Hip fracture in the elderly is associated with frequent mortality and prolonged rehabilitation and often requires long-term medical care (1). There is a frequent incidence of under-nutrition and weight loss in this population, which seems to be an important determinant of both frequency of hip fracture and clinical outcome after surgical repair (2,3). The loss of body protein, a characteristic feature of the catabolic stress response to surgical tissue trauma, may induce or exacerbate preexisting malnutrition, which will prolong convalescence and further increase the risk of postoperative complications and mortality (4,5). Therefore, preservation of whole body protein in patients undergoing hip surgery represents a clinically relevant goal.
Many studies demonstrate that the catabolic response to surgery can be modified by the anesthetic technique. Neuraxial block of afferent and efferent signals with epidural local anesthetics has often been shown to modulate protein economy after abdominal surgery, most likely mediated through its suppressive effect upon the hypothalamopituitary-adrenal stress response (6). Although the impact of epidural blockade upon protein economy after abdominal surgery has been extensively studied, its potential role in modifying protein catabolism after lower extremity surgery remains unclear. The findings of one study reported that perioperative epidural blockade lead to a decrease in muscle amino acids (glutamine, valine, and asparagine) after hip replacement surgery (7). In contrast, another study demonstrated that epidural blockade did not attenuate postoperative protein loss, as measured by the urinary excretion of nitrogen and 3-methylhistidine (8).
The purpose of the present protocol was to test the hypothesis that combined spinal and epidural blockade (CSE) exerts an inhibitory effect on amino acid oxidation after hip replacement. To gain an integrated insight into the catabolic responses after hip surgery, glucose and protein kinetics were assessed by a stable isotope dilution technique using primed continuous infusions of [6,6-2H2]glucose and L-[1-13C]leucine.
After approval by the Ethics Committee of the University of Regensburg, 16 patients undergoing elective surgery for primary total hip arthroplasty were admitted to the study. Written informed consent was obtained from all patients. Exclusion criteria were any cardiac, hepatic, renal, endocrine or metabolic disorders, ingestion of any medication known to affect metabolism (such as corticosteroids or β-adrenergic blockers), and history of severe sciatica or back surgery, which contraindicates the use of epidural catheters.
Patients were randomly assigned to receive either general anesthesia followed by patient-controlled analgesia (PCA) with piritramide IV (control group; n = 8) or CSE with bupivacaine and ropivacaine, respectively (CSE group; n = 8). Randomization was performed using a sealed envelope with a computer-generated random allocation.
All patients received premedication (20 mg of clorazepate p.o.) at 8 pm the night before surgery. In the control group, general anesthesia was induced by 1.5–2 mg/kg of propofol and 2–3 μg/kg of fentanyl. Rocuronium 0.6 mg/kg was administered to facilitate endotracheal intubation, and patients’ lungs were ventilated with 30% oxygen in air to maintain normocapnia. General anesthesia was maintained by supplemental doses of fentanyl (1.5 μg/kg) and desflurane at end-tidal concentrations as required to keep heart rate within ±20% of preoperative values. The degree of muscle relaxation was monitored using train-of-four ratio and supplemental doses of rocuronium were applied as required for complete surgical muscle relaxation.
In the CSE group, an epidural catheter was inserted at a lumbar level between L2 and L3 before the operation and a test dose of bupivacaine 0.5% (3 mL) was administered to eliminate accidental intrathecal placement of the catheter. Afterwards, spinal anesthesia was performed at the lumbar interspace 3/4 using isobaric bupivacaine 0.5% (mean dose, 3.3 ± 0.3 mL).
The sensory block to cold stimulus was tested, and a bilateral sensory block level at least up to T10 was confirmed in all patients. During the operation, patients received boluses of midazolam (1 mg) for adequate sedation. Fluid was given as balanced electrolyte solution (VE®; Serumwerk Bernburg, Bernburg, Germany) at a rate of 8–10 mL·kg−1·h−1 during surgery and 1.5–3 mL·kg−1·h−1 thereafter. Blood loss was replaced with colloids (Voluven®, 6% HES 130/0,4; Fresenius, Bad Homburg, Germany). During surgery, patients were covered with a warming blanket to maintain normothermia. Hemodynamic monitoring was performed using a three lead electrocardiogram monitor and radial artery catheterization for continuous arterial blood pressure measurement.
In the control group, postoperative pain relief was achieved with IV piritramide. In the postanesthesia care unit (PACU), patients received piritramide boluses as required to achieve pain scores less than 4 on a visual analog scale (mean dose, 9 ± 9 mg). Thereafter, PCA was set to deliver 1.5–2 mg IV bolus doses of piritramide, with a 10-min lockout and a 4 h maximum dose of 20 mg.
