Effect of Carboxyhemoglobin on Postoperative Complications And

Pediatric Anesthesia ISSN 1155-5645

ORIGINAL ARTICLE Effect of carboxyhemoglobin on postoperative complications and pain in pediatric tonsillectomy patients Onur Koyuncu1, Selim Turhanoglu1, Kasım Tuzcu1, Murat Karcıoglu1, Isil Davarcı1, Ercan Akbay2, Cengiz Cevik2, Cahit Ozer3, Daniel I. Sessler4 & Alparslan Turan4

1 Department of Anesthesiology and Department of Outcomes Research, Tayfur Ata Sokmen Medicine Faculty, Mustafa Kemal University, Hatay, Turkey 2 Department of Ear Nose Throat, Tayfur Ata Sokmen Medicine Faculty, Mustafa Kemal University, Hatay, Turkey 3 Department of Family Medicine, Tayfur Ata Sokmen Medicine Faculty, Mustafa Kemal University, Hatay, Turkey 4 Department of Outcomes Research, Cleveland Clinic, Cleveland, OH, USA

Keywords Summary carbon monoxide; carboxyhemoglobin; tonsillectomy; child; postoperative Background: Carbon monoxide (CO) is a product of burning solid fuel in complications; pain stoves and smoking. Exposure to CO may provoke postoperative complications. Furthermore, there appears to be an association between COHb con- Correspondence centrations and pain. We thus tested the primary hypothesis that children Onur Koyuncu, Department of with high preoperative carboxyhemoglobin (COHb) concentrations have Anaesthesiology, Tayfur Ata Sokmen more postoperative complications and pain after tonsillectomies, and second- Medicine Faculty, Mustafa Kemal University, Serinyol street, Hatay 31000, arily that high-COHb concentrations are associated with more pain and anal- Turkey gesic use. Email: [email protected] Methods: 100 children scheduled for elective tonsillectomy were divided into low and high carbon monoxide (CO) exposure groups: COHb ≤3or Section Editor: Andrew Davidson ≥4gÁdlÀ1. We considered a composite of complications during the 7 days after surgery which included bronchospasm, laryngospasm, persistent cough- Accepted 25 August 2014 ing, desaturation, re-intubation, hypotension, postoperative bleeding, and doi:10.1111/pan.12531 reoperation. Pain was evaluated with Wong-Baker Faces pain scales, and supplemental tramadol use recorded for four postoperative hours. Results: There were 36 patients in the low-exposure group COHb [1.8 Æ 1.2 gÁdlÀ1], and 64 patients were in the high-exposure group [6.4 Æ 2.1 gÁdlÀ1]. Indoor coal-burning stoves were reported more often by families of the high- than low-COHb children (89% vs 72%, P < 0.001). Sec- ond-hand cigarette smoke exposure was reported by 54% of the families with children with high COHb, but only by 24% of the families of children with low COHb. Composite complications were more common in patients with high COHb [47% vs 14%, P = 0.0001, OR:7.4 (95% Cl, lower = 2.5- upper = 21.7)], with most occurring in the postanesthesia care unit. Pain scores in postanesthesia care unit and one hour after surgery were statistically signiﬁcantly lower in the low-exposure group [respectively, P = 0.020 (95% CI, lower = À1.21-upper = À0.80), P = 0.026 (95% CI, lower = À0.03- upper = 0.70)], and tramadol use increased at 4 h (3.5 (interquartile range: 0–8) vs 6 (5–9) mg, P = 0.012) and 24 h (3.5 (0–8) vs 6 (5–9) mg, P = 0.008). Conclusion: High preoperative COHb concentrations are associated with increased postoperative complications and pain.

