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OBSTETRIC ANESTHESIA

The Effects of an Increase of Central Blood Volume Before Spinal Anesthesia for Cesarean Delivery: A Qualitative Systematic Review

Department of Anesthesia, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario

Address correspondence to P. J. Morgan, MD, CCFP, FRCPP, Department of Anesthesia, Sunnybrook and Women’s College Health Sciences Centre, Women’s College Campus, 76 Grenville St., Toronto, Ontario, Canada, M5S 1B2. Address e-mail to pam.morgan @utoronto.ca.

	Abstract

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We evaluated in this qualitative systematic review the efficacy of increasing central blood volume on the incidence of hypotension after spinal anesthesia for elective cesarean delivery. Randomized controlled trials investigating any method of increasing central blood volume before the initiation of obstetric spinal anesthesia were sought by using MEDLINE (1966–2000), Embase (January 1988–April 2000), and the Cochrane Library (Issue 1, 2000). Additional reports from retrieved and review articles, hand searching of non-MEDLINE journals, and abstracts of major anesthesia meetings (1994–1999) were located. The primary outcome was the incidence of hypotension. Secondary outcomes included: ephedrine use, Apgar scores, umbilical cord pH values, and maternal nausea and vomiting. Twenty-three articles met our inclusion criteria with the use of crystalloid preload, colloid preload, and mechanical methods of increasing central volume. Crystalloid preload was inconsistent in preventing hypotension, whereas colloid appeared to be effective in all but one study. Leg wrapping and thromboembolic stockings decreased the incidence of hypotension compared with leg elevation or control. Few differences in fetal outcomes or maternal nausea and vomiting were reported. Increasing central blood volume by using colloid and leg wrapping decreases but does not abolish the incidence of hypotension before spinal anesthesia for elective cesarean delivery.

Implications: We performed a systematic review to determine whether fluid loading reduced the incidence of low blood pressure after spinal anesthesia for cesarean delivery. Although no technique totally eliminates the occurrence of hypotension, colloid administration (starch or gelatin containing fluids) and leg wrapping were the most effective.

	Introduction

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Spinal anesthesia is commonly used for elective cesarean delivery. Associated hypotension is caused by an increase in venous capacitance and a reduction in systemic vascular resistance. Because uterine blood flow is dependent on perfusion pressure, hypotension results in reduced uterine blood flow, with a potential compromise in fetal oxygenation. Maternal nausea and vomiting may also occur.

An early study reported that hypotension could be prevented with a crystalloid fluid bolus (1). Although this observation has not been replicated, fluid preload has become standard practice before regional anesthesia for cesarean delivery. Since this early work, many studies have been performed with contradictory results. Recently, the role of preload in the prevention of hypotension has been questioned (2).

This systematic review evaluates the role of central blood volume augmentation in reducing the incidence of hypotension with spinal anesthesia for cesarean delivery.

	Methods

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Literature Review
We systematically sought reports of randomized controlled trials investigating any method of increasing central blood volume to prevent hypotension during elective cesarean delivery under spinal anesthesia. Authors independently searched MEDLINE (1966–2000) and Embase (January 1988–April 2000) using medical subject (MESH) headings of "cesarean section," "hypotension," and "anesthesia, spinal." "Leg wrapping" and "trendelenberg" were also used as text terms to capture other methods of increasing preload. The last search was performed on May 1, 2000. The Cochrane Library (Issue 1, 2000) was also searched. Additional reports from reference lists of retrieved and review articles, hand searching of non-MEDLINE journals, and abstracts of major anesthesia meetings (1995–2000) were used to locate subsequent publications. No abstracts, correspondences, or unpublished observations were included.

Quality of the Trials
At least two authors assigned a quality score to each report using a three-item, validated scoring system (3). We gave one point to studies described as randomized and an additional point if randomization was described and appropriate (i.e., randomization table, random number generator). A randomization point was deducted if an inappropriate method was used (chart number, day of the week, alternate allocation). One point was given if the study was blinded and an additional point if the blinding was appropriate. Finally, a point was awarded if all enrolled patients were accounted for, either by showing to which group(s) they were allocated or by describing why they were withdrawn from the study. Thus, a total of five points were possible. Any disagreements in scoring were resolved by consensus.

Outcome Measurements
The primary outcome was the incidence of hypotension, as defined by the authors of the original studies. Patients receiving no volume expansion were the Control group. In some cases, a small volume of fluid was compared with a large volume; in that case, the former was considered the Control group. Secondary outcomes included maternal nausea, the use of vasopressors, neonatal Apgar scores, and umbilical cord pH.

