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A Randomized Trial Comparing Colloid Preload to Coload During Spinal Anesthesia for Elective Cesarean Delivery

Siddik-Sayyid, Sahar M., MD, FRCA; Nasr, Viviane G., MD; Taha, Samar K., MD; Zbeide, Reine A., MD; Shehade, Jules-Marie A., MD; Al Alami, Ashir A., MD; Mokadem, Farah H., MD; Abdallah, Faraj W., MD; Baraka, Anis S., MD, FRCA; Aouad, Marie T., MD

Section Editor(s): Wong, Cynthia A.

doi: 10.1213/ane.0b013e3181b2bd6b
Obstetric Anesthesiology: Research Reports
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BACKGROUND: Hypotension after spinal anesthesia for cesarean delivery is common. Previous studies have demonstrated that a crystalloid fluid “coload” (rapid administration of a fluid bolus starting at the time of intrathecal injection) is superior to the conventional crystalloid preload (fluid administered before the intrathecal injection) for preventing hypotension. Colloid preload provides a sustained increase in central blood volume. We hypothesized that, in contrast to crystalloid, a colloid preload may be more effective than colloid coload for reducing the incidence of spinal anesthesia-induced hypotension.

METHODS: In this double-blind study, 178 patients were randomly assigned to receive a preload of 500 mL of hydroxyethyl starch over a period of 15–20 min before initiation of spinal anesthesia (n = 90) or an identical fluid bolus of hydroxyethyl starch starting at the time of identification of cerebrospinal fluid (n = 88). Vasopressors (ephedrine or phenylephrine) were administered if systolic arterial blood pressure decreased less than 80% of the baseline pressure and <100 mm Hg, or with smaller decreases in blood pressure if accompanied by nausea, vomiting, or dizziness. The primary outcome was the incidence of hypotension (defined as the administration of at least one dose of vasopressor).

RESULTS: There was no significant difference between the groups in the incidence of hypotension (68% in preload group and 75% in coload group, 95% confidence interval of difference −6%–20%; P = 0.28), doses of ephedrine and phenylephrine, and number of vasopressor unit doses. The incidence of severe hypotension (systolic blood pressure <80 mm Hg) was 16% in the preload group and 22% in the coload group (P = 0.30). There were no differences in the incidence of nausea and/or vomiting, or neonatal outcome between the groups.

CONCLUSION: There was no difference in the incidence of hypotension in women who received colloid administration before the initiation of spinal anesthesia compared with at the time of initiation of anesthesia. Both modalities are inefficient as single interventions to prevent hypotension.

Published ahead of print July 29, 2009

From the Department of Anesthesiology, American University of Beirut Medical Center, Beirut, Lebanon.

Accepted for publication June 7, 2009.

Published ahead of print July 29, 2009

Supported by the Department of Anesthesiology.

Accepted in part as abstract at the American Society of Anesthesiology Annual Meeting 2008, Orlando, FL.

Address correspondence and reprint requests to Marie T. Aouad, MD, Department of Anesthesiology, American University of Beirut Medical Center, PO Box 11-0236, Beirut, Lebanon. Address e-mail to mm01@aub.edu.lb.

Hypotension after spinal anesthesia for cesarean delivery is a common clinical problem; if severe, it can be associated with maternal and fetal morbidity.1 A qualitative systematic review found that administration of a colloid compared with crystalloid solution before initiation of spinal anesthesia (preload) is consistently more effective in preventing hypotension, and the risk of hypotension is twice as high if subjects received crystalloid compared with colloid solution.2 Our standard clinical practice, therefore, is to administer colloid solution 15–20 min before initiation of spinal anesthesia.

An alternative technique to decrease the incidence of hypotension is to rapidly administer crystalloid solution at the time of initiation of anesthesia (coload).3,4 Crystalloid has a short intravascular half-life because of its rapid distribution into the interstitial space. This is the likely reason that studies have demonstrated that administering a crystalloid coload is superior to the conventional practice of administering a crystalloid preload; a coload provides additional intravascular fluid at the time of maximum vasodilation.3,4 In contrast to crystalloid, colloid remains for a longer period within the intravascular space.5 Thus, a preload with colloid provides a sustained increase in central blood volume and cardiac output, which overlaps with the hemodynamic events that follow the induction of spinal anesthesia. Because sympathetic blockade occurs quickly after the initiation of spinal anesthesia (within minutes), the time of maximum intravascular volume expansion from a colloid coload may not correspond to the period of maximum hemodynamic changes after initiation of spinal anesthesia. The purpose of the study was to test the hypothesis that preload with colloid may be more effective than coload in reducing the incidence of spinal-induced hypotension.

