(Adapted from Georgeson KE, Inge TH, Albanese CT: Laparoscopically assisted anorectal pull-through for high imperforate anus: a new technique, J Pediatr Surg 35:927, 2000.)

Laparoscopic gastrostomy involves placement of an umbilical port and a left subcostal cannula (the future site of the gastrostomy). The stomach is pulled to the abdominal wall and the gastrostomy is performed using the Seldinger technique (Fig. 23-2). Operative time is approximately 30 minutes (Tomicic et al., 2002). The risks may be lower than in percutaneous endoscopic gastrostomy in small children, because the procedure is done under direct vision. There is less trauma than with open surgery, and feedings are initiated within 24 hours. Laparoscopic fundoplication for the treatment of gastroesophageal reflux disease is associated with a complication and recurrence rate comparable with or less than that for open surgery (Esposito et al., 2000).

FIGURE 23-2 Laparoscopic gastrostomy. The stomach is entered and pulled up to the anterior abdominal wall (A) and is sutured in place (B). The gastrostomy tube is then placed (C). See related video online at www.expertconsult.com.

The laparoscopic treatment of appendicitis in children has been controversial, particularly in complicated cases (e.g., gangrene, perforation). Experience indicates, however, that laparoscopic appendectomy is not associated with an increased risk compared with open surgery, even in the presence of perforation (Meguerditchian et al., 2002). The incidence of wound infections and intraabdominal abscesses may be less in laparoscopic than in open appendectomy (Paya et al., 2000). Surgical times are comparable, and postoperative pain and length of hospital stay are diminished (Canty et al., 2000; Lintula et al., 2001). Comparable results have been reported for laparoscopic cholecystectomy (Esposito et al., 2001) and laparoscopic splenectomy in pediatric patients (Danielson et al., 2000; Park et al., 2000). Infants undergoing laparoscopic pyloromyotomy have shorter times to enteral feeding and hospital discharge (Hall et al., 2009). Diagnostic laparoscopy and laparoscope-guided cholangiography are being used in the evaluation of neonatal conjugated hyperbilirubinemia, avoiding the need for laparotomy and operative cholangiography (Hay et al., 2000).

The role of laparoscopy in the treatment of solid neoplasms is evolving. Indications include biopsy of suspected malignancies, staging or determination of resectability, second-look procedures to help determine response to chemotherapy, and diagnosis of recurrent or metastatic disease (Sailhamer et al., 2003). Laparoscopic tumor ablation or curative resection may have a role in selected cases. Open surgery may be required when complete resection of the intact specimen with delineation of surgical margins is part of the protocol design in patients enrolled in multicenter studies. Although advocates of laparoscopic surgery maintain that it can reduce hospital costs, promote earlier patient discharge, produce less postoperative pain, improve cosmetic results, and allow patients a more rapid return to full activity, evidence for this is questionable so far (Rangel et al., 2003).

Anesthetic Considerations

Although regional anesthesia may be used alone in older children, general anesthesia is nearly always used for laparoscopic procedures. The use of the laryngeal mask airway (LMA) has been described in adults undergoing laparoscopy. The reliability of the standard LMA to provide adequate gas exchange during positive pressure ventilation is controversial (Maltby et al., 2000; Lu et al., 2002). More favorable ventilation and a reduction in inadvertent gastric insufflation have been reported with the LMA-ProSeal (Laryngeal Mask Company Limited, Henley on Thames, UK) (Maltby et al., 2002). The pediatric ProSeal LMA has been shown to be effective for short laparoscopic procedures (Sinha et al., 2007). In infants and children, however, endotracheal tube (ETT) placement remains the standard.

After tracheal intubation, the stomach is suctioned with an orogastric tube to decrease the risk for visceral injury during trocar insertion. The surgeon may prefer to place the patient near the foot of the table, especially for procedures in infants. The table position may need to be changed repeatedly during the operation, and both the Trendelenburg and the reverse Trendelenburg positions are often used. Accordingly, care must be taken to secure the patient to the table (e.g., using rolls of gauze and tape) while ensuring that the extremities are well padded and are not subject to inadvertent movement and untoward pressure during the operation. Inadvertent endobronchial intubation may occur as a result of cephalad displacement of the diaphragm associated with the Trendelenburg position or abdominal insufflation with gas. As a part of routine monitoring, a precordial stethoscope should be placed over the left sternal border at the nipple line of the chest to detect this complication readily.