Statistical Analysis
We intended to combine studies statistically and stratify results into three groups: 1) crystalloid preloading, 2) colloid versus crystalloid, and 3) mechanical methods of increasing autotransfusion. This was not done because: 1) in general, quality of the studies was poor, 2) outcome measures were not uniform across studies, 3) control groups were not comparable to each other (for example, some of the control groups also received a fluid bolus) (4–7), 4) different local anesthetics and doses were used, and 5) some studies used prophylactic vasopressors while others did not. Therefore qualitative methods and tables summarize the results. Also, l’Abbé scatter plots were calculated for each method of increasing central blood volume. L’Abbé plots, tools used to graphically represent information found in a number of trials, assist the reader in understanding the collected data (8). Each point on the scatter plot represents one trial with the proportion of patients receiving a control treatment plotted against the proportion receiving an experimental treatment.

	Results

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The MEDLINE search yielded 91 articles in English, of which 23 identified randomized controlled trials that met our inclusion criteria. They occurred in three categories: comparisons of large versus small dose of crystalloid, colloid versus crystalloid or different colloid regimens, and mechanical or patient positioning as a means of increasing preload. The studies include 1504 patients, with individual studies ranging from 16–160 patients. ( Tables 1–3)

Prevention of Hypotension Using Crystalloid Preload Before Spinal Anesthesia
We retrieved 9 articles comparing two crystalloid volumes. (Table 1) (1,4–7,9–12). One article was divided into two groups, Group 1 having elective cesarean delivery and Group 2 having cesarean delivery after labor (10). Neither group received prophylactic left uterine displacement. All remaining studies involved healthy women at full-term gestation undergoing elective cesarean delivery. In total, 533 patients were involved, 312 in the Experimental group (larger preload volume) and 221 in the Control group (smaller preload volume). Only three articles had a quality score > 2 (7,11,12); one was not assigned a quality score (9), and the earliest study had a quality score of 0 (1).

In all studies, a balanced salt solution was used, and in two studies, the solution contained dextrose (1,10). Total volume of the administered preload varied widely, ranging from 0–1787 mL in the Control group to 997–2970 mL in the Experimental group.

There was a significant effect on the incidence of hypotension in patients receiving a larger preload volume in three studies (1,9,10). The remaining studies demonstrated no significant difference (4–7,11,12). Three of the studies showed a trend toward a decreased incidence of hypotension in the treated group (6,7,12), whereas the other three studies (4,5,11) had similar incidences of hypotension in both groups.

The use of prophylactic and therapeutic ephedrine was different between studies and is outlined in Table 1. The l’Abbé plot for crystalloid preload is depicted in Figure 1. Because Olsen’s study did not report the incidence of hypotension, it could not be included in the graph.

View larger version (25K): [in this window] [in a new window]   Figure 1. The l’Abbé plot of crystalloid preload is shown. The treatment group received a larger volume of preload than the control group, who received a smaller volume or no preload. The dot size is proportional to the sample size of each study. The reference number is in parentheses after the first author’s name.

Prevention of Hypotension Before Spinal Anesthesia Using Colloid
Seven studies compared crystalloid and colloid. (Table 2) (13–19). Six had a crystalloid control (13–16,18,19), and one (17) compared different colloid types and regimens. Some investigators used equal volumes of crystalloid and colloid, whereas others used larger volumes of crystalloid to account for redistribution from the intravascular compartment. Only three studies attempted to blind the investigators to the type of solution given (15,18,19). Sample sizes varied between 26 and 160 patients with a total of 559 parturients.

Mathru et al. (13) used albumin whereas later studies used either hetastarch (HES), pentastarch, modified gelatin, or dextran. Five studies showed a significant decrease in the incidence of hypotension comparing crystalloid to colloid (13,15,16,18,19). The difference in incidence of hypotension in Karinen et al.’s (14) study was similar to that of other investigators but was not statistically significant because of low power. Vercauteren et al. (17) found less hypotension with HES compared with modified gelatin.

Six studies examined neonatal outcomes by using Apgar scores or umbilical artery pH (13–15,17–19). Only Mathru et al. (13) showed improved neonatal outcome in the colloid group. All studies had protocols to rapidly treat hypotension with ephedrine. No difference in nausea and vomiting was noted in the two studies that addressed this issue.

The l’Abbé plot for colloid preload is depicted in Figure 2. Vercauteren’s study did not compare crystalloid to colloid and is therefore not included.

