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Table of Contents  
Year : 2022  |  Volume : 16  |  Issue : 2  |  Page : 255-262  

Assessment of intraoperative hemodynamics and recovery characteristics in pediatric patients receiving buprenorphine and propofol anesthesia for cleft palate surgery: A prospective observational study

1 Department of Anesthesiology and Critical Care (Superspeciality), Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
2 Department of Anesthesiology and Critical Care, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
3 Department of Anesthesiology (Superspeciality), Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India

Date of Submission14-Jun-2022
Date of Decision24-Aug-2022
Date of Acceptance26-Aug-2022
Date of Web Publication07-Oct-2022

Correspondence Address:
Dr. Pooja Thaware
Department of Anesthesiology and Critical Care, All India Institute of Medical Sciences, Bhopal - 462 020, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aer.aer_95_22

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Background: Children with cleft palate are usually operated on before 18 months of age. Cleft palate surgery demands stable hemodynamic parameters, a bloodless surgical field, and an awake and pain-free child after surgery. Aims: We aimed to study the anesthesia technique using buprenorphine and propofol for cleft palate surgery. Settings and Design: The design involves prospective observational study. The study was conducted at a tertiary care hospital. Materials and Methods: After the Institutional Ethics Committee approval, 42 patients aged 6 months to 12 years undergoing cleft palate surgery were enrolled. Anesthesia induction commenced with sevoflurane or propofol 3−1. After intubation, buprenorphine 3 μ−1 was given, and propofol infusion was started at 2–8−1.h−1. Hemodynamic parameters, awakening time, and surgeon's satisfaction score were noted. After extubation, pain score, emergence agitation (EA) score, sedation score, recovery score, and adverse events were noted. Statistical Analysis: All statistical analyses were performed using the 20.0 version of the Statistical Package for the Social Science (SPSS) software program. Continuous data were summarized as mean and standard deviation, and were analyzed using a two-sided Student's unpaired t-test. Categorical data were represented using frequencies and proportions. Results: The single dose of buprenorphine with propofol infusion started immediately postintubation causes a significant decrease in heart rate after 1 h. This contributed to a favorable operative field, increasing the surgeon's satisfaction score. In the recovery room, patients were essentially pain-free till 2.5 h after surgery, with only one patient requiring rescue analgesia. Furthermore, 90% of patients showed a smooth and calm recovery with no EA. The Steward's recovery score remained high throughout without any complication. Conclusions: In cleft palate surgeries, a single-dose buprenorphine 3 μ−1 and propofol maintenance infusion 2–8−1.h−1 were effective in maintaining hemodynamic parameters and a bloodless surgical field and managing postoperative pain with a good recovery profile.

Keywords: Buprenorphine, cleft palate, pain, propofol, sevoflurane

How to cite this article:
Lakra PR, Thaware P, Bharati. Assessment of intraoperative hemodynamics and recovery characteristics in pediatric patients receiving buprenorphine and propofol anesthesia for cleft palate surgery: A prospective observational study. Anesth Essays Res 2022;16:255-62

How to cite this URL:
Lakra PR, Thaware P, Bharati. Assessment of intraoperative hemodynamics and recovery characteristics in pediatric patients receiving buprenorphine and propofol anesthesia for cleft palate surgery: A prospective observational study. Anesth Essays Res [serial online] 2022 [cited 2022 Dec 6];16:255-62. Available from:

   Introduction Top

In today's scenario, the anesthesiology branch has progressed to the point where not only intraoperative management but also the patient's postoperative well-being is paramount. Pediatric cleft palate surgery necessitates stable intraoperative hemodynamics and adequate analgesia, aiding the child's smooth and calm recovery. Anesthesiologists have practiced various standards and newer anesthesia techniques to achieve these goals, such as total intravenous anesthesia (TIVA), inhalational agents, nerve blocks, nonsteroidal anti-inflammatory drugs, opioids, local site infiltration, and dexmedetomidine.[1],[2],[3],[4],[5] There are not many studies quoting the effect of long-acting opioids on hemodynamics and perioperative analgesia in cleft palate surgery.[6] In our tertiary care facility, buprenorphine is commonly used for perioperative analgesia in cleft palate surgery. Therefore, we evaluated the efficacy of the combination of a single-dose buprenorphine 3 μ−1 with propofol infusion 2–8−1.h−1 as regards intraoperative hemodynamics, favorable operative field, perioperative analgesia, and recovery profile.