A variety of general anesthetic techniques have been used for laparoscopic surgery. Regional anesthesia is not commonly used as an adjunct to general anesthesia in pediatric patients unless the laparoscopy is converted to an open procedure. The use of nitrous oxide is controversial. Concerns have been raised that nitrous oxide may cause bowel distention, compromising visibility and exposure during surgery (Eger and Saidman, 1965; Cunningham and Brull, 1993). In addition, nitrous oxide may exacerbate the already increased incidence of nausea and vomiting after laparoscopy (Lonie and Harper, 1986; Divatia et al., 1996; Tramer et al., 1996), although the findings of several studies have failed to confirm these effects of nitrous oxide (Taylor et al., 1992; Jensen et al., 1993). However, nitrous oxide can also support combustion. Because of its antiemetic effect, propofol has been recommended for maintenance of anesthesia during laparoscopy (Martin et al., 1993; Song et al., 1998). The combination of propofol and remifentanil has been advocated because the patient emerges rapidly and without an increase in postoperative nausea and vomiting compared with the use of inhalation anesthesia (Grundmann et al., 2001). Because of the increased incidence of postoperative nausea and vomiting associated with laparoscopy, prophylactic treatment with antiemetics and histamine blockers (droperidol, metoclopramide) have been commonly used. Orogastric suctioning at the end of the operation may also help reduce the risk for postoperative nausea and vomiting.

For most surgical procedures, postoperative pain is reduced with laparoscopy compared with open surgery, and postoperative analgesia can usually be achieved with intravenous (IV) and oral agents. Although diminished compared with open surgery, pain after laparoscopic surgery is associated with the incision, visceral manipulation, irritation and traction of nerves, vascular traction and injury, the presence of residual gas in the abdomen, and inflammatory mediators (Alexander, 1997). Pain is frequently localized to the back or shoulder. Laparoscopic repair has been associated with more postoperative pain than open hernia repair (Koivusalo et al., 2009).

A variety of approaches to prevent and treat pain after laparoscopy have been described. Bupivacaine infiltration at incision sites before skin incision has been shown to decrease postoperative pain (Kato et al., 2000; Moiniche et al., 2000). Bupivacaine infiltration has been found to be superior to IV fentanyl or tenoxicam in reducing postoperative pain (Salman et al., 2000). Low-dosage intrathecal morphine and bupivacaine also decrease postoperative pain (Motamed et al., 2000). Intraperitoneal local anesthetic instillation and mesosalpinx block may diminish postoperative pain after laparoscopy and may be beneficial in reducing postoperative shoulder pain (Kiliç et al., 1996). Intraperitoneal instillation of both bupivacaine and meperidine has been shown to be more efficacious than the combination of intraperitoneal bupivacaine and intramuscular meperidine (Colbert et al., 2000).

Caution must be used to avoid toxic plasma concentrations of local anesthetics due to systemic absorption in infants and children, however. Perioperative acetaminophen, nonsteroidal antiinflammatory agents, and other nonopioid analgesics should be used in combination with opioids as needed for postoperative analgesia. Clonidine has been shown to reduce the requirement for postoperative opioids, and it has the advantage of decreasing the tachycardia associated with pneumoperitoneum (Yu et al., 2003).

Physiologic changes during laparoscopic surgery are related to positioning (Trendelenburg, reverse Trendelenburg), increased abdominal pressure resulting from gas insufflation, and increased arterial CO₂ tension associated with insufflation. The magnitude of physiologic changes associated with laparoscopic surgery is influenced by the patient’s age, underlying myocardial function, and anesthetic agents. The reverse Trendelenburg position may cause hypotension, especially in the anesthetized patient with intravascular hypovolemia. The Trendelenburg position causes cephalad displacement of the diaphragm, restricting lung excursion and posing a risk for endobronchial intubation. In addition, central venous pressure and heart rate increase, and systemic arterial pressures and cardiac output decrease (Hirvonen et al., 1995). The pulmonary effects depend on the patient’s age, weight, pulmonary function, extent of Trendelenburg position, anesthetic agents, and ventilation technique (Sprung et al., 2002). Atelectasis and a decrease in functional residual capacity and pulmonary compliance may be observed. Ventilation/perfusion mismatch may result in decreased arterial oxygen tension. Neuromuscular blockade, endotracheal intubation, and positive pressure ventilation may help to reduce the pulmonary effects of the Trendelenburg position. As long as intraabdominal pressure is kept below 15 mm Hg, oxygen saturation can generally be maintained during position changes and pneumoperitoneum despite adverse changes in respiratory mechanics (Sprung et al., 2003). Significant hypercarbia may occur despite adjustments in mechanical ventilation, especially in infants.