View larger version (27K): [in this window] [in a new window]   Figure 2. The l’Abbé plot of colloid preload is shown. The treatment group received a colloid preload, and the control group received a crystalloid preload. The volume of administered colloid preload varied between studies. The dot size is proportional to the sample size of each study. The reference number is in parentheses after the first author’s name.

Most studies were small (range, 24–97) with two to four groups. Quality scores were poor, with only one score > 2. All patients received between 500 and 2000 mL of prophylactic crystalloid, and none received prophylactic ephedrine. Except for one study (23), patients had left uterine displacement ensured. There were 447 patients in the Control group and 339 patients in the Experimental group.

Wrapping the legs consistently and significantly reduced the incidence of hypotension compared with control or leg elevation. (Table 3) (20–22) Tilting the patient head down was ineffective (24). Inflatable splints reduced the incidence of hypotension from 83% to 48% after a 15-mL/kg crystalloid preload (26). This was statistically significant but the authors concluded that the incidence of this complication was still unacceptably frequent. The use of inflatable boots did not reduce the incidence of hypotension but reduced the need for vasopressors and delayed the onset of hypotension (23) (Table 3).

There was no difference in the incidence of adverse outcomes between groups in studies that measured cord pH or Apgar scores. There was a significant reduction in maternal nausea when inflatable splints were used (26).

The l’Abbé plot for mechanical interventions is depicted in Figure 3.

View larger version (29K): [in this window] [in a new window]   Figure 3. The l’Abbé plot of mechanical interventions is shown above. The treatment group received any form of mechanical intervention including leg wrapping, leg elevation, thromboembolic stockings (TED), inflatable boots and inflatable splints. Control groups received no mechanical intervention. The dot size is proportional to the sample size of each study. The reference number is in parentheses after the first author’s name.

	Discussion

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Only one article, involving the largest number of patients, addressed the issue of a power analysis in the study design (9). Because of ethical concerns of not administering a preload, the authors chose a statistical model incorporating a sequential design using a "play the winner" rule allowing the study to be terminated if a large difference in treatment effect was noted (9). The study, designed to detect a 20% difference in the incidence of hypotension between groups, assumed an approximate incidence of 50% in the preload group with statistical significance at the 10% level ( = 0.1), one-tailed and 90% power (9). The study was terminated after the third statistical analysis with 78 patients in the preload and 62 in the Nonpreload group. The authors reported a statistically significant decreased incidence of hypotension in the Preload group but commented that the administration of a fluid bolus did not eliminate the risk of hypotension and they did not advocate routine fluid loading. However, more patients were entered into the Experimental or larger preload group, indicating that the "winners" were the patients who received a preload. This adds additional support to the notion that volume preloading made a difference in the incidence of hypotension.

Another limitation of the studies listed was the wide variation in preload volume in the control and experimental groups. In five studies, the control group received little or no preload (1,9–12). In contrast, "control" (Nonpreload group) received preload volumes ranging from 750 to 1800 mL in four other studies (4–7).

Criteria for vasopressor administration were not standardized, but in most cases, ephedrine was given in bolus doses to maintain blood pressure at 80%–90% of baseline values. In two studies, investigators gave prophylactic ephedrine to the Control or Nonpreload group (6,11). Jackson et al. (11) began an infusion of 500 mL of Hartmann’s solution with 60 mg of added ephedrine at an unspecified rate when spinal medications were given. The Experimental group received ephedrine as deemed necessary by the anesthesiologist. Olsen et al. (6) administered a bolus dose of ephedrine 0.15 mg/kg IV followed by an infusion of ephedrine 0.4 mg/kg to patients who did not receive a preload. Husaini and Russell (12) used prophylactic ephedrine infusions for both groups, and either an increase in the infusion rate or bolus doses of ephedrine were used to treat hypotension and to maintain blood pressure in the "normal" range. In summary, differences in study protocols account for the heterogeneity of the results reported. (Fig. 1) Crystalloid loading will not reliably prevent hypotension.

Prevention of Hypotension Using Colloid Preload Before Spinal Anesthesia
These studies indicate that colloid is superior to crystalloid in preventing postspinal hypotension for elective cesarean delivery. Only the study with the smallest sample size showed no difference (14). The study by Vercauteren et al.(17) did not have a crystalloid control but was included in this section because two volumes of colloid were compared.