   Materials and Methods Top

Source of data

Patients undergoing cleft palate repair surgery under general anesthesia at a tertiary care hospital from January 2016 to September 2017.

Methods of collection of data

Study design

This was a prospective study.

Study period

This study was conducted from January 2016 to September 2017.

Place of study

This study was conducted at a tertiary care hospital.

Sample size

The sample size was 42, calculated based on the previous literature for an outcome variable of emergence time and postoperative analgesic requirement, considering 80% statistical power with a 95% confidence interval, 5% level of Type I error (α), and a 20% Type II error rate (β).[7]

Inclusion criteria

  1. Patients whose guardians were willing to give written informed consent
  2. Patients aged 6 months to 12 years of either gender undergoing cleft palate surgery
  3. The American Society of Anesthesiologists Physical Status I and II patients.

Exclusion criteria

  1. Guardian or patient refusal
  2. Children with a history of allergic reactions to any drug used in the study
  3. The American Society of Anesthesiologists Physical Status III and IV patients.

Primary outcome measures

  1. To assess hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and oxygen saturation (SPO2) at regular intervals during the surgery
  2. Awakening time (time from reversal to opening of eyes on verbal command) and extubation time (time from reversal to extubation)
  3. Surgeon's satisfaction score after surgery based on bleeding from the operative field
  4. To assess the pain score in the postoperative period using the Face, Legs, Activity, Cry, and Consolability (FLACC) pain score
  5. Time to achieve the Steward's recovery score (SRS) >6 in the postoperative period.

Secondary outcome measures

  1. To assess emergence agitation (EA) using the Watcha EA score
  2. To assess Ramsay sedation score in the postoperative period.

It is a nonrandomized study. Guardian was made to understand the nature and purpose of the study in the local language and was allowed to make an informed decision. Therefore, the bias due to nonparticipation was kept at a minimum. Multiple blinded observers did the data collection, and a blinded statistician did the analysis.

Approval from the Institutional Ethics Committee (Approval Number-IEC/DISS/127/2015, dated December 15, 2015) was taken. All the procedures followed the guidelines in the Declaration of Helsinki (2013). Written informed consent from the guardians and assent was obtained from children aged over 7 years for participating in the study and the use of patient data for research and educational purposes.

All the children were examined preoperatively and investigated according to the institutional protocol. After confirmation of adequate starvation, the child was taken inside the operation theater. Baseline data HR, SBP, DBP, MAP, and SPO2 were measured using standard monitors such as electrocardiogram, noninvasive blood pressure cuff, and pulse oximeter. The child was taken under anesthesia with sevoflurane on the Jackson-Rees circuit. An intravenous (i.v.) line was established, and i.v. glycopyrrolate (5 μ−1) was administered. In older children, an i.v. line was placed in the preoperative area (in the presence of parents), and induction was performed with propofol 3−1 i.v. after administration of i.v. glycopyrrolate 5 μ−1. Succinylcholine at 1.5−1 i.v. was given after assessing ventilation. The trachea was intubated with an appropriate-sized Ring–Adair–Elwyn orotracheal tube (South Polar tube). The throat was packed after confirming tube position. The patient was put on controlled mechanical ventilation with 50% oxygen and 50% nitrous oxide, and muscle relaxation was maintained with atracurium.

Now, buprenorphine 3 μ−1 i.v. was given, and anesthesia was further maintained with propofol infusion, which was administered at 8–6−1.h−1 for 10 min, followed by 6–4 mg. kg−1.h−1 for 10 min, followed by 4–2−1.h−1 till 45 min prior to the end of surgery. Sevoflurane at a dial concentration of 0.5–1 volume percent was titrated as needed to maintain a mean alveolar concentration (MAC) ≤0.6 based on hemodynamic parameters. Children over 1 year were given a rectal diclofenac sodium suppository (2−1), while children under the age of 1 year were given a rectal paracetamol suppository (30−1) after intubation. Hemodynamic parameters were recorded at baseline, following intubation, and then every 5 min for the first 45 min, and subsequently, every 10 min until the procedure was completed. Surgical events were noted, if any. Blood loss was estimated according to the standard protocol. The body temperature was maintained. All patients received i.v. fluid ringer lactate with dextrose as per Holliday-Segar Formula.