Both pneumoperitoneum and the Trendelenburg position reduce femoral venous flow, increasing the risk for thrombotic complications (Rosen et al., 2000). Cardiovascular instability associated with laparoscopy has also been attributed to hypercarbia-induced arrhythmias, venous gas embolus, compression of the vena cava, pneumothorax, and pneumomediastinum (Lalwani and Aliason, 2009). Insufflation to an intraabdominal pressure of 12 mm Hg can cause septal hypokinesis and left ventricular wall motion abnormalities (Hoymork et al., 2003; Huettemann et al., 2003). The increase in intraabdominal pressure associated with gas insufflation results in increased intrathoracic pressure and increased pulmonary and systemic vascular resistances and decreased cardiac output (Hirvonen et al., 1995, 2000). Arterial blood pressure may be decreased, maintained, or even elevated by an increase in systemic vascular resistance. Reduction in splanchnic, hepatic, and renal blood flow and increases in the plasma concentrations of catecholamines, cortisol, prolactin, growth hormone, and glucose levels have been reported with CO₂ pneumoperitoneum (Hashikura et al., 1994; Mikami et al., 1998; Ishizuka et al., 2000).

Hypothermia is avoided by warming the insufflating gas or by maintaining insufflating flows of less than 2 L/min.

A new technique, known as gasless laparoscopy, eliminates the risks of pneumoperitoneum by using mechanical retraction (Canestrelli et al., 1999). Reduced visualization is associated with this technique, but its application to pediatrics remains uncertain (Lukban et al., 2000).

Inguinal Herniorrhaphy and Umbilical Herniorrhaphy

During the seventh month of gestation, the testicle descends from the abdomen through the inguinal wall into the scrotum. The processus vaginalis, a peritoneal covering, encloses the testicles during their descent. In term infants, the processus vaginalis is usually closed at birth, but it remains patent in 15% to 37% of people. In premature infants, the incidence of closure is much higher, depending on the gestational age at the time of birth. The continued patency of the processus vaginalis is the principal factor in the development of congenital hernias and hydroceles.

Inguinal hernia repair is the most frequent general surgical procedure performed by pediatric surgeons. Males are more frequently affected than females, and the incidence of inguinal hernia is highest in the first year of life. Right-sided hernias (60%) occur more frequently than left-sided (30%) and bilateral (10%) hernias. Other risk factors associated with inguinal hernias are prematurity, chronic respiratory illness, and excessive intraperitoneal fluid (ventriculoperitoneal shunts, ascites, peritoneal dialysis).

The surgical technique for this procedure is well described (Rowe and Lloyd, 1986). Laparoscopic techniques have also been described (Lobe and Schropp, 1992; Lee and Liang, 2002; Schier et al., 2002), as well as needleoscopic techniques (Prasad et al., 2003). The overall complication rate after an elective hernia repair is about 2%, and it increases to 14% after operations for incarcerated hernia. A major surgical issue in patients with a unilateral inguinal hernia is whether the contralateral side should be explored, thereby subjecting the patient to possible unnecessary damage to the contralateral vas deferens and spermatic cord. In a number of studies, a patent contralateral processus vaginalis occurs about 60% of the time. However, this patency appears to be age related, with the highest rate occurring in infants (63%), and with the incidence decreasing until 2 years of age, when it appears to plateau at 41% (Rowe and Lloyd, 1986). Despite the high incidence of patent processus vaginalis, the incidence of contralateral hernias is about 15%. The development of a contralateral hernia is also age dependent. If the initial hernia developed in the first year of life, there is a fourfold greater chance that a contralateral hernia will develop compared with children whose initial hernia manifested after 1 year of age. In girls with unilateral inguinal hernias, the incidence of positive explorations for contralateral hernias is 60%. Consequently, girls almost always undergo contralateral exploration. Laparoscopy without a separate incision has been advocated to examine the contralateral side for a patent process vaginalis when the ipsilateral hernia sac is of sufficient width to allow passage of a laparoscope (Yerkes et al., 1998) (Fig. 23-3).

