Hormonal, physical, and psychological fluctuations occur during the menstrual cycle.1,2 Anesthetic, analgesic, and antiemetic requirements, and perception of pain and serum noradrenaline levels, can change during the different stages of the menstrual cycle.1–6 Tracheal intubation (TI) stimulates somatic and visceral nociceptive afferents in the airway and can significantly increase arterial blood pressure and catecholamine levels.7–9
However, to the best of our knowledge, there are no studies addressing the effects of the phases of the menstrual cycle on the hemodynamic response to TI. The hypothesis of our study was that the luteal phase of the menstrual cycle results in an increased rate pressure product (RPP) after TI in comparison with that in the follicular phase. To test this hypothesis, we chose times during the menstrual cycle at which hormonal profiles are different from each other, the follicular and luteal phases.
This prospective and double-blind study was done to evaluate the effects of the follicular and luteal phases of the menstrual cycle on the RPP response to TI.
After obtaining approval of the hospital ethics committee and written informed consent, 62 women, 18 to 49 years old, ASA physical status I, scheduled to have general anesthesia with TI for elective surgery were enrolled in this study. Exclusion criteria were the presence of neurological or psychiatric diseases, difficulty of communication, history of combined oral contraceptive use, irregular menstrual cycle, amenorrhea, total abdominal hysterectomy and/or bilateral salphingoopherectomy, pregnancy, anticipated difficult TI, body mass index >30 kg/m2, intake of analgesics <24 hours before the operation, receiving medications known to affect arterial blood pressure and heart rate (HR), and hypersensitivity to the study drugs.1,7
All patients were premedicated with 0.07 mg/kg IM midazolam 1 hour before the induction of anesthesia. Upon arrival in the operating room, a 20-gauge IV cannula was inserted into a vein on the dorsum of the hand, and an IV infusion of lactated Ringer's solution was started at a rate of 5 mL/kg/hr.
The patients were assigned into 2 groups according to the phase of their menstrual cycle. The patients who were on the 1st to 12th days after the first day of their last menstruation were considered to be in the follicular phase of the cycle and assigned to group F. Those on the 20th to 24th days after the first day of the last menstruation were considered to be in the luteal phase of the cycle and assigned to group L. Because luteinizing hormone peaks on the 13th day and progesterone starts to increase at the 18th day of the menstrual cycle, patients in the 13th to 19th days of their last menstruation cycles were excluded to better discriminate between the follicular and luteal phases.1,3,10 Blood progesterone levels start to decrease on the 24th day of the cycle, so we also excluded patients on the 24th or more day of their cycle, using the same rationale.1,3,10 Menstrual cycle duration and the patients' day after the first day of the last menstruation were recorded.
Patients in both groups were monitored with continuous electrocardiography (Drager Fabius GS®, Drager Medical AG Ko, Lübeck, Germany), cyclic noninvasive arterial blood pressure measurement with a standard adult cuff size, and pulse oximetry.
Administration of oxygen was performed for 3 minutes with 5 L/min fresh gas flow of 100% oxygen. After oxygen administration, all patients were administered 3 mg/kg propofol over 30 seconds. After loss of eyelash reflex to touch, mask ventilation was initiated. Rocuronium 0.9 mg/kg was given to facilitate TI. Sixty seconds later, TI was attempted.
All TIs were performed by the same anesthesiologist, who had not been informed of the patients' group assignments (Sedat Hakimoğlu), to minimize bias. A Macintosh 3 laryngoscope blade and a 7.5-mm endotracheal tube were used to perform tracheal intubation in the minimum possible time, and the duration from start of tracheal intubation was recorded. Intubation time was defined as the period from termination of manual ventilation with a facemask to the restoration of ventilation through the endotracheal tube,7 and was recorded by a researcher using a stopwatch. We planned to exclude patients requiring >120 seconds to achieve successful TI.
Patients' systolic blood pressure, diastolic blood pressure, mean arterial blood pressure (MAP), HR, and SPO2 were recorded before and after administration of the IV anesthetic and muscle relaxant, immediately after TI and cuff inflation and 1, 2, 3, 4, 5, and 10 minutes later.
RPP, which is calculated by the formula RPP = HR × systolic blood pressure, was calculated for each time point and recorded.