After confirming adequate spontaneous respiratory attempts, residual neuromuscular block was reversed at the end of the surgery, and the child was extubated after confirming the adequate return of tone, power, and reflexes. The awakening time, as well as the extubation time, were recorded. On a scale of 1–3, surgeon satisfaction was measured based on bleeding from the surgical field; a score of 1 meant severe bleeding, a score of 2 meant moderate bleeding, and a score of 3 meant mild bleeding.

The FLACC pain score was used to assess pain in the recovery room [Appendix 1].[8] Rescue analgesia fentanyl 1 μ−1 was given to children with severe pain (FLACC pain score ≥4). Patients were monitored in the recovery room postoperatively till the SRS was >6 or till 2 h, whichever was later [Appendix 2].[9] After extubation, the EA score was noted according to the Watcha EA score [Appendix 3].[10]

In the recovery room, a sedation score was recorded using the Ramsay sedation score (1 = anxious and agitated or restless or both; 2 = cooperative, oriented, and calm; 3 = responsive to commands only; 4 = exhibiting brisk response to light glabellar tap or loud auditory stimulus; 5 = sluggish response to light glabellar tap or loud auditory stimulus; and 6 = unresponsive).[11]

Adverse events such as hypotension, bradycardia, bronchospasm, or any other during surgery, and postoperative nausea vomiting, desaturation, delayed emergence, EA, or any other adverse event in the postoperative period were noted.

According to the Pediatric Advanced Life Support guidelines, hypotension in infants (1–12 months) is defined as SBP <70 mmHg, in 1–10-year-old children SBP <2 times of age added to 70 mmHg (SBP <70 mmHg + [age in years ×2]), and in more than 10-year-old children, SBP <90 mmHg.[12] Hypotension was treated with i.v. fluid bolus of 10−1 of ringer lactate. If hypotension does not respond to fluid bolus, the injection of mephentermine 3 mg intravenously was given.

Bradycardia is defined as HR <60 min−1, and it was managed by atropine 0.01−1 (i.v.). Postoperative nausea and vomiting were managed with ondansetron 0.1−1 (i.v.). Postoperative desaturation is defined as a sustained decrease in SPO2 >5% from baseline for 1 min, despite facemask oxygen delivery at 6 L.min−1, head repositioning, suctioning, and physical stimulation. Desaturation was treated by lifting the jaw, inserting of the oropharyngeal or nasopharyngeal airway, positive pressure ventilation, and intubation, if required. Hypertension and tachycardia were defined as >20% rise in SBP or HR above baseline in more than two readings, which was managed by titrating propofol infusion and sevoflurane volume percent.

Statistical analysis

All statistical analyses were performed using the 20.0 version of the Statistical Package for the Social Science (SPSS) software program. Quantitative data (HR, SBP, DBP, and MAP) were summarized using summary statistics, number of observations, and mean and standard deviation, and were analyzed using two-sided Student's unpaired t-test. Qualitative (categorical) data (FLACC pain score, Steward's recovery score, the profile of Watcha EA scale, and Ramsay sedation score) were estimated using frequencies and proportions. P < 0.05 is considered statistically significant.

   Results Top

Demographic data of patients are depicted in [Table 1]. The mean baseline HR was 130.69 ± 09.72 min−1. The mean baseline SBP, DBP, and MAP were 99.86 ± 10.61, 61.60 ± 8.50, and 74.57 ± 8.06 mmHg, respectively. After intubation, an insignificant rise in HR was observed [Figure 1]. At the end of 1 h and 5 min, the mean HR showed a statistically significant fall from baseline, well within the normal limits. The same pattern continued until 2 h and 55 min.
Figure 1: Changes in HR at different time points during surgery (*P < 0.05 significant). HR: Heart rate

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Table 1: Demographic data of patients