sis was that there is an association between carboxyhe- Background moglobin and acute postoperative pain and analgesic Almost half of the world’s population uses solid fuel consumption. including biomass (wood, crop residues, and animal dung) or coal for heating and cooking. Because stoves Methods are usually centrally positioned in homes and often the only source of heat, families tend to congregate around This prospective observational, assessor-blinded study them and sleep nearby (1). Proximity to indoor stoves is was conducted at Mustafa Kemal University Hospital. problematic because many generate and release pollu- The work was approved by the Hospital Ethics Commit- tants into household air including particulate matter, tee (number 207, April 2012), and written consent was organic compounds, trace metals such as mercury, and obtained from the parents of all enrolled children. carbon monoxide (CO) (2,3). Household air pollution We enrolled 100 American Society of Anesthesiolo- from indoor combustion of biomass or coal is thought gists Physical Status I–II children scheduled for elective to be the third major cause of global disease burden, tonsillectomy under general anesthesia over the course and especially affects young children (4). Children are of 3 months starting August 2013. Patients were also exposed to CO via second-hand smoke (5). The excluded if they were active smokers, had a history of prevalence of smoking is 21% (45 million) for adults (6), prematurity, bleeding disorders, hemolysis, severe and about 10% of nonsmokers are exposed to second- pulmonary disease, home oxygen use, chronic pain, or hand smoke in the United States (7). It is almost certain inpatient hospitalization within the week. that both smoking prevalence and exposure of children is far higher in most developing countries. Protocol Inhaled CO diffuses rapidly across alveolar and capil- lary membranes, forming a bond with hemoglobin that Children were premedicated with midazolam hydrochlo- is 200 times tighter than with oxygen, resulting in carbo- ride 0.6 mgÁkgÀ1 orally about 40 min before surgery. A xyhemoglobin (COHb) (8). COHb remains in the circu- local decongestant, oxymetazoline (Iliadin, Merck, lation for hours and is thus a marker of recent exposure Istanbul, Turkey), was applied to the both nasal pas- to CO. Chronic exposure to carbon monoxide may lead sages 10 min before surgery. Anesthesia was induced to neurotoxicity, cognitive impairment, and visual with sevoflurane 8% and nitrous oxide 70% in oxygen. impairment; unconsciousness and death occur at COHb After mask induction, an intravenous cannula was concentrations exceeding 50% (9). inserted and rocuronium 0.5 mgÁkgÀ1 and fentanyl Carbon monoxide exposure also causes inflamma- 1mgÁkgÀ1 were given intravenously before tracheal tion through multiple pathways that are independent intubation. Anesthesia was maintained with sevoflurane of the pathways to hypoxia (9), and it is these path- 2–3% and nitrous oxide 50% in oxygen. ways rather than hypoxia per se that cause most com- Before surgery, the nasal passages and oropharynx plications consequent to exposure. Carbon monoxide were aspirated. The same surgeons, using a standardized also impairs lung structural and functional develop- snare technique, performed all tonsillectomies. Opera- ment (10). Consequently, forced expiratory volume in tions were completed after homeostasis was obtained by 1 s and vital capacity of the lungs are reduced after ligation with absorbable suture materials. A moist chronic childhood exposure (11); asthma and airway throat pack was placed around the endotracheal tube at hyperreactivity are common sequellae (12). CO expo- the laryngeal inlet to prevent the passive ingestion of sure is also pronociceptive via activation of a cGMP- blood. The oropharyngeal cavity was rinsed with a stan- PKG signaling pathway (13,14) and may thus enhance dardized volume of saline solution at room temperature. pain sensitivity. Perioperative blood loss was estimated from the volume Exposure to environmental cigarette smoke is associ- in the suction canister after subtracting the volume of ated with various respiratory complications in children saline solution used, compensating for the increase in (15,16). But the perioperative effect of presumably much the weight of the throat pack. greater CO exposure that results from indoor stoves At the end of the surgery, neuromuscular block was remains to be quantified. In a prospective observational reversed with intravenous neostigmine 0.03 mgÁkgÀ1 study, we therefore tested the a priori primary hypothe- and atropine 0.01 mgÁkgÀ1. Anesthesia was discontin- sis that there is an association between preoperative car- ued and the tracheal tube was removed in the operating boxyhemoglobin concentration and postoperative room when airway reflexes returned. Children free of complications during the initial 7 days after pediatric postoperative nausea and vomiting were given 100 ml tonsillectomy surgery. Our secondary a priori hypothe- of water four hours later. PONV was treated with