We designed a randomized double-blind study to compare the incidence of hypotension in women undergoing elective cesarean delivery under spinal anesthesia who received 500 mL of colloid solution administered as a preload versus a coload. Secondary outcomes included the severity of hypotension and the need for vasopressors, as well as the incidence of nausea and/or vomiting and neonatal outcomes.

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METHODS

After IRB approval, written informed consent was obtained from 183 nonlaboring parturients more than 37-week gestation, ASA PS I or II scheduled for elective cesarean delivery. Exclusion criteria were pregnancy-induced hypertension, chronic hypertension, multiple gestation, known fetal compromise, diabetes mellitus, polyhydramnios, weight >100 kg, major systemic disease, anemia (hemoglobin concentration <10 g/dL), or clotting diathesis. On arrival to the operating room, an 18-gauge IV cannula was placed on the left arm/hand of the patient, and lactated Ringer’s solution was connected to keep the IV line patent. Patients did not receive any IV fluid or premedication before entering the study. All fluids were administered at room temperature.

Patients were randomly assigned using a computer-generated table of random numbers to receive a colloid preload (Group P) or coload (Group C). In the operating room, the patients were placed comfortably in the left supine wedged position and were monitored by automated noninvasive arterial blood pressure (BP) monitoring on the right arm, electrocardiogram, and peripheral pulse oximetry. Baseline BP was the mean of three consecutive readings at 3-min intervals during which the systolic blood pressure (SBP) did not vary by more than 10% from the average value. The patient, the anesthesiologist performing the spinal block, collecting the data, and treating the side effects, and the pediatrician assessing neonatal outcome were unaware of the patient’s group assignment. To ensure blinding, the infusion bag was prepared and hidden behind a drape, and administered by a dedicated anesthesia nurse who was not involved in the anesthetic management of the patient. Patients received a preload of 500 mL of hydroxyethyl starch (6% HES 130/0.4) (Voluven®; Fresenius Kabi, Bad Homburg, Germany) administered by gravity at a wide-open rate over a period of 15–20 min (Group P) before spinal anesthesia or continued to receive lactated Ringer’s solution at a minimal rate (Group C). The unblinded anesthesia nurse decided when the patient should sit up for the spinal procedure. To maintain blinding, this occurred after completion of colloid administration in Group P (which lasted approximately 15–20 min) or 15–20 min from the time of starting lactated Ringer’s solution in Group C. Spinal anesthesia was initiated in the sitting position at the L2-3 or L3-4 interspace with 0.75% hyperbaric bupivacaine (Marcaine® Spinal; bupivacaine hydrochloride in dextrose injection, USP, Lake Forest, IL) 12.75 mg (1.7 mL) combined with morphine (Laboratoire Renaudin, Itxassou, France) 0.2 mg (0.2 mL). At the time of identification of cerebrospinal fluid, Group C patients received 500 mL of colloid using a pressure infusion system to administer the fluid at the maximal possible rate. Parturients in both groups were placed promptly in the supine position with 15 degrees of left lateral tilt, and supplemental oxygen was delivered through a face mask. After administration of the colloid, lactated Ringer’s solution was infused at a rate of 10 mL · kg−1 · h−1 in both groups.

BP was measured every minute for 20 min and every 3 min thereafter until the completion of surgery. Vasopressors were administered if SBP <80% of the baseline BP and <100 mm Hg. Vasopressors consisted of ephedrine given in 6 mg IV bolus if heart rate (HR) was <90 bpm, or phenylephrine 0.1 mg IV bolus if HR was more than 90 bpm. Vasopressor treatment was repeated every 1 min if hypotension persisted or recurred. Smaller decreases in BP were similarly treated if accompanied by nausea, vomiting, or dizziness. A vasopressor unit was defined as one bolus of ephedrine or phenylephrine. Hypotension was considered present if the patient received at least one dose of vasopressor. An additional rapid bolus infusion of lactated Ringer’s solution was administered at the time of hypotension (approximately 100 mL at each episode of hypotension).

The cephalad extent of sensory blockade was assessed every 5 min after intrathecal injection using loss-to-pinprick sensation. Surgery was allowed to proceed after T6 sensory blockade had been established. The extent the sensory blockade at 20 min, other drugs and their doses, and the duration of administration of colloid were recorded in both groups as well as episodes and timing of nausea and/or vomiting. Metoclopramide 10 mg IV was administered if nausea and/or vomiting were unrelated to hypotension or not corrected by vasopressor bolus alone.