FIGURE 23-3 Laparoscopic hernia repair with patent process vaginalis.

Herniorrhaphies are commonly performed as an elective procedure; however, in children with incarceration and signs of bowel obstruction, a rapid-sequence induction with application of cricoid pressure is needed.

The following discussion pertains to elective, uncomplicated hernias. Anesthesia can be induced by mask inhalation of volatile agents or by IV or rectal technique. Endotracheal intubation is usually unnecessary for herniorrhaphy, except in infants younger than 1 year, in whom it may be difficult to maintain an adequate airway with bag and mask ventilation without distending the stomach. However, the use of the LMA in these patients may make tracheal intubation unnecessary. The patient must be well anesthetized when the spermatic cord is being manipulated. Inadequate depth of anesthesia at this stage can result in laryngospasm or bradycardia. Caudal epidural anesthesia or ilioinguinal/iliohypogastric nerve block can be quite effective, both in providing postoperative pain relief and in diminishing the intraoperative anesthetic requirements (Markham et al., 1986). Premature infants have a particularly high incidence of inguinal hernias. In these infants, for whom an inhalation anesthetic may have increased risks, spinal anesthesia (Harnik et al., 1986) and caudal epidural (Spear et al., 1988) anesthesia have been used successfully to avoid general anesthesia and endotracheal intubation (Williams et al., 2006).

Orchiopexy

Cryptorchidism affects approximately 0.8% of 1-year-old boys. The undescended testicle may lie within the abdomen, the inguinal canal, or the external ring just proximal to the scrotum. Although the undescended testicle is usually associated with a hernia, the most significant medical risk for the patient is the chance of developing a malignancy, which is 10-fold greater than in a normally descended one.

The objectives of repair for undescended testicles are to alter the course of the spermatic artery from the renal pedicle to the internal ring to the external ring, and to create in its place a direct line from the renal pedicle to the scrotum. However, the surgical approach to patients with undescended testes is not uniform (Hinman, 1987; Heiss and Shandling, 1992). The general approach to patients with a nonpalpable testis is inguinal exploration. If neither the testis nor proof of its absence is found, the lower posterolateral surface of the peritoneal cavity is explored. When the testis is found, it is either removed or surgically placed in the scrotum. This can be accomplished by a staged orchiopexy, autotransplantation of the testis, or Fowler-Stephens procedure. The Fowler-Stephens approach takes advantage of the vascular arcades between the deferential and spermatic arteries in the cord. Because of this collateral blood flow, high ligation of the testicular vessels can preserve the testicular blood supply and provide the surgeon with mobility in bringing the testicle down into the scrotum. The Fowler-Stephens approach has undergone modification and is now generally done in two stages. The first stage involves clipping the spermatic vessel, whereas the second stage, performed months later, involves the formal orchiopexy. With the advent of laparoscopic surgery, both stages of the Fowler-Stephens approach can be done with the aid of a laparoscope (Atlas and Stone, 1992; Bogaert et al., 1993).

The anesthetic considerations are similar to those for inguinal hernia repair. Because of the traction and manipulation of the spermatic cord and testicle, the incidence of intraoperative bradycardia and laryngospasm is somewhat increased. Consequently, a deeper level of anesthesia is required. However, the need for a deeper plane of anesthesia and the risk for bradycardia and laryngospasm can be lessened by the use of intraoperative nerve blocks or regional anesthesia. If an intraabdominal exploration or the use of laparoscopy is anticipated, the trachea is generally intubated. Because the incidence of postoperative nausea and pain is significant, caudal nerve blocks and prophylactic antiemetics, such as ondansetron (0.1 mg/kg) are recommended.

Surgery for Pyloric Stenosis

Pyloric stenosis is one of the most common gastrointestinal abnormalities appearing in the first 6 months of life. This disorder has a polygenic mode of inheritance and occurs four times more commonly in males and more frequently in white infants. The frequency of this disorder ranges from 1.4 to 8.8 per 1000 live births (Zeidan et al., 1988; Dubé et al., 1990; Saunders and Williams, 1990; Bissonnette and Sullivan, 1991; Murtagh et al., 1992). Some controversy exists regarding the associated risk for pyloric stenosis with the maternal postnatal exposure to macrolides (Louik et al., 2002; Sorensen et al., 2003). Pyloric stenosis has been associated with cleft palate and esophageal reflux.