In the CSE group, an epidural infusion of 5–7 mL/h of 0.2% ropivacaine supplemented with 0.5 μg/mL of sufentanil was commenced as soon as regression of motor block (Bromage score ≤2) was obvious. Patients could receive additional boluses through a patient-controlled epidural analgesia pump on demand (4–6 mL, 45 min lockout interval, 4 h maximum dose = 45 mL). Analgesic effectiveness was monitored every 6 h, and treatment in both groups was adjusted to obtain a dynamic pain score on movement <4 on a visual analog scale (0–10).
The rates of appearance of glucose (Ra glucose; endogenous glucose production) and leucine (Ra leucine) were determined 1 day before and 1 day after surgery by stable isotope tracer technique using primed continuous infusions of [6,6-2H2]glucose and L-[1-13C]leucine (Euriso-Top, Saarbrücken, Germany). Sterile solutions of the isotopes were prepared by the hospital pharmacy and kept refrigerated at 4°C until 2 h before each study period.
Both tests were performed beginning between 8 and 9 am after fasting for at least 12 h. A catheter was placed in a superficial vein in the dorsum of the hand and kept patent with balanced electrolyte solution (2 mL·kg−1·h−1). A superficial vein of the contralateral arm was cannulated to provide access for the infusion of [6,6-2H2]glucose and L-[1-13C]leucine. Blood and expired air samples were taken to determine baseline isotopic enrichments. Thereafter, priming doses of NaH13CO3 1 μmol/kg, L-[1-13C]leucine 4 μmol/kg, and [6,6-2H2]glucose 22 μmol/kg were administered followed immediately by continuous infusions of [6,6-2H2]glucose 0.22 μmol·kg−1·min−1 and L-[1-13C]leucine 0.06 μmol·kg−1·min−1, respectively. Isotope infusion was uninterrupted throughout the entire study period. Expired breath and blood samples for the determination of isotopic enrichments as well as for the measurement of metabolic substrates (glucose, lactate, and free fatty acids) and hormones (insulin, glucagon, and cortisol) were collected, as indicated in Figure 1. Breath samples were collected through a mouthpiece in a 3-l bag and transferred immediately to 5-mL vacutainers until analysis. Blood samples were immediately transferred to a heparinized tube, centrifuged at 4°C (3000 g; 10 min), and the obtained plasma was stored at −70°C until analysis.
Oxygen consumption (V̇o2) and carbon dioxide production (V̇co2) were measured before and after surgery by indirect calorimetry using the open system indirect calorimetry device Deltatrac Metabolic Monitor (Datex Instrumentarium, Helsinki, Finland). The values of V̇o2 and V̇co2 and the calculated respiratory quotient (RQ) represent an average of the data obtained over a period of 20 min on each occasion, with a coefficient of variation (CV) <10%.
After derivatization of plasma glucose to its pentaacetate compound, the [6,6-2H2]glucose enrichment was quantified by gas chromatography-mass spectrometry using positive chemical ionization (9). Plasma α-[1-13C]ketoisocaproate (α-[1-13C]KIC) enrichment was analyzed by selected-ion monitoring gas chromatography-mass spectrometry using a Pentafluorobenzyl-derivate in negative chemical ionization mode (10). Expired 13CO2 enrichment for the calculation of leucine oxidation was analyzed by isotope ratio mass spectrometry (Iso-Analytical Ltd, Cheshire, UK).
Plasma concentrations of glucose and lactate were quantified using a blood gas analyzer (Rapidlab 865; Bayer Health Care Diagnostica, Fernwald, Germany) based on a glucose and lactate oxidase method. Free fatty acid plasma concentrations were determined by an enzymatic colorimetric kit (Roche Diagnostics, Mannheim, Germany). Plasma cortisol, insulin, and glucagon concentrations were analyzed by means of a double antibody radioimmunoassay (cortisol: Bayer Health Care Diagnostica; insulin and glucagon: DPC Biermann, Bad Nauheim, Germany).
During physiologic and isotopic steady-state, the rate of appearance of unlabeled substrate can be derived from the plasma isotope enrichment (atom percent excess [APE]) calculated by: Ra = I × (APEinf/APEpl − 1), where APEinf is the tracer enrichment in the infusate, APEpl is the tracer enrichment in plasma, and I is the infusion rate of the labeled tracer. The APE values used for the calculation of the rate of appearance were the average of four APE measurements. Steady-state conditions were assumed when the CV of the APE values at isotopic plateau were <5%.