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The mean SBP and MAP showed a significant rise from baseline after intubation, which persisted until the end [Figure 2] and [Figure 3]. Similarly, after the intubation, the mean DBP also showed a significant rise from baseline, but at the end of 1 h and 15 min, the mean DBP showed an insignificant fall from baseline and this continued till 2 h and 45 min [Figure 4].
Figure 2: Changes in SBP at different time points during surgery (*P < 0.05 significant). SBP: Systolic blood pressure

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Figure 3: Changes in MAP at different time points during surgery (*P < 0.05 significant). MAP: Mean arterial pressure

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Figure 4: Changes in DBP at different time points during surgery (*P < 0.05 significant). DBP: Diastolic blood pressure

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The mean awakening time was 1.84 ± 0.91 min, and the extubation time was 2.99 ± 1.38 min. In 33 cases (79%), the surgeon's satisfaction score was 3; whereas in the remaining nine cases (21%), the surgeon's satisfaction score was 2 [Figure 5].
Figure 5: Proportion of Watcha emergence agitation score

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The FLACC pain score was 4 or less during the complete postoperative monitoring in all cases except for one patient who required rescue analgesia with fentanyl 1 μ−1 i.v. at 45 min after extubation [Figure 6].
Figure 6: Profile of FLACC pain score. FLACC: Face, Legs, Activity, Cry, and Consolability

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In the recovery room, six patients (14%) achieved SRS >6 at 30 min, 14 patients (33%) achieved SRS >6 at 1 h and 45 min, and 32 patients (76%) achieved SRS >6 at 2 h and 45 min [Figure 7] and [Table 2]. After extubation on the Watcha EA scale, 27 (64%) children out of 42 were calm, 11 (26%) children rated crying but could be consoled, and four children (10%) rated crying but could not be consoled [Figure 8].
Figure 7: Profile of Steward's recovery score

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Figure 8: Proportion of surgeon's satisfaction score

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Table 2: Number of patients achieved Steward's recovery score >6 at different time intervals

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We found that in the recovery room, 15 min after extubation, all the children had achieved a Ramsay sedation score of 4 or less. In our study, not a single case had any complication.

   Discussion Top

Hemodynamic parameters

In our study, we observed a rise in HR in response to intubation; however, a single dose of buprenorphine 3 μ−1 with propofol infusion at 2–8−1.h−1 started immediately postintubation had caused a significant yet acceptable decrease in HR approximately 1 h after starting it. These surgeries took an average of 2.5 h to complete. Thus, the fall in HR appears to be beneficial in reducing blood loss and creating a favorable operative field, leading to a higher surgeon's satisfaction score. Although buprenorphine and propofol infusion could not control the rise in SBP, DBP, and MAP during the surgery, the rise in blood pressure was well within the normal limits and did not appear to have an impact on the surgical field. The mean DBP did, however, indicate a nonsignificant decrease from baseline after 1 h 15 min.

Awakening and extubation time

Omara et al. compared continuous propofol infusion (9−1.h−1) to sevoflurane maintenance anesthesia in cleft palate surgeries.[13] They found that the EA and postoperative respiratory problems were significantly lower in the propofol group than in the sevoflurane group. However, the propofol group's extubation time was longer. In our study, all children awoke quickly, with average awakening and extubation times of <3 and 5 min, respectively. In this study, we believe that titrated propofol infusion (2–8−1.h−1) and ceasing the infusion 45 min before the conclusion of the surgery, as well as intermittent sevoflurane up to MAC 0.6, contributed to quick awakening.

Surgeon's satisfaction score

Cleft palate surgeries require a relatively bloodless field, since the surgical site is highly vascular and it is difficult for surgeons to keep suctioning all of the time, and the tolerable blood loss in this age group is also relatively low. Fillies et al. studied perioperative complications in infant cleft palate repair.[14] Their study revealed frequent complications that may be attributed directly or partially to intraoperative blood loss. Shortening of the duration of a cleft palate surgery is an important step in reducing total blood loss. Our study found no severe surgical complications such as fulminant blood loss. We asked the surgeons to rate the surgical field in the range of 1–3 after the surgery. In 33 cases (79%), the surgeon's satisfaction score was 3 (minimal blood loss).

