Baseline low-to-high frequency ratio (LF/HF) of heart rate variability predicted hypotension after subarachnoid block (SAB). LF/HF-guided treatment of hypotension with vasopressors or colloids was investigated.
In 80 women scheduled to undergo cesarean delivery during SAB, LF/HF and systolic blood pressure (SBP) were analyzed. Patients were randomly assigned to a control group (n = 40) or a treatment group (n = 40). Control patients were assigned by their baseline LF/HF to one of two subgroups: LF/HF less than 2.5 or LF/HF greater than 2.5. Treatment patients with baseline LF/HF greater than 2.5 were treated with vasopressor infusion right after SAB (n = 20) or colloid prehydration until LF/HF decreased below 2.5 (n = 20). The incidences of hypotension (SBP < 80 mmHg) and hypertension (SBP > 140 mmHg) were investigated. LF/HF is presented as median and range, and SBP is presented as mean +/- SD.
Three of 17 control patients with low baseline LF/HF (1.7 [1.3/1.8]) demonstrated hypotension, and mean SBP remained stable (lowest SBP = 105 +/- 14 mmHg). In contrast, 20 of 23 control patients with high baseline LF/HF (3.8 [3.3/4.8]; P < 0.0001 vs. low baseline LF/HF) demonstrated hypotension after SAB: lowest SBP = 78 +/- 15 mmHg (P < 0.0001 vs. lowest SBP of control group with low baseline LF/HF). LF/HF-guided vasopressor therapy prevented hypotension in 19 of 20 patients: baseline SBP = 123 +/- 15 mmHg, lowest SBP = 116 +/- 17 mmHg. Mean prophylactic colloid infusion of 1,275 +/- 250 ml reduced elevated baseline LF/HF from 5.4 (4.1/7.5) to 1.3 (0.8/1.59) (P < 0.0001). Hypotension was prevented in 17 of 20 patients: baseline SBP = 115 +/- 13 mmHg, lowest SBP = 104 +/- 19 mmHg. No hypertensive episode was recognized.
LF/HF may be a tool to guide prophylactic therapy of patients at high risk for hypotension after SAB. Vasopressor therapy tended to be more effective compared with colloid prehydration.
SUBARACHNOID block (SAB) is the preferred anesthesia regimen for cesarean delivery because of its lower risk of maternal complications compared with general anesthesia.1Nevertheless, hypotension is a common adverse effect of SAB in these patients.2So far, no prophylactic strategy of preventing hypotension—intravenous fluids or vasopressors—has proved entirely satisfactory and applicable to all patients.3–9Still, a considerable number of women develop hypotension despite prophylactic measures, whereas other patients are at risk of side effects from excessive prehydration or vasopressor infusion.4,5,10
Hypotension during central neuraxial block is mainly a result of decreased systemic vascular resistance after blockade of preganglionic sympathetic fibers. Pregnant women are known to have increased sympathetic activity.11–13Differences of the regulation of the autonomic nervous system among pregnant patients may explain hemodynamic differences in response to SAB. A noninvasive method that reflects the activity of the autonomic nervous system is the analysis of heart rate variability (HRV).14Recently, two studies demonstrated the value of HRV analysis, especially that of the low-to-high frequency ratio (LF/HF) for the prediction of spinal hypotension in pregnant patients.15,16Preoperative determination of the autonomic nervous system regulation may provide an opportunity to guide prophylactic therapy with either volume prehydration or vasopressor infusion and may significantly decrease the risk of spinal hypotension as well as adverse effects of these measures.
We hypothesized that (1) prospectively analyzed HRV can predict hypotension after SAB; (2) an increased LF/HF can be reduced by prehydration, decreasing the risk of hypotension after SAB; and (3) prophylactic vasopressor infusion in patients with increased LF/HF will prevent hypotension after SAB without adverse effects.