During steady-state conditions, leucine flux is defined by the equation: Q = S + O = B + I, where S is the rate of leucine uptake for protein synthesis, O is the rate of leucine oxidation, B is the rate at which leucine enters the free amino acid pool from endogenous protein breakdown, and I is the rate of leucine intake, including tracer and diet. Therefore, under postabsorptive conditions when there is no exogenous leucine entering the plasma pool, the only source of leucine is that derived from endogenous protein breakdown and consequently, the rate of leucine breakdown equals leucine flux. Plasma α-[1-13C]KIC enrichment was used for calculating both flux and oxidation of leucine, because it has been demonstrated to reflect the intracellular precursor pool enrichment more precisely than leucine itself (11). In the calculation of leucine oxidation, a correction factor of 0.76 was used to account for the fraction of 13CO2 released from leucine but retained within slow turnover rate pools of the body (11).
Under steady-state conditions, whole body glucose uptake equals the rate of endogenous glucose production. However, glucose uptake increases with increasing blood glucose concentration because most glucose uptake occurs in noninsulin sensitive tissues and therefore depends on the diffusion gradient of glucose. Therefore, whole body glucose uptake is not an accurate measure of the tissue’s ability to take up glucose. The fractional glucose clearance rate represents an index of the tissue’s capacity to take up glucose. The plasma clearance rate of glucose was calculated as the Ra glucose divided by the corresponding plasma glucose concentration.
The primary end-point of the study was whole body leucine oxidation on the first postoperative day. The sample size calculation was based on the results of a previous report demonstrating a 25% reduction of leucine oxidation by epidural blockade after abdominal surgery (12). For an expected difference in leucine oxidation of 25% between the groups (power 80%; α = 0.05), 16 patients were calculated to be sufficient.
Differences between and within groups were analyzed by analysis of variance with post hoc test by the Dunnett test. Differences were judged significant if P was 0.05 or less. Data are presented as mean ± sd.
Because of insufficient postoperative analgesia, one patient in the CSE group required additional piritramide IV and was excluded from analysis. Therefore, we present data on seven patients in the CSE group and eight patients in the control group. Both groups were comparable with regard to age, height, weight, sex, and ASA classification (Table 1). There were no differences in duration of surgery, estimated blood loss, and the total amount of fluid administered throughout the study period. The total amount of piritramide administered in the control group during the entire study period was 38 ± 24 mg. Patients in the CSE group received a total of 147 ± 22 mL of the epidural medication with ropivacaine 0.2% and sufentanil 0.5 μg/mL after the operation. There was no difference in pain visual analog scores between groups during the postoperative study period (CSE, 1.6 ± 0.7; control, 2.1 ± 0.8).
Perioperative heart rate remained unchanged with both anesthetic techniques (Table 2). In the control group, mean arterial blood pressure decreased during surgery and remained lower than before surgery (P < 0.05). In the CSE group, mean arterial blood pressure decreased 60 min after skin incision and in the PACU when compared with preoperative values (P < 0.05). Hemoglobin concentration decreased during and after surgery to a similar extent in both groups (P < 0.05).
Perioperative plasma glucose concentration increased in the control group and remained unchanged in the CSE group, leading to significant differences between the groups at 60 min after skin incision and in the PACU (P < 0.05; Fig. 2). However, this difference was abolished on the first postoperative day.
An isotopic plateau of [6,6-2H2]glucose, α-[1-13C]KIC, and expired 13CO2 was achieved in all patients (CV < 5%), permitting the use of the steady-state equation. There were no significant changes in Ra glucose and plasma glucose clearance (Table 3). Perioperative Ra leucine and protein synthesis also remained unchanged. However, leucine oxidation rate increased in the control group and remained unaltered in the CSE group, leading to a significant difference between the groups one day after surgery (P < 0.05). Whole body V̇o2, V̇co2, and the RQ did not change during the study period.
Plasma lactate and free fatty acid concentrations remained unaltered with both anesthetic techniques (Table 4). Insulin plasma concentration decreased during surgery in the control group (P < 0.05) and did not change in the CSE group. There were no changes in glucagon plasma concentrations with both anesthetic techniques. Plasma cortisol concentrations increased during and after the operation in the control group (P < 0.05) and remained unchanged in the CSE group, leading to lower intraoperative values in the CSE group than in the control group (P < 0.05).
Neuraxial blockade with spinal or epidural local anesthetic is a widely used anesthetic technique for hip surgery. It has been associated with a number of advantageous effects, such as superior pain relief, better mobilization, and less risk of deep vein thrombosis and pulmonary embolism (6,13–15). A meta-analysis demonstrated a reduced mortality in patients undergoing major orthopedic surgery on the lower extremities with this anesthetic technique (14).