Steward's recovery score

Schmidt et al. compared propofol-remifentanil anesthesia to sevoflurane-remifentanil anesthesia in pediatric lower abdominal surgeries.[15] They utilized propofol at 5–10−1.h−1. In the propofol-remifentanil group, postoperative recovery, extubation time, and the time taken until a Steward's postanesthetic recovery score of >4 were significantly shorter. Drasković and Cvejanov studied the adverse effects and recovery after TIVA in children, in whom propofol infusion was used at the rate of 10–15−1.h−1.[16] They discovered that within the first 15 min, all patients had reached the maximum value of the SRS. The SRS is a conventional and simple tool. We observed that by the end of 2 h 45 min, 32 patients (76%) achieved SRS >6. At 2 h 45 min, the remaining 10 patients had achieved SRS = 5 (responding to verbal stimuli, maintaining a good airway, and moving limbs purposefully). The single-dose buprenorphine and propofol infusion did not prolong postoperative recovery in our study.

Face, Legs, Activity, Cry, and Consolability pain score

Maunuksela et al. conducted a multidose comparison of buprenorphine and morphine in the postoperative pain of children undergoing orthopedic surgery. They found that the mean duration of action of buprenorphine was slightly but not significantly longer than that of morphine. However, two patients receiving buprenorphine developed a degree of ventilatory depression after repeated doses of buprenorphine in the postoperative period.[17] Takahashi et al. conducted a dose–response study of preincisional buprenorphine on emergence time and postoperative analgesic requirements in patients anesthetized with sevoflurane for otolaryngeal surgeries.[7] They concluded that buprenorphine in doses between 2 and 4 μ−1 reduced analgesic requirements during the first 24 h after surgery without delaying emergence from sevoflurane anesthesia. We observed that, from the conclusion of surgery until 2 h 45 min later, patient's FLACC pain score remained ≤4, which is critical in patients with cleft palate surgery to minimize postoperative hemorrhage. Only one patient required fentanyl 1 μ−1 rescue analgesia. Furthermore, none of the children showed signs of postoperative respiratory depression.

Emergence agitation

EA is a dissociative state of consciousness, where the child is irritable, inconsolable, uncooperative, thrashing, crying, and moaning. EA is linked to complications such as bleeding from the surgical site, damage to the surgical repair, cannula removal, and increased pain. In order to avoid these issues, a smooth and calm recovery is critical after cleft palate surgery. EA is well known for common inhalational anesthetics such as sevoflurane and desflurane.[18] In our study, 90% of the children recovered smoothly and calmly without EA. We believe that the analgesic effect of the long-acting opioid buprenorphine contributed to the reduced incidence of emerging agitation. Furthermore, in our cases, the fair use of sevoflurane (MAC 0.6) contributed to a lower prevalence of emerging agitation.

Ramsay sedation score

Olkkola et al. compared the pediatric ventilatory effects of morphine (50 or 100 μ−1) and buprenorphine (1.5–3 μ−1) in repeated doses to achieve equal levels of analgesia after thoracotomy. They found that the buprenorphine group had a significantly lower ventilatory rate than the morphine group until 7 h postoperatively.[19] However, PaCO2 remained within the normal limits throughout. They, nevertheless, recommend that children who received intraoperative buprenorphine be monitored closely in the postoperative period to ensure that the ventilatory rate has normalized. In our study, a single-dose buprenorphine 3 μ−1 was used, and we found that all children had Ramsay sedation score ≤4 after 15 min in the recovery room.

Strength of the study

This research contributes to the literature by demonstrating an effective and safe anesthetic approach for cleft palate surgery. Although a few previous studies used and compared buprenorphine to other long-acting opioids, none of these studies implicated the beneficial use of buprenorphine in cleft palate surgery. This work leaves the door open for larger scale research in the future.

Limitation of the study

The sample size was small because this was a single-center study. Furthermore, the postoperative monitoring period may have been extended. Patients were closely observed in the ward after being transferred from the recovery room; however, data on the total duration of analgesia and the need for rescue analgesia could not be recorded due to technical limitations.

Interpretation and implications

Vicencio-Rosas et al. performed an updated meta-analysis on the implementation of buprenorphine in the treatment of pain in the pediatric population as regards its various formulations and routes of administration. In this meta-analysis, they concluded that a few studies demonstrate the efficacy and safety of buprenorphine use in the pediatric population.[20] The literature lack systematic reviews on the use of long-acting opioid in cleft palate surgeries, particularly buprenorphine. This study was a primary research using buprenorphine in cleft palate surgery; a systematic review can be done in the future.