Materials and Methods
After approval of the Institutional Ethics Committee of the University-Hospital Schleswig-Holstein, Campus Kiel, Germany, and written informed consent, 105 women (American Society of Anesthesiologists physical status class I) with an uneventful pregnancy, at term, scheduled to undergo elective cesarean delivery during SAB, were enrolled. Exclusion criteria were as follows: signs of active labor, gestational or chronic hypertension, preeclampsia, hypertension elevated liver enzymes low platelets syndrome, coexisting infections, bleeding disorder, emergency cases, age < 18 yr, and known fetal abnormalities. All preanesthetic laboratory values were within normal limits. All women showed sinus rhythm, normal heart rate (heart rate < 110 min−1), and stable blood pressure (100 mmHg < systolic blood pressure [SBP] < 140 mmHg, 50 mmHg < diastolic blood pressure < 90 mmHg) on the day before surgery. Patients received no premedication and no intravenous fluids before entering the study. Cesarean delivery was scheduled as the first operation in the morning, starting at 8:00 am. A nothing-per-os state started at midnight at the day before surgery. Therefore, preoperative fasting period lasted for 8 h.
Heart rate variability analyses were performed before SAB as follows, with every measurement done in the left lateral decubital position: (1) on the day before surgery between 6:00 and 8:00 pm; (2) on the day of surgery, baseline before prehydration; and (3) after prehydration. In addition, in patients who were assigned to colloid prehydration, HRV measurement was repeated after each colloid infusion. A maximum of 1,500 ml was infused as total prehydration. Therefore, three analyses were performed during colloid infusion in the colloid treatment group: Colloid 1, Colloid 2, and After (total) Prehydration. HRV analysis was performed according to Task Force recommendations.17Five-minute recordings of the fast peaks of R waves on the electrocardiogram were acquired with a sampling rate of 1,024 Hz. The beat-to-beat variability of consecutive R waves of the sinus rhythm was measured and continuously stored in a personal computer. Data were analyzed using fast Fourier transformation (Varia Cardio TF4; Olomuoc, Czech Republic). Power spectrum densities were calculated for very low frequencies (VLFs: 0.003–0.04 Hz), lower frequencies (LFs: 0.04–0.15 Hz), and higher frequencies (HFs: 0.15–0.4 Hz) in normalized units, defined as VLF’s, LF’s, or HF’s proportional part of the total power. VLF is thought to reflect regulation of the renin angiotensin system, thermoregulatory processes, and sympathetic activity,18whereas LF is thought to reflect sympathetic and parasympathetic control, and HF is thought to reflect parasympathetic control.19The ratio of absolute values of LF and HF (LF/HF) was reported to correlate with sympathovagal balance.20During measurements, patients were asked to lay quietly in the supine position with left uterine displacement. HRV analysis was performed immediately after the measurement by an investigator blinded to randomization and therapy. Artifacts were eliminated by computer-based artifact detection. Beats were rejected if they varied more than 40% from the preceding beat. These intervals were replaced by the mean of the previous and consecutive beat-to-beat intervals. At most, 5% of a measurement was allowed to be replaced. Otherwise, this specific measurement was not included in the analysis.
Systolic blood pressure, heart rate, and oxygen saturation were recorded at five different events according to HRV measurements: (1) day before surgery; (2) baseline; (3) Colloid 1, Colloid 2, After Prehydration; (4) 5 min after SAB, patient positioned supine with left uterine displacement (SAB + 5 min; hemodynamic parameters were measured minute-by-minute until SAB was fixed and SBP remained stable); and (5) lowest value between onset of SAB and delivery of the newborn (LOW). The time between administration of SAB and event LOW as well as between administration of SAB and delivery of the newborn was recorded.
After baseline measurement, all patients received rapid colloid infusion of 500 ml (6%/130/0.4 hydroxyethyl starch, Voluven®; Fresenius Kabi, Bad Homburg, Germany) according to textbook recommendations.21Thereafter, standardized SAB was performed: The puncture site was interlumbar space L2–L3 or L3–L4 with the patient in a sitting position. Hyperbaric bupivacaine, 12.5 mg (0.5%), was injected via a 25-gauge Sprotte needle with the side port of the needle pointing cephalad. The level of sensory blockade was aimed at thoracic 4–5. Immediately after injection, patients were positioned supine with left uterine displacement. Oxygen (4 l/min) was administered via facemask. The level of sensory blockade was tested by pinprick test. After surgery, all patients remained in the delivery unit and were monitored until they were able to move their legs freely.