248 © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 247–252 O. Koyuncu et al. Carboxyhemoglobin and perioperative complications in children intravenous metoclopramide (0.1 mgÁkgÀ1 for children and requiring either administration of continuous posi- <6 years old and 2.5–5 mg for children ≥6 years old). tive pressure or a neuromuscular blocking agent to All children were given 10–15 mgÁkgÀ1 intravenous restore ventilation), persistent coughing (duration longer paracetamol. If pain exceeded a score of two on the than 15 s), desaturation (SpO2 < %95), re-intubation, Wong-Baker FACES Pain Rating Scale (17), hypotension (decrease in systolic arterial pressure of 0.25 mgÁkgÀ1 tramadol was given. Patients were dis- >10 mmHg from baseline), postoperative bleeding, and charged when they had no bleeding, no nausea and vom- reoperation were recorded. iting, were able to drink liquids, and had pain scores of ≤2. Patients stayed at least 24 h in the hospital per surgi- Data analysis cal routine. Qualifying patients were divided a prior starting study into two groups according to COHb concentrations Measurements À measured: (i) COHb ≤3gÁdl 1 as low group or Demographic and morphometric characteristics were (ii) COHb ≥4gÁdlÀ1 as high group (22). For our sam- recorded. Parents were asked to complete a 7-item ques- ple-size analysis, we used data from a pilot of 10 patients tionnaire about the child’s environmental air quality for each group. 50% of patients with high carboxyhe- including major sources of CO, highlighting second-hand moglobin levels (COHb ≥4gÁdlÀ1) and 20% of the smoke and indoor coal use (Appendix 1). Questions patients with low carboxyhemoglobin levels (COHb related to air quality in the questionnaire were based on ≤3gÁdlÀ1) had postoperative complications. This ratio a survey from the Healthy Public Housing Initiative (18). suggested that 30 patients in each group would provide Children’s COHb levels were measured noninvasively a significance (a) of 0.05 and a power (b) > 0.80. using a CO-Oximeter (Radical-7 Rainbow SET Pulse Normality was evaluated with the Kolmogorov– CO-Oximeter; Masimo, Irvine, CA, USA) during prein- Smirnov test. Continuous data were compared using traoperative period (19,20). Roth et al. found a bias Mann–Whitney U-test and Wilcoxon rank sum tests. between noninvasive and blood carboxyhemoglobin of Fisher exact test was used to compare categorical 3%, and a precision of 3.3% in a cohort of emergency variables. Results are presented as percentages, department patients. Other studies have also shown that means Æ SDs, medians and interquartile range, or num- multiwave pulse-oximetry measures COHb with an bers as appropriate. Statistical Package for the Social acceptable bias and precision (21–24). An age-appropri- Sciences (SPSS) version 15.0 (SPSS Inc., Chicago, IL, ate sensor was applied to the child’s hand or foot. In chil- USA). P < 0.05 was considered significant. dren weighing more than 10 kg, reusable finger sensors were used, whereas smaller children received disposable Results adhesive sensors to insure appropriate fit and measurement according to the manufacturer’s specifications. The One hundred consenting patients who fulfilled the entry system was calibrated before anesthesia induction. criteria were enrolled; all patients completed the entire Parents were asked to identify their child’s pain inten- study and were included in the final analysis. 36 patients sity using the Wong-Baker Faces Pain Rating Scale (17) were in the low-COHb group [mean Æ SD COHb upon admission to the postanesthesia care unit; 1, 2, 4, 1.8 Æ 1.2 gÁdlÀ1]; 64 patients were in the high-COHb 6, 12, and 24 h after anesthesia ended, and 7 days after group [6.4 Æ 2.1 gÁdlÀ1]. Patients with low- and high- surgery by phone. Specifically, they were told: ‘Each face COHb concentrations were comparable with respect to is a person who feels happy because he has no pain or age, height, body weight, ASA physical status, and gen- sad because he has more pain; choose the face that best der (Table 1). describes how your child is feeling.’ An anesthetist Indoor coal-burning stoves were reported more often blinded to preoperative COHb concentrations queried by families of the high- than low-COHb children (89% patients about postoperative sedation level using Ram- vs 72%, P < 0.001). Second-hand cigarette smoke expo- sey sedation scale at admission to the postanesthesia sure was reported by 54% of the families with children care unit; 1, 2, 4, 6, 12, and 24 h after anesthesia ended. with high COHb, but only by 24% of the families of Heart rate, noninvasive blood pressure, respiratory children with low COHb. There were no statistically sig- rate, and SpO2 were evaluated at admission to the pos- nificant differences between high and low-COHb groups tanesthesia care unit; 1, 2, 4, 6, 12, and 24 h after anes- in regard to who smoked at home or whether windows thesia ended; and 7 days after surgery by phone. Side were left open. effects including bronchospasm, laryngospasm (charac- The high-COHb group had significantly more post- terized by an inability to ventilate the patient’s lungs operative complications [36 (54%)] than the low-COHb