The study period started when the patients in Group P started receiving their preload and finished at the end of skin closure. The induction-skin incision, induction delivery, and uterine incision-delivery intervals, and duration of anesthesia and surgery were recorded. After delivery of the baby, 30 IU of oxytocin was added to 1 L lactated Ringer‘s solution and a bolus of approximately 100 mL was given, followed by an infusion at a rate of 150 mL/h. Apgar scores at 1 and 5 min were assessed by the pediatric resident; neonatal weight and umbilical venous and arterial blood gases obtained from a double-clamped segment of the umbilical cord were also documented.

Sample size analysis was performed to determine the size of the treatment groups. Allowing for the probability of a Type II error of 0.2 with α = 0.05 and assuming an incidence of hypotension of 55%5 with a relative 40% change as being clinically significant, a sample size of 88 per group was required using a two-tailed test (Interactive Statistical Pages. Available at: http://statpages.org/proppowr.html. Accessed April 25, 2009). Continuous data were reported as mean ± sd and were analyzed using Student’s t-test. SBP and HR were analyzed using a two-factor (treatment and time) repeated measures analysis of variance model. Categorical data were reported as numbers and percentages and were analyzed using χ2 or Fisher’s exact test as appropriate. Nonparametric data were reported as median and range and were analyzed using Mann–Whitney U-test. P < 0.05 was considered significant. All analyses were performed using SPSS (version 15; Chicago, IL).

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RESULTS

One hundred eighty-three patients were enrolled in the study (Fig. 1). Two patients from Group P and three patients from Group C were excluded because of protocol violations. Therefore, Group P included 90 patients and Group C 88 patients. There was no significant difference in demographic data between the groups (Table 1). Sensory blockade extended to T6 and above within 10–15 min in all patients. There were no differences in the extent of sensory blockade or time-intervals, except for a shorter duration of colloid administration in Group C (Table 2).

Figure 1.

Figure 1.

Table 1

Table 1

Table 2

Table 2

Both groups had similar baseline SBP and HR. Serial SBP and HR values for 20 min after onset of spinal anesthesia were not significantly different between the two groups (Fig. 2). The incidence of hypotension after spinal anesthesia was 68% in Group P and 75% in Group C (95% confidence interval of the difference −6%–20%; P = 0.28), and the incidence of severe hypotension, defined as SBP <80 mm Hg, was 16% in Group P and 22% in Group C (P = 0.30). The median (range) time to hypotension was 6 (1–47) min in the preload group and 5 (1–38) min in the coload group (P = 0.09). There were no differences between the two groups in the total doses of ephedrine and phenylephrine and the number of unit doses of vasopressor administered to treat hypotension (Table 3). Approximately one-third of the hypotensive patients in both groups (21/61 in Group P and 20/66 in Group C, P = 0.6) developed nausea and vomiting.

Figure 2.

Figure 2.

Table 3

Table 3

There was no significant difference in the incidence of nausea and/or vomiting between the two groups (Table 3). Most nausea and/or vomiting episodes in the predelivery period coincided with the maternal hypotension and were successfully treated by correcting hypotension. There was no difference in the total lactated Ringer’s solution given to the patients during the operation. No intraoperative analgesia or sedation was required. Neonatal outcomes were not different between the groups (Table 4).

Table 4

Table 4

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DISCUSSION

The important finding of this study is that there is no difference in the incidence of hypotension when colloid solution is administered as a preload versus a coload in patients undergoing elective cesarean delivery under spinal anesthesia.

Several methods of preventing and treating spinal anesthesia-induced hypotension in obstetric patients have been used. These include left uterine displacement, IV fluid administration before the initiation of anesthesia (preload), vasopressors, and physical methods to improve venous return.6,7 Rapid infusion of a large volume of fluid is commonly used as prophylaxis. The goal of administering fluid before spinal block is to increase venous return and preserve central blood volume and cardiac output,6,8 both of which decrease after subarachnoid block.9 However, several studies have questioned the value of crystalloid administration before the initiation of spinal anesthesia for cesarean delivery, suggesting that it is relatively ineffective,10–13 with up to 85% of patients developing hypotension.14 Crystalloid preload is rapidly distributed and may induce atrial natriuretic peptide secretion, resulting in peripheral vasodilation followed by an increased rate of excretion of the fluid.15 In contrast, more recent data suggest that fluid administration immediately after induction of spinal anesthesia may be useful to prevent hypotension.