The cardinal features of pyloric stenosis are projectile vomiting, visible peristalsis, and a hypochloremic, hypokalemic, metabolic alkalosis. Although hypokalemia is a frequent finding, Schwartz and colleagues (2003) reported in a retrospective chart review that 36% of patients with pyloric stenosis were noted to have hyperkalemia. Nonbilious vomiting is the classic presenting symptom and generally occurs between 2 and 8 weeks of age. Jaundice occurs in less than 5% of patients and is thought to be associated with caloric deprivation and hepatic glucuronyl transferase deficiency. The jaundice resolves after successful treatment. Diagnosis is made by palpation of an olive-sized mass in the upper abdomen and is frequently confirmed by radiographic studies. Although false-positive studies are rare, false-negative findings can occur in up to 19% of the ultrasound examinations and in 10% of the contrast studies. Preoperative ultrasound measurements of the pylorus correlate well with intraoperative surgical measurements (Muramori et al., 2007).

The pathologic condition involves gross thickening of the circular muscles of the pylorus, resulting in a gradual obstruction of the gastric outlets. Vanderwinden and coworkers (1992) noted a deficiency of nitric oxide synthetase in the muscle layers of infants with pyloric stenosis. The pathophysiology of pyloric stenosis frequently leads to hypovolemia and a hypochloremic metabolic alkalosis.

Winters (1973) outlined the pathophysiology that leads to hypochloremic, hypokalemic, metabolic alkalosis. In pyloric stenosis, persistent vomiting results in a loss of gastric juices rich in hydrogen and chloride ions and, to a lesser extent, sodium and potassium ions. Because the obstruction is at the level of the pylorus, the vomitus does not contain the usual alkaline secretions of the small intestine; the patient develops a metabolic alkalosis. As an increased bicarbonate load is presented to the kidneys, the resorptive capacity of the proximal tubule is overwhelmed, and an increased amount of NaHCO₃ and water is delivered to the distal tubule. Because NaHCO₃ cannot be reabsorbed in the distal tubule, aldosterone secretion occurs. Increased aldosterone increases sodium reabsorption and kaliuresis. Potassium loss is further exacerbated by potassium being exchanged in the tubule for hydrogen in an effort to maintain normal plasma pH.

With persistent vomiting and intravascular volume depletion, the renal response shifts to maintain the patient’s intravascular volume, and sodium conservation occurs. Increased secretion of aldosterone promotes sodium conservation and potassium excretion. In the distal tubule, sodium is also conserved in exchange for hydrogen ions. This may result in a paradoxical aciduria and worsening metabolic alkalosis.

Surgical pyloromyotomy, a relatively simple procedure in the hands of skilled pediatric surgeons, is curative (Fig. 23-4). The operative mortality rates of 10% has declined to less than 0.5%. The surgery can be performed either as an open procedure or laparoscopically. In a comparative study, Campbell and colleagues (2002) noted that laparoscopic pyloromyotomy has become the dominant approach.See related video online at www.expertconsult.com Hall and coworkers (2009) have shown that laparoscopically performed procedures have shorter times for patients to achieve full enteral feeds and faster hospital discharge times than patients having open pyloromyotomy. However, laparoscopic pyloromyotomy is associated with an increased rate of complications, higher hospital charges, and a reduction in the general surgical resident’s operating experience (Campbell et al., 2002). Pyloromyotomy for pyloric stenosis is not a medical emergency that requires immediate surgical intervention. The major anesthetic considerations are recognizing and treating dehydration and acid-base abnormalities before beginning anesthesia. In addition, the patient is at risk for aspirating gastric contents.

FIGURE 23-4 Pyloric stenosis. Operative technique of pyloromyotomy: A, Incision made on anterosuperior surface through avascular area. B, Cross-section of hypertrophied pylorus after operation has been completed. C, Circular muscle is separated, allowing submucosa to bulge. Laparoscopic view of pyloromyotomy: D, Hypertrophied pyloris. E, Incision. F and G, Spreading the incision to the mucosae. H, Upper GI study demonstrates the antral “teat:” shouldering (black arrows), and the elongated, narrowed, double-tracked pyloric channel (white arrows).