A limitation of these results is the difference in the volumes chosen by the investigators. Three investigators chose a ratio of 2:1 for crystalloid to colloid to account for the redistribution of crystalloid out of the intravascular space (14,15,18), whereas two chose to give the same volume (13,19) and one performed a dose ranging study with ratios of 2:1 and 3:1 (16). Different definitions of hypotension and ephedrine protocols were used, but all studies rapidly treated hypotension when it occurred.

A physiologic explanation of the differences between crystalloid and colloid can be found in Ueyama et al.’s (16) study which elegantly showed that, at 30 minutes, only 28% of the administered lactated Ringer’s solution remained in the intravascular space compared with 100% of the HES solution. With increasing volumes of HES, there was an increase in blood volume and cardiac output and a decrease in the incidence of hypotension. Colloid is a more effective volume expander because it remains longer in the intravascular compartment. Nevertheless, even aggressive expansion of the intravascular space cannot completely abolish the risk of hypotension.

Rout and Rocke (2) suggest that colloids may contribute to decreased afterload via atrial natriuretic peptide release from a stretched atrium or by peripheral vasodilation caused by reduced arterial blood oxygen content. Reducing before central sympathetic block may play an important role in the prevention of postspinal hypotension.

Excessive amounts of intravascular fluid may cause volume overload and pulmonary edema. Karinen et al. (14) attempted to measure central volume by monitoring central venous pressure. They noted a significant increase in central venous pressure in both groups after preloading, a return toward normal after the induction of spinal anesthesia, followed by a steady increase until delivery and no change thereafter. There were no differences between 1 L of crystalloid and 500 mL of colloid. There were no reports of pulmonary edema in any study.

Various colloids were used and Vercauteren et al. (17) showed that HES was superior to modified gelatin but failed to offer an explanation. All of the artificial colloids carry a risk of anaphylactoid reactions although no cases were reported (27). Ring and Messmer (28) reported the incidence of allergic reactions to colloids to be: human serum albumin, 0.011%; gelatin, 0.115%; dextran, 0.32%; and hydroxyethyl starch, 0.085%. Pentastarch, currently available in Europe and Canada, but not in the United States, has the smallest risk (29). Albumin, as a human blood product, carries a theoretical risk of disease transmission.

Overall, colloids can be effective at reducing the incidence of hypotension, with no significant maternal or neonatal side effects. The l’Abbé plot shows a cluster of trials to the left of the equality line, suggesting the usefulness of the intervention. This benefit must be weighed against the increased cost of the colloid and the incidence of adverse reactions (30).

Prevention of Hypotension Using Mechanical Means
Leg wrapping, by using an Esmarch bandage from the foot or ankle to mid-thigh, was the most effective means of reducing the incidence of hypotension compared with the control groups (no intervention or leg elevation alone). In each case, the incidence of this complication, as defined by the authors was reduced to less than 20% (20–22). The use of antithromboembolic stockings was also effective (25). No study demonstrated a reduction in the amount of ephedrine used in each group or any difference in neonatal outcome.

In contrast to other methods of leg compression, inflatable boots or splints seemed to be less effective (23,26). Both interventions describe compression from the foot to the upper thigh. The reason for the discrepancy is not apparent, although these methods may be less effective in increasing central blood volume compared with leg wrapping or antithromboembolic stockings.

There may be several factors accounting for the success of leg wrapping in increasing central blood volume at cesarean delivery. First, there is approximately 150 mL of blood in the legs of nonpregnant subjects without spinal anesthesia (31). During pregnancy, venous blood volume increases in the lower extremities, particularly after the 30th week of gestation, with spinal anesthesia further increasing the volume of blood in the legs by induction of a sympathectomy (32,33). The effect of leg wrapping on the central volume has not yet been measured in parturients. The l’Abbé plot shows a cluster of trials to the left of the equality line, which suggests that mechanical means of increasing central blood volume appears better than no intervention in the prevention of hypotension with spinal anesthesia.

The common clinical practice of volume expansion with crystalloid is not uniformly effective in reducing the incidence of maternal hypotension after spinal anesthesia for cesarean delivery. Colloid administration is more consistent but is associated with additional risks and costs. Mechanical means of central blood volume expansions also appear to be effective but have not come into widespread use. Due to common differences in study design, it is impossible to determine whether prophylactic volume administration affects therapeutic vasopressor use.

In all studies, hypotension of short duration had no adverse effect on the neonate in normal term pregnancies. However, maternal side effects were not measured. This deficiency should be addressed in future studies.

	Acknowledgments

 
This study was supported by the Department of Anesthesia, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999