Table 1 Baseline characteristics Table 4 Postoperative pain scores

COHb ≤3gÁdlÀ1 COHb ≥4gÁdlÀ1 COHb ≤3gÁdlÀ1 COHb ≥4gÁdlÀ1 (n = 36) (n = 64) (n = 36) (n = 64) P

Age (year) 7 Æ 26Æ 2 PACU 2 (1–3) 3 (2–4) 0.020 Height (cm) 119 Æ 20 113 Æ 20 Postoperative (1 h) 2 (2–2) 2 (2–3) 0.026 Weight (kg) 25 Æ 9.7 22 Æ 7.8 Postoperative (2 h) 2 (2–2) 2 (2–2) 0.820 ASA physical status (I/II) 25/9 49/17 Postoperative (4 h) 2 (2–2) 2 (2–2) 0.195 Sex (M/F) 18/18 38/26 Postoperative (6 h) 2 (2–2) 2 (2–2) 0.707 COHb (gÁdlÀ1) 1.8 Æ 1.2 6.4 Æ 2.1 Postoperative (12 h) 2 (1–2) 2 (2–2) 0.593 Postoperative (24 h) 2 (1–2) 2 (1–2) 0.987 Results presented as numbers or median and range. Only COHb dif- Day 7 0 (0–2) 1 (0–2) 0.137 fered significantly (P < 0.001). Results presented as interquartile ranges. group [8 (24%, P = 0.003)]. Composite complications were more common in patients in the high-COHb hours were statistically significantly lower in the group in postanesthesia care unit: 14% vs 47%, low-exposure group [respectively, (P = 0.011 95% P = 0.0001 [odds ratio:7.4 (95% Cl, lower = 2.5- CI, lower = À0.51-upper = À0.11), (P = 0.012 95% CI, upper = 21.7)] (Table 2). The most common complica- lower = À4.16-upper = À0.61), (P = 0.008 95% CI, tions were coughing (46%) and desaturation (15%) lower = À4.32-upper = À0.80)] (Table 5). (Table 3). In only high-COHb group, two patients Total blood loss was also similar in the high and low- needed re-intubation. Pain scores in postanesthesia care exposure groups: 22 ml vs 25 ml (P = 0.75). Only one unit and one hour after surgery were statistically signifi- child needed reoperation in high-COHb group because cantly lower in the low-exposure group [respectively, of secondary hemorrhage. P = 0.020 (95% CI, lower = À1.21-upper = À0.80), P = 0.026 (95% CI, lower = À0.03-upper = 0.70)] Discussion (Table 4). Furthermore, total supplemental tramadol in the PACU, and at the 4th and 24th postoperative Generally, COHb concentrations up to 1% are accepted as safe in children (25). In our patients, the mean COHb Table 2 Postoperative complications concentration was 5% in children having elective tonsillectomies. This concentration is similar to the 5.9% À1 À1 COHb ≤3gÁdl COHb ≥4gÁdl reported by Yee et al. in children exposed to second- n = n = P ( 36) (%) ( 64) (%) hand smoke (26). PACU 5 (14) 35 (47) 0.001 A number of pollutants commonly found indoor Postoperative 1 h 5 (14) 25 (22) 0.342 impair respiratory defenses including ciliary function Postoperative 2 h 1 (2) 2 (3) 0.980 (27). Larson and Konig reviewed six studies of exposure Postoperative 4 h 1 (2.9) 0 (0) 0.161 to biomass pollution in school-aged children in the Uni- Postoperative 6 h 0 (0) 3 (4.5) 0.207 ted States, and found that exposure was associated with Postoperative 12 h 0 (0) 1 (1.5) 0.471 Postoperative 24 h 0 (0) 1 (1.5) 0.471 chronic respiratory symptoms, worsened lung function, Day 7 0 (0) 1 (1.5) 0.471 and increased hospital visits (28). A study conducted near where ours was found in a group of 617 9–12-year- Results presented as numbers (percentile). old children that those in homes in which coal stoves were used coughed more than those living homes in Table 3 Total number of each postoperative complications in 24 h which kerosene, oil, or electricity was used (27). COHb ≤3gÁdlÀ1 COHb ≥4gÁdlÀ1 n = n = ( 36) ( 64) Table 5 Postoperative analgesic consumption