This study was performed as a randomized, prospective, clinical trial. Patients were assigned to one of two groups by use of a randomization table before any treatment or HRV measurement at the day of surgery. Forty control patients were treated according to clinical routine at our hospital. Control patients were assigned to one of two subgroups by their baseline LF/HF according to our previous findings.16Patients with baseline LF/HF less than 2.5 (C < 2.5, n = 17) were compared with those with baseline LF/HF greater than 2.5 (C > 2.5, n = 23). If patients were assigned to the treatment group, further investigations depended on baseline LF/HF. Patients were treated only if baseline LF/HF exceeded 2.5. Patients with low baseline LF/HF, randomly assigned to the treatment group (n = 25), were not further investigated to ensure equal group size of control and treatment group and because of limited HRV equipment. Forty patients with baseline LF/HF greater than 2.5 were assigned to the treatment group. Twenty patients were randomly assigned to the colloid prehydration group (T-colloid). They were consecutively prehydrated with 500 ml colloid infusion up to a total of 1,500 ml. After each infusion HRV was analyzed instantly. If LF/HF decreased to low-risk values (LF/HF < 2.5), no further colloid fluid was infused, and crystalloid fluid was administered to keep the intravenous line open. Total colloid infusion was limited to 1,500 ml, even if LF/HF remained increased. Twenty patients were assigned to the vasopressor group (T-vasopressor). Right after SAB, rapid infusion of vasopressor (Akrinor®; AWD pharma, Dresden, Germany: 200 mg cafedrin-1HCl, 10 mg theodrenalin-HCl in 500 ml crystalloid fluid) was started. Vasopressor was infused at 1,000 ml/h. Thereafter, crystalloid fluid was administered to keep the intravenous line open.
Hypotension after SAB was stepwise defined as moderate hypotension (SBP < 100 mmHg) and severe hypotension (SBP < 80 mmHg). The incidence of hypotension and hypertension, defined as SBP greater than 140 mmHg, was investigated in both prophylactic treatment groups. In all patients, hypotension and bradycardia after SAB were treated in a standardized manner if necessary. No treatment was administered if the SBP was greater than 100 mmHg. Treatment of hypotension also was defined in a stepwise manner. Moderate hypotension (100 mmHg > SBP > 80 mmHg) was treated with rapid infusion of another 500 ml hydroxyethyl starch, 6%/130/0.4. If SBP increased to no-treatment levels, no further therapy was administered. If moderate hypotension was still present after a second colloid infusion, an additional intravenous vasopressor bolus of 50 mg cafedrin-1HCl and 2.5 mg theodrenalin-HCl was given. Severe hypotension was treated immediately with intravenous vasopressor administration and simultaneous rapid infusion of 500 ml colloid until SBP increased to 100 mmHg. Treatment for possible side effects of prophylactic therapy was defined as follows: SBP > 140 mmHg: vasopressor infusion was stopped; SBP > 160 mmHg: vasopressor infusion was stopped, and urapidil administration of 10–20 mg was injected until SBP decreased below 160 mmHg. If signs of volume overload occurred in the T-colloid group (shortness of breath, arterial oxygen saturation < 95%), infusion was stopped immediately, and 8 l/min oxygen was delivered via facemask. The incidence of moderate and severe hypotension (including the total need for vasopressor boluses) and the number of patients demonstrating side effects of prophylactic treatment were documented. In Germany, ephedrine is not approved by the national drug administration. The mechanisms of action of the administered vasopressor cafedrin/theodrenalin are comparable to those of ephedrine.
Group size was calculated based on a power analysis. The primary end point was SBP after SAB. Power calculation was based on a clinically significant difference of SBP of 20 mmHg between the low-risk control subgroup and high-risk control subgroup, as well as the treatment group. It indicated that a sample size of 15 patients per treatment subgroup would have a power of 80% at the 5% significance level to detect a difference of 20 mmHg of SBP. To cover for dropouts, 20 women per treatment subgroup were compared. The sample size of the control group matched the sample size of the treatment group. Therefore, a total of 80 patients were enrolled in the study. Data were analyzed using standard software (PRISM 4.02 GraphPad Software; San Diego, CA). All numeric data were checked for normal distribution using the Kolmogorov-Smirnov test based on the Dallal and Wilkinson approximation to the Lilliefors method. Normally distributed data and normalized HRV data during different events were analyzed using two-way analysis of variance factoring for event and treatment. Within-group differences over time were analyzed using one-way analysis of variance followed by Bonferroni correction for multiple comparisons. All parametric data are expressed as mean ± SD; nonparametric data are expressed as median, 25th to 75th percentiles, and range. A value of P < 0.05 was considered statistically significant.