Kamenik et al. studied the effects of a lactated Ringer’s solution coload compared with preload, or no load on cardiac output after spinal anesthesia. Cardiac output remained elevated above baseline in the coload group 30 min after induction of anesthesia, whereas it returned to baseline in the preload group and decreased in the group that received no fluid.16 Additionally, Dyer et al. and Mojica et al.3,4 showed in obstetric and nonobstetric populations, respectively, that rapid administration of crystalloid at the time of induction of spinal anesthesia was more effective in preventing hypotension compared with administering crystalloid before spinal anesthesia. The rapid administration of crystalloid provides additional intravascular fluids during the period of maximal risk of spinal-induced hypotension and may also have the simple beneficial effect of facilitating rapid circulation of the vasopressor.1 However, in the rare patient, the administration of a large volume of crystalloid as a preload or coload may entail maternal risks, such as decreased oxygen-carrying capacity17 and increased risk of pulmonary edema.18

Colloid solutions are an alternative choice to crystalloid solutions; they remain in the circulation for a longer period. A smaller volume of colloid than crystalloid is needed to obtain equivalent expansion of plasma volume. Ueyama et al. showed that administration of a crystalloid preload (1500 mL in 30 min), resulted in an 8% increase in blood volume. However, only 28% of the crystalloid remained in the circulation at the conclusion of the 30-min infusion. In contrast, 500 mL 6% HES administered as a preload increased the blood volume by 10%, and 1000 mL by 20%, with 100% remaining in the circulation at 30 min.5 Thus, the maximum expansion of the intravascular volume with prehydration with colloid persists at the time of induction of spinal anesthesia and immediately after induction when vasodilation is evolving. In our study, the median time to hypotension was 5–6 min in both groups. Therefore, hypotension usually occurred before the colloid infusion was completed in the coload group. Hypotension was frequent in both groups, which mandated timely and judicious use of vasopressors. Prevention of hypotension using a combination technique, such as colloid loading with prophylactic vasopressors, may be more appropriate than single interventions.1The incidence of hypotension in our study was higher (68%–75%) than that reported in earlier studies using colloid solution. Karinen et al.19 reported a 38% incidence of hypotension in 13 patients who received 500 mL 6% HES as preload before initiation of spinal anesthesia with intrathecal bupivacaine 13 mg. Vercauteren et al.20 showed a 40% incidence of hypotension (BP <90 mm Hg) in 30 parturients receiving 1 L 6% HES before intrathecal injection of 6.6 mg isobaric bupivacaine and sufentanil 3.3 μg as part of combined spinal-epidural technique. Ueyama et al.5 studied the effect of intravascular volume preload with either crystalloid or colloid before induction of anesthesia with tetracaine 8 mg plus morphine 100 μg; the incidence of hypotension was 58% for the 500 mL HES group and 17% for the 1 L HES group. Riley et al.14 reported a 45% incidence of hypotension in 20 patients who received 500 mL 6% HES plus 1 L lactated Ringer after intrathecal bupivacaine 12 mg, morphine 0.2 mg, and fentanyl 10 μg. Nishikawa et al. compared the effects of a colloid coload with 6% HES (15 mL/kg) versus preload (15 mL/kg) versus control in parturients undergoing cesarean delivery under spinal anesthesia with bupivacaine (11.5–13.5 mg). The incidence of hypotension was significantly lower in HES preload (11.1%) and HES coload groups (16.7%) than the control group (55.6%).21 Similar to our results, there was no difference between the colloid preload and coload groups.

The higher incidence of hypotension in our study as compared to these above-mentioned reports may be explained by the use of a larger volume of colloid (1 L and 15 mL/kg)5,20,21 as opposed to 500 mL in our study, or to the administration of a smaller dose of intrathecal local anesthetic,5,20 which is expected to cause a lower block and less extensive sympathectomy than larger doses. Finally, the definitions of hypotension and vasopressor regimen varied widely among these different studies, making interpretation and comparison of results difficult.

Despite a 60%–70% incidence of hypotension in the predelivery period, neonatal outcome was good in both groups. This reflects previous experience that transient decreases in BP rapidly treated with vasopressors do not usually affect fetal acid-base status.22

Anaphylactoid reactions have been rarely reported (<0.1%) with HES (6%, 130/0.4). The allergic potential of starch solutions is seven times lower (1/2100) than that of the gelatin solutions.23 No adverse reactions occurred in this study, and no serious reactions have occurred after many years of routine use of HES in our obstetric service.

In conclusion, our study showed that the incidence of hypotension is similar after a colloid preload versus coload with 500 mL of 6% HES in patients undergoing elective cesarean delivery under spinal anesthesia. The incidence of nausea and vomiting and neonatal outcomes were similar between the groups. Therefore, a coload with colloid solution can replace a preload to shorten preparation time and avoid any delay in performing spinal anesthesia. However, both modalities are inefficient as single interventions and should be combined with timely and judicious use of vasopressors. Further studies comparing crystalloid coload to colloid coload for the prevention of spinal-induced hypotension are required in the future.

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