased Uterine Blood Flow (UBF) temporarily by redistributing cardiac output to the cerebral cortex, this compensatory reflex, however, is inhibited by both intravenous and inhalational anesthetics while ketamine does not suppress it due to its ability to increase maternal BP and UBF, thus improving uterine perfusion [21]. Ketamine at doses less than 2 mg/kg i.v. does not suppress the neonates assessed by Apgar scores making ketamine an attractive alternative in obstetric anesthesia in cases of severe fetal distress [22]. In the current study, umbilical artery ABG and Apgar scores were not affected in either groups.

In this study, although the sedation score was higher among the ketamine group in the first 15 minutes compared to the study group, the parturients were able to maintain airway reflexes with no desaturation at any time. Several studies confirm that ketamine preserves spontaneous respirations and protective airway reflexes [23, 24].

Hallucinations that occurred in 4 parturients after ketamine injection was in fact not true hallucinations but some sensory distortions that did not in any way affect the patients postoperatively (no nightmares, vivid dreams and with intact memory). This is in accordance with the study conducted by Powers et al. [25] to describe the ketamine-induced hallucinations and stated that a subanesthetic dose of ketamine does not produce frank hallucinations.

Although no catastrophic events occurred, this study was conducted on a small group of parturients which is considered a limitation to the use of ketamine safely in parturients. Other studies are needed with a much larger group of parturients to consider safety issue.

We concluded that ketamine in subanesthetic dose is an effective agent to be used in preventing post-spinal hypotension in parturients undergoing CS delivery.