A total of 105 patients were randomly assigned to either the control group or the treatment group. Forty patients were assigned to the control group (17 patients with low baseline LF/HF [43%] and 23 patients with high baseline LF/HF [57%]). Sixty-five patients were assigned to the treatment group. However, 25 patients (38%) randomly assigned to prophylactic treatment demonstrated low baseline LF/HF as an exclusion criterion. These patients were not further analyzed. The remaining 40 patients were equally assigned to either the T-vasopressor or the T-colloid subgroup. Patients of all groups were comparable with respect to demographic and intraoperative data. Activity; pulse; grimace; appearance; respiration levels (Apgar) at 1, 5, and 10 min after delivery; umbilical artery pH; infant height and weight; time period between administration of SAB and delivery of the newborn; and time period between administration of SAB and event LOW were comparable between groups (table 1). To reduce an increased LF/HF by intensified colloid prehydration, 1 patient received 500 ml colloid infusion, 7 patients received 1,000 ml, and 12 patients received the maximum amount of 1,500 ml colloid infusion (mean, 1,275 ± 250 ml).
HRV data are shown in table 2and figure 1. No differences were found in any of the investigated parameters at the day before surgery. VLFs tended to be lower in the C < 2.5 group at the day before surgery and at baseline on the day of surgery. However, VLFs did not demonstrate significant differences between groups at any of the defined events. The two control subgroups showed the defined differences with significantly higher LF/HF and LF as well as significantly lower HF in group C > 2.5 compared with group C < 2.5 at baseline and event After Prehydration. Baseline LF, baseline HF, and baseline LF/HF of treatment groups were comparable to those of control group C > 2.5 and thus significantly different compared with baseline HRV parameters of C < 2.5. The T-colloid group demonstrated significant changes of HRV parameters in the course of colloid infusions in terms of significant decrease of LF (P = 0.045) and LF/HF (P = 0.012), as well as a significant increase of HF (P = 0.018, baseline versus After Prehydration).
Hemodynamic parameters as well as peripheral oxygen saturation are shown in table 3. No significant differences were found between groups in terms of heart rate, peripheral oxygen saturation, and diastolic blood pressure. No adverse effects due to prophylactic treatment were recorded in the T-vasopressor or T-colloid groups. There was no difference in SBP (figs. 2A and B) between groups at baseline. Three of 17 patients (19%) in the low baseline LF/HF control group developed hypotension (1 patient had moderate hypotension with additional colloid infusion, 2 patients had severe hypotension with two and three additional vasopressor boluses, respectively). Twenty of 23 control patients (90%) with high baseline LF/HF demonstrated postspinal hypotension (12 patients with moderate hypotension and 8 patients with severe hypotension; mean vasopressor boluses 2.3 ± 0.5; P = 0.037, high baseline LF/HF versus low baseline LF/HF). The mean SBP in the C < 2.5 subgroup showed no significant decrease after SAB, whereas it decreased significantly in patients in the C > 2.5 subgroup (P < 0.0001, baseline vs. event LOW). Values at event LOW were significantly lower in the C > 2.5 group compared with the C < 2.5 group (P < 0.0001). The mean SBP of the T-vasopressor group remained stable throughout SAB. Mean values demonstrated neither hypotension nor hypertension after SAB. Only one individual patient (5%) showed a severe decrease of SBP, from 113 mmHg at baseline to 78 mmHg at event LOW. This patient required two vasopressor boluses and additional colloid infusion. The SBP of the T-colloid group at event After Prehydration was comparable to that of the T-vasopressor group. A mean of 1,275 ± 250 ml colloid was infused before SAB. SBP of 3 patients (15%) decreased considerably after SAB: patient 1 SBP (LOW) = 70 mmHg (three vasopressor boluses), patient 4 SBP (LOW) = 55 mmHg (four vasopressor boluses), patient 20 SBP (LOW) = 76 mmHg (two vasopressor boluses). Additional colloid infusion was administered in all patients demonstrating hypotension. Patients 1 and 20 showed an LF/HF at event After Prehydration of less than 2.5, whereas patient 4 demonstrated an increased LF/HF even after maximum colloid infusion.