Controversies raised by this study and future research directions

The current literature is inclining toward diminishing the use of opioids in cleft palate surgery to avoid respiratory complications postoperatively, although previous literature and this study provide evidence of excellent analgesia with minimal respiratory complications.[21] The long-acting opioid can further be explored parallel with the newer nonopioid drugs and regional techniques for cleft palate surgery.

   Conclusions Top

The use of buprenorphine in a dose of 3 μ−1 and propofol for induction at 3−1 and maintenance infusion at 2–8−1.h−1 is an encouraging combination that can be used for cleft palate repair in the pediatric age group. Further large-scale studies need to be carried out. Furthermore, a close monitoring of patients is recommended after receiving buprenorphine.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Moggi LE, Ventorutti T, Bennun RD. Cleft palate repair: A new maxillary nerve block approach. J Craniofac Surg 2020;31:1547-50.  Back to cited text no. 1
Chiono J, Raux O, Bringuier S, Sola C, Bigorre M, Capdevila X, et al. Bilateral suprazygomatic maxillary nerve block for cleft palate repair in children: A prospective, randomized, double-blind study versus placebo. Anesthesiology 2014;120:1362-9.  Back to cited text no. 2
Carr L, Gray M, Morrow B, Brgoch M, Mackay D, Samson T. Opioid sparing in cleft palate surgery. Cleft Palate Craniofac J 2018;55:1200-4.  Back to cited text no. 3
Surana P, Parikh DA, Patkar GA, Tendolkar BA. A prospective randomized controlled double-blind trial to assess the effects of dexmedetomidine during cleft palate surgery. Korean J Anesthesiol 2017;70:633-41.  Back to cited text no. 4
Flowers T, Winters R. Postoperative pain management in pediatric cleft lip and palate repair. Curr Opin Otolaryngol Head Neck Surg 2021;29:294-8.  Back to cited text no. 5
Fenlon S, Somerville N. Comparison of codeine phosphate and morphine sulphate in infants undergoing cleft palate repair. Cleft Palate Craniofac J 2007;44:528-31.  Back to cited text no. 6
Takahashi S, Tanaka M, Matsumiya N, Kondo T, Miyabe M, Toyooka H. Dose-response study of preincisional buprenorphine on emergence time and postoperative analgesic requirement in patients anesthetized with sevoflurane. Masui 2001;50:256-60.  Back to cited text no. 7
Manworren RC, Hynan LS. Clinical validation of FLACC: Preverbal patient pain scale. Pediatr Nurs 2003;29:140-6.  Back to cited text no. 8
Welborn LG, Hannallah RS, Norden JM, Ruttimann UE, Callan CM. Comparison of emergence and recovery characteristics of sevoflurane, desflurane, and halothane in pediatric ambulatory patients. Anesth Analg 1996;83:917-20.  Back to cited text no. 9
Bajwa SA, Costi D, Cyna AM. A comparison of emergence delirium scales following general anesthesia in children. Paediatr Anaesth 2010;20:704-11.  Back to cited text no. 10
Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2:656-9.  Back to cited text no. 11
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Omara AF, Abdelrahman AF, Elshiekh ML. Recovery with propofol anesthesia in children undergoing cleft palate repair compared with sevoflurane anesthesia. Anesth Pain Med 2019;9:e92076.  Back to cited text no. 13
Fillies T, Homann C, Meyer U, Reich A, Joos U, Werkmeister R. Perioperative complications in infant cleft repair. Head Face Med 2007;3:9.  Back to cited text no. 14
Schmidt J, Fechner J, Fritsch B, Schmitz B, Carbon R, Rösch W, et al. Propofol-remifentanil versus sevoflurane-remifentanil for anesthesia for pediatric procedures in infants, children and adolescents. Anaesthesist 2001;50:757-66.  Back to cited text no. 15
Drasković B, Cvejanov M. Adverse effects and recovery after total intravenous anesthesia in children. Med Pregl 1998;51:68-72.  Back to cited text no. 16
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[PUBMED]  [Full text]  
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2]


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