(A to C, From Benson CO: Infantile hypertrophic pyloric stenosis. In Welch KJ, et al., editors: Pediatric surgery, ed 4, Chicago, 1986, Year Book Medical; H from Blickman JG, Parker R, Barnes PD: Pediatric radiology, St Louis, 2009, Mosby.)

The initial therapeutic approach is aimed at repletion of intravascular volume and correction of electrolyte and acid-base abnormalities (e.g., 5% dextrose in 0.45% NaCl with 40 mmol/L of potassium infused at 3 L/m² per 24 hours). Most children respond to therapy within 12 to 48 hours, after which surgical correction can proceed in a nonemergent manner. The use of cimetidine has also been shown to rapidly normalize the metabolic alkalosis in patients with hypertrophic pyloric stenosis (Banieghbal, 2009).

Once the child is satisfactorily hydrated and after the appropriate monitors (precordial stethoscope, electrocardiogram, pulse oximeter, and blood pressure cuff) are placed, the infant is ready for induction of anesthesia. The obstructed pylorus and associated vomiting increase the possibility of aspirating gastric contents during induction of anesthesia. A thorough evacuation of stomach contents through a nasogastric or orogastric tube, with proper preoxygenation and monitoring, greatly reduces the chance of regurgitation during induction, although it does not completely eliminate the possibility of aspiration (Cook-Sather et al., 1997). Infants with pyloric stenosis are thus considered by some anesthesiologists to have a status equivalent to that of infants with a full stomach; therefore, a rapid-sequence induction is preferred to secure the airway and minimize the risks of aspiration (Dierdorf and Krishna, 1981; Battersby et al., 1984). On the other hand, mask inhalation induction preceded by careful emptying of the stomach has been used safely in several pediatric centers (MacDonald et al., 1987). In a prospective nonrandomized observational study of 76 infants with pyloric stenosis, Cook-Sather and colleagues (1998) compared three techniques: awake intubation, rapid-sequence intubation, and modified rapid-sequence intubation (ventilation through cricoid pressure). In this study, awake intubation was not superior to anesthetized, paralyzed intubations. Awake intubation prevented neither bradycardia nor oxygen desaturations.

After induction and intubation of the trachea, a nasogastric or an orogastric tube is reinserted and left in place during the operative procedure. This allows the surgeon to test the integrity of the pyloric mucosa after pyloromyotomy. A small volume of air is injected down the nasogastric tube, and the surgeon manipulates the air bubble into the duodenum and occludes the bowel lumen both proximal and distal to the incision. Mucosal perforation is indicated if there is air leakage. After the operation, which usually requires less than 30 minutes, the effects of any nondepolarizing muscle relaxant are reversed. The infant can then be safely extubated when fully awake and with intact protective airway reflexes. Some believe that opioid analgesia is seldom necessary (Battersby et al., 1984) and may predispose patients to a prolonged emergence from anesthesia (MacDonald et al., 1987). It is not unusual to encounter lethargy or drowsiness in these infants in the immediate postoperative period. Respiratory depression has been noted to occur postoperatively and is possibly related to cerebrospinal fluid pH and hyperventilation (Andropoulos et al., 1994). Rare occurrences of hypoglycemia, apnea, convulsions, and cardiac arrest in the early postoperative period have also been cited. These events have been ascribed to the cessation of IV glucose infusions and the depletion of liver glycogen (Shumake, 1975). Infants usually begin oral feedings 8 hours after the procedure. The choice of maintenance anesthetic agent for infants with pyloric stenosis has been studied (Wolf et al., 1996; Chipps et al., 1999; Davis et al., 2001; Galinkin et al., 2001).

Wolf and coworkers (1996) found that clinical postoperative apnea occurred in 3 of 11 infants anesthetized with isoflurane, and in none of the nine infants anesthetized with desflurane. In a multicenter study comparing halothane and remifentanil, where both drugs were administered to similar clinical endpoints, remifentanil was not associated with postoperative respiratory depression. In this study, all infants received both preoperative and postoperative pneumograms, and remifentanil (as opposed to halothane) was not associated with new pneumogram abnormalities in the postoperative period (Davis et al., 2001; Galinkin et al., 2001).