Persistent Coughing 7 24 COHb ≤3gÁdlÀ1 COHb ≥4gÁdlÀ1 Desaturation 1 9 (n = 36) (n = 64) P Postoperative Nausea-vomiting 2 6 PACU (0 h) 0 (0–2.25) 4 (0–5) 0.011 Laryngospasm 1 5 Postoperative (1 h) 0 (0–4.75) 0 (0–4.75) 0.943 Bronchospasm 1 3 Cumulative (4 h) 3.5 (0–8) 6 (5–9) 0.012 Postoperative bleeding 0 3 Cumulative (24 h) 3.5 (0–8) 6 (5–9) 0.008

Results presented as numbers. Results presented as interquartile ranges.

CO exposure is also a risk factor for postoperative Although the related questions were included in a vali- complications in infants and children. Lakshmipathy dated questionnaire, it remains possible that parents et al. concluded that the risk of developing postoperative failed to accurately or completely report passive laryngospasm is an order-of-magnitude great in children smoking exposure at home for various reasons, includ- exposed to second-hand smoke (15). Skolnick et al. and ing personal embarrassment. An additional limitation is Drowngowski et al. noted that laryngospasm and severe that we used a relatively new, noninvasive device to coughing in the postanesthesia care unit were more com- evaluate carboxyhemoglobin rather than blood concen- mon in children exposed to second-hand smoke (16,29). trations; however, the system is well validated and there There is possibility that there are confounding variables were strong associations between COHb concentrations known or unknown that may have influenced the identified noninvasively and adverse outcomes. Baker outcome and that the CO is an association and not causa- et al. in their study exposed volunteers to carbon mon- tion. For example, CO may be a marker of socioeco- oxide until COHb level reached 15% and later results nomic status that can affect certain outcomes. were compared with the laboratory blood measure- We observed that pain and analgesic requirements ments, which proved a bias of À1.22% and precision of were increased in the high-CO patients, especially in the Æ2.19% (absolute range of error was À6to+8%) (19). initial postoperative period. This result is consistent with Studies in emergency department demonstrated a bias Gilbert et al. who demonstrated that long-term expo- value of À4.2% (95% CI À2.8% to 5.6%) (22,35). sure to CO augments pain perception (30). Akmal et al. In summary, children with substantial environmental described the association between smoking and low- CO exposure who were given general anesthesia had back pain via anoxia because of COHb in the blood more postoperative complications, more pain, and (31). Rahman et al. suggested a different mechanism, needed more analgesics than those with less exposure. A explaining that smoking introduces a variety of toxic history of coal stove use and second-hand smoke expo- substances (e.g., carbon monoxide) that may damage sure thus has clinical implications and is worth eliciting the interior lining of blood vessels, thus decreasing their —especially as carboxyhemoglobin concentrations can capacity to carry oxygen, leading to tissue starvation, now be confirmed noninvasively. degeneration, and death (32). Furthermore. carbon monoxide has been found to play a role in regulation of Ethical approval nociception by the activation of CGMP-PKG signaling pathway (33,34). There was an obvious correlation There is no any necessary ethical approval. between COHb and pain ratings especially in early postoperative period in our study. This mechanisms support Funding our secondary hypothesis that patients with high-CO concentrations have more pain; our results support the This study was not associated with any grand funding. hypothesis, as analgesic consumption was greater in Supported by internal funds only. high-COHb patients. Although, overall pain scores are low in both groups which may be related to surgical Conflict of interest technique, making it difficult to interpret. We relied on children’s parents and caregivers to No conflicts of interest declared. identify and quantify second-hand smoke exposure.

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Appendix 1: The child’s environmental air quality questionnaire (26).

1 Does your house have an indoor coal-burning stove? a Yes b No a Yes b No 5 Does the father smoke? 2 How often do you open open the windows during a Yes b No winter? 6 Is your child permitted to be present in the same room a Can not open them or car where smoking occurs? b 2-3 days per week a Yes b No c Daily 7 Is there any smoker caregiver at home? 3 Does anyone in your household smoke? a Yes b No a Yes b No 4 Does the mother smoke?