The effect of CSE on the catabolic stress response during and after hip surgery, however, has not been studied. Using stable isotope tracers, we demonstrated that CSE inhibits the increase in amino acid oxidation on the first postoperative day, and thus, it is a useful anticatabolic strategy in patients undergoing hip surgery. Because protein catabolism has been identified as an important factor contributing to postoperative fatigue, prolonged convalescence, and increased morbidity, preservation of whole body protein may be a possible mechanism by which CSE exerts it beneficial clinical effects after hip surgery.
The observed anticatabolic effect is in line with a previous study showing reduced muscle amino acid concentrations in patients receiving epidural anesthesia and analgesia during and after hip replacement (7). In contrast, another investigation reported no protein-sparing effect by epidural blockade after hip arthroplasty (8). It has to be noted, however, that epidural blockade in our study was maintained for 24 hours after the operation, whereas the study showing negative results limited the use of epidural blockade to the period of surgery. Because previous investigations in abdominal surgery support the contention that epidural blockade has to be continued into the postoperative period to exert a protein-sparing effect (16), this difference in study design may explain the discrepancy between our results and the findings of Carli and Schricker (16). It is also of interest to note that we used spinal anesthesia during surgery, whereas Carli and Schricker administered epidural blockade with local anesthetic. Because spinal anesthesia has been shown to produce a more efficient afferent blockade (17) and to lead to a more pronounced reduction of the metabolic-endocrine response than epidural blockade (18), this different anesthetic technique might be an additional reason for the conflicting results.
Protein catabolism, however, represents a surrogate variable for clinical outcome. Whether the observed anticatabolic effect of CSE is beneficial in patients with uncomplicated recovery from hip surgery cannot be answered by the present protocol. Although recent evidence indicates that epidural analgesia represents a key component of strategies to enhance functional exercise capacity and quality of life after colorectal surgery, it remains to be determined if these findings can be transferred to patients undergoing extremity surgery. The 24-hour protocol represents another potential limitation to our investigation. Because our study was terminated on the first postoperative day, we cannot determine the duration of the protein-sparing effect of neuraxial blockade. In patients undergoing abdominal surgery, however, epidural analgesia has often been shown to exert a protein-sparing effect, even on the second day after the operation (6,12).
Another characteristic feature of the metabolic response to surgery is the increase in plasma glucose concentration, a consequence of both stimulated glucose production and impaired glucose use. Considering the adverse effects of hyperglycemia, such as compromised immune function(19), increased wound infection (20), enhanced protein catabolism (21), poor clinical outcome after myocardial infarction (22), and cerebral ischemia (23), preservation of perioperative glucose homeostasis represents a clinically relevant goal. In agreement with previous investigations (6), CSE in the present protocol inhibited the increase in glucose plasma concentration during hip surgery. However, observations based on plasma substrate concentrations alone provide no insight into dynamic metabolic pathways, i.e., the smaller glucose plasma concentration in the CSE group could have been the consequence of decreased glucose production, increased glucose use, or a combination of both. Although the present study was not designed to elucidate the underlying mechanism, it was demonstrated in patients undergoing abdominal surgery that the inhibitory effect of epidural blockade on the hyperglycemic response during surgery is mediated through a suppressive effect on endogenous glucose production (24). On the first postoperative day, however, patients in both groups were normoglycemic, and there was no difference in glucose production rate between the groups. These results further indicate that the hyperglycemic reaction to surgery is most pronounced during the acute phase of the stress response and diminishes during the postoperative period.
Because the present investigation was not designed to elucidate the biochemical factors responsible for the metabolic effects of CSE, we can only speculate on the underlying endocrine mechanisms. Many of the catabolic responses to surgery have been ascribed to characteristic endocrine changes, in particular to the increased plasma concentrations of the counter-regulatory hormones cortisol, glucagon, epinephrine, and norepinephrine. Although plasma catecholamines were not determined in our study and glucagon plasma concentrations remained unchanged, intraoperative cortisol plasma levels were significantly lower in the CSE group than in the control group. Considering the well known catabolic influence of cortisol and its counteracting effect on insulin, it seems conceivable that the inhibition of the hypothalamic-pituitary adrenal response by CSE played a major role in mediating its inhibitory effect on intraoperative glucose metabolism and postoperative protein catabolism.
In conclusion, we have found that CSE inhibits the increase in plasma glucose concentration during hip surgery but does not modify glucose metabolism on the first postoperative day. In addition, CSE reduces protein loss one day after hip arthroplasty and thus represents a useful anticatabolic strategy for patients undergoing hip surgery.
The excellent technical assistance of Regina Lindner is gratefully acknowledged.
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