After intubation, anesthesia in all patients was maintained with 66% nitrous oxide in oxygen and 0.5% sevoflurane.
Ventilation was adjusted to maintain end-tidal CO2 (ET CO2) between 35 and 40 mm Hg. During the data collection period, no surgery was performed. The incision was delayed and no painful stimuli were given until the end of the study period.
If TI could not be performed successfully in the first attempt, the patient was excluded from the study. Atropine at a dose of 0.5 mg was administered for bradycardia (HR <50 beats per minute [bpm]). If MAP decreased 30% below the control value for a minimum of 60 seconds, 5 mg ephedrine was administered and recorded. If MAP increased above 30% control value for a minimum of 60 seconds, 1 μg/kg fentanyl was administered and recorded. Complications occurring during intubation—such as coughing, laryngospasm, or bronchospasm—were also recorded.
Our primary hypothesis was that the luteal phase of the menstrual cycle resulted in a larger increase in RPP at 1 minute after endotracheal intubation. Sample size estimation was based on the SD of a similar study performed by Skinner et al.11 To use the RPP (15,882 ± 4077) determined by Skinner et al.,11 we administered propofol and rocuroniun for intubation. To detect a 20% change in RPP, with an α error of 0.05 and a power of 80%, we calculated that sample size should be at least 25 patients per group. Estimating an approximately 20% dropout rate, we included 31 patients in each group. The sample size estimation was performed using Power Calculator (Department of Statistics, University of California, Los Angeles; http://www.stat.ubc.ca/∼rollin/stats/ssize).7,11
Statistical Package for the Social Sciences (SPSS) 11.5 was used for data analysis. Numerical data were given as mean ± SD and were analyzed using the Student's t test. P < 0.05 was considered statistically significant.
The groups were similar in terms of demographic data (P > 0.05). Patient characteristics are shown in Table 1.
All TIs were successful on the first attempt with a mean duration of 53 ± 10 and 54 ± 9 seconds (ranging from 30 to 70 seconds) in groups F and L, respectively (P = 0.705). None of the patients were excluded for long TI time.
Before administration of the IV anesthetic, hemodynamic variables were similar between the groups (P > 0.05).
RPP values at the first minute after intubation were significantly higher in group L than in group F (14,686 ± 2278 mm Hg · bpm and 11,167 ± 2069 mm Hg · bpm, respectively) (P < 0.001). Changes in the hemodynamic variables are presented in Figures 1 and 2.
Intergroup and intragroup analysis of the SPO2 and ET CO2 values revealed no statistical difference (P > 0.05). No patient in either group required atropine, ephedrine, or fentanyl. No patient had laryngospasm or bronchospasm.
In this study we have demonstrated that RPP at 1 minute after TI significantly increases in the luteal phase in comparison with that in the follicular phase of the menstrual cycle.
Previous studies and meta-analyses have shown that thermal, pressure, ischemic, venipuncture, and propofol injection pain increased in the luteal phase in comparison with the follicular phase.1,2,12–19 Studies have demostrated significant correlation between increased pain sensitivity and increased progesterone, and decreasing estrogen levels.12,13 In addition, previous studies have shown that in healthy women, plasma norepinephrine levels and sympathetic activity were significantly higher in the luteal phase than in the follicular phase.6,20–23 The mechanism of the change of RPP response to endotracheal intubation in the different phases of the menstrual cycle may be related to the increased response to nociceptive stimulus, plasma norepinephrine levels, and sympathetic activity during the luteal phase.
The limitation of our study is that we did not measure estrogen and progesterone levels as was done in other similar studies.1,4,5,24–27 However, we chose our sample group from patients on the 1st to 12th and 20th to 24th days of their cycle to have 2 very distinctive hormonal profiles in the groups. We chose a single time point to assess the impact of endotracheal intubation on the phases of the menstrual cycle, because time itself may become a covariate in the model, requiring more sophisticated modeling. We tested a simple hypothesis that the time of the menstrual cycle may impact the hemodynamic response after a noxious stimulus. In addition, the measurement of serum catecholamine would have been useful.
In conclusion, we suggest that menstrual cycle phases can affect the severity of the RPP response to TI. Female patients may have significantly increased RPP response to TI in the luteal phase of their menstrual cycle. Therefore, future studies investigating the hemodynamic response to noxious stimulation should consider the phases of the menstrual cycle.
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