In a prospective, randomized clinical trial, the value of baseline LF/HF-guided prophylactic treatment of postspinal hypotension was investigated in 80 pregnant women scheduled to undergo elective cesarean delivery. Control patients showed significant differences in lowest SBP after SAB depending on baseline LF/HF, suggesting that patients with an increased baseline LF/HF are at high risk of hypotension due to sympatholysis in the course of SAB. Two different prophylactic treatments were tested in patients with increased baseline LF/HF. LF/HF-guided intensified colloid prehydration reduced baseline LF/HF before SAB to a low mean value. Post-SAB hypotension occurred in 15% patients. In the vasopressor treatment group, stable blood pressure was maintained throughout anesthesia by vasopressor infusion right after SAB. In this group, hypotension occurred in 5% of patients. None of the patients developed any signs of adverse effects of prophylactic therapy.
There has been much attention in the literature to methods of preventing and treating hypotension in obstetric anesthesia. Uterine displacement is routine,22whereas the use of intravenous fluids or vasopressor is controversial.7,23,24Colloid prehydration reduces hypotensive episodes significantly,8,9but still, a considerable number of patients develop hypotension. Therefore, the rationale of prehydration is generally questioned.7Vasopressors significantly reduce the incidence of hypotension after SAB. Higher dosages were demonstrated to be more effective, but the incidence of hypertensive episodes increased at the same time.3,25The risk of adverse effects of prophylactic measures could be minimized if prophylactic treatment could be adapted to the individual risk of hypotension after SAB by previous assessment risk. Recently, Chamchad et al. ,15as well as our group,16demonstrated the predictive value of HRV analysis. Chamchad et al. 15demonstrated a correlation of point correlation dimension, a measure of HRV for hypotension accompanying spinal anesthesia for cesarean delivery. In 60 women scheduled to undergo elective cesarean delivery during SAB, our group demonstrated that baseline LF/HF, which may reflect sympathovagal balance, was increased in patients with severe hypotension after SAB.16Control patients of the current study confirmed these previous findings. Patients with low baseline LF/HF did not develop hypotension, whereas a high baseline LF/HF was correlated with significant decreases of SBP. We concluded that baseline LF/HF predicts the risk of post–spinal anesthesia hypotension.
Different vasopressors have been investigated for therapy and prophylaxis of hypotension.3,23,24Ephedrine and phenylephrine are routinely used for treatment of postspinal hypotension.24In the international literature, ephedrine is still the vasopressor of first choice for prophylactic infusion and therapy of hypotension after SAB. In a nationwide survey of practice, ephedrine was found to be used by 95% of the interviewed anesthesiologists of Great Britain.24,26In Germany, ephedrine is not approved by the national drug administration. The vasoactive drug cafedrin/theodrenalin was administered instead, exerting direct β-adrenergic agonist action with additional activation of cyclic adenosine monophosphate. Increase of blood pressure is achieved by an increase of cardiac output and reduction of venous pooling without increase of systemic vascular resistance.27,28The mechanisms of action of the administered drug are comparable to those of ephedrine.
