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Rocuronium is associated with an increased risk of reintubation in patients with soft tissue infections
Journal of Clinical Anesthesia (2016) 34, 186–191
Original contribution
Rocuronium is associated with an increased risk of reintubation in patients with soft tissue infections☆ Karla M. Greco MD, MHS (Assistant Professor)a,⁎, Bianca M. Conti MD (Assistant Professor, Director of Education)a,1 , Cynthia J. Bucci MD (Assistant Professor)a,1 , Samuel M. Galvagno Jr. DO, PhD (Associate Professor)a,b,1 a
Division of Trauma Anesthesiology, Department of Anesthesiology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD 21201 b Division of Critical Care Medicine University of Maryland School of Medicine, Baltimore, MD 21201 Received 7 January 2016; revised 22 February 2016; accepted 29 March 2016
Keywords: Reintubation; Rocuronium; Soft tissue infection; Extubation failure; Structural equation modeling; Neuromuscular blockade drugs
Abstract Study Objective: To determine risk factors associated with reintubations in adult patients with soft tissue infections. Design: A retrospective case-control design. Setting: Operating room and postoperative recovery area. Patients: There were 39 patients who presented for surgical intervention of their soft tissue infection and 222 controls having general surgery who were matched for age, sex, and body mass index. All patients were older than the age of 18 years and mostly American Society of Anesthesiologists physical status of III to IV and presented to our level 1 trauma center. Interventions: Reintubation within 2 hours after planned extubation. Measurements: The following data were collected: reintubation rates, train of four ratio, reversal agents, age, sex, creatinine, smoking history, transfusion requirements, Sequential Organ Failure Assessment score, hemoglobin, and lactate. Main Results: The use of rocuronium was independently associated with increased odds of reintubation. Patients with a higher train of four ratio were more likely to be reintubated and less likely to be reversed as compared to those with a lower train of four ratio. Conclusions: Soft tissue patients who have received rocuronium are at increased risk for reintubation, particularly those with renal failure. In addition, this article supports the use of neuromuscular blockade reversals, even in patients with a strong train of four ratio. © 2016 Elsevier Inc