In the current literature, it is widely agreed that intravenous vasopressor infusion reduces the incidence of spinal hypotension significantly. The higher the injected vasopressor dosage, the lower is the incidence of hypotension. Ngan Kee et al. demonstrated that 30 mg intravenous ephedrine was superior to 20 as well as 10 mg intravenous ephedrine. Hypotension was prevented in 85 versus 80 versus 35% of the patients, respectively.3Nevertheless, the incidence of hypertension increased simultaneously. Forty-five percent of the 30-mg group compared with 25% of the 20-mg group and 5% of the 10-mg group developed hypertension due to prophylactic treatment. These dose-dependent side effects were also demonstrated in a current meta-analysis.5Despite all prophylactic measures, a considerable number of patients develop hypotension. An incidence of at least 20–30% has been reported. Besides, the risk of hemodynamic disorders and fetal acidosis is correlated with the use of ephedrine.5,24,29–31Therefore, prophylactic measures must be administered carefully, and it is preferable that they be adapted to individual needs. HRV analysis, especially the measurement of LF/HF, is a tool to identify patients at high risk preoperatively and to guide individual therapy. Accordingly, hypotension was reduced to a lower incidence compared with any measure described in the current literature. In addition, we demonstrate no adverse effects in the current study. No patient developed hypertension in the course of vasopressor infusion. We conclude that (1) increased baseline LF/HF, which may reflect an increased sympathovagal balance, may identify patients at risk of spinal hypotension; (2) sympatholysis due to regional anesthesia can be successfully diminished by intravenous vasopressor infusion in these patients; and (3) individual risk stratification averts adverse effects.
Fluid prehydration has been investigated as a prophylactic measure for prevention of hypotension. Prophylactic infusion of crystalloid fluid only marginally reduced the incidence of hypotension after SAB because of its short intravascular half-life.6,9,32In contrast, colloid prehydration decreased hypotensive episodes significantly.8,9Intravascular volume expansion reduced the relative hypovolemia caused by SAB-induced vasodilation. Venous return increases, resulting in an increase of cardiac output.9Nevertheless, a considerable number of patients develop hypotension; therefore, the rationale of prehydration was generally questioned.7The incidence of hypotension published in the literature after 500–1,000 ml colloid prehydration is at least 16%.8,9,33Our results suggest that prehydration must be adapted to individual needs. We demonstrated a significant decrease of LF/HF and LF as well as increase of HF due to colloid prehydration. Changes may reflect an autonomic nervous system shift from high sympathetic activity to lower sympathetic activity and higher parasympathetic activity in the course of prehydration. Nevertheless, prehydration was less effective compared with vasopressor infusion. Three patients (15%) developed hypotension despite therapy. This incidence is comparable to published results. This may be due to inadequate prehydration in some of the patients. Despite 1,500-ml colloid infusion, LF/HF of one hypotensive patient remained increased. Study design restricted volume at this point. It can be speculated that this woman might have benefited from even more fluid before SAB. Increased LF/HF even after maximum colloid prehydration supports the predictive value of LF/HF for hypotension. However, two patients demonstrated hypotension after reduction of increased LF/HF due to colloid prehydration. Physiologic reactions to excessive preload may explain the limited use of fluids. There is evidence that volume prehydration before SAB induces atrial natriuretic peptide distribution, resulting in increased diuresis and vasodilation abolishing the desired effects.7,34,35We conclude that colloid prehydration decreased the incidence of hypotension to levels comparable to published results. HRV-guided individual treatment did not further reduce the incidence of hypotension. This may be due to the study design, physiologic reactions to fluid infusion, and timing of the measure.
As described in our previous work, differences in HRV parameters were only present on the day of surgery. No significant differences were found on the day before surgery.16Reasons for differences between the day before surgery and the day of surgery remain speculative. The nothing-per-os state, stress, and anxiety may cause these differences on the day of surgery.36Further studies are necessary to investigate reasons for these differences and potential impact on prophylaxis and treatment of hypotension.
Some limitations of our study should be noted. Artifacts during HRV data recording, e.g. , due to movements of the patient, were inevitable to some degree. However, artifacts were eliminated by computer-based artifact detection followed by an evaluation by an expert blinded to the hemodynamic effects of SAB. No measurement had to be deleted completely. Unfortunately, a device routinely analyzing HRV is not yet commercially available. Therefore, conversion of our results to a clinically routine setting is currently not possible.
Risk evaluation for spinal hypotension was based on a simple analysis of standard electrocardiographic recordings at high acquisition rates. Theoretically, if HRV monitoring were commercially available, the technique could be easily implemented in routine clinical monitoring, and physicians could be trained for interpretation in a reasonable time. It was demonstrated that HRV analysis of short intervals predicts hypotension after SAB in an obstetric setting. HRV-guided therapy significantly reduces the incidence of hypotension and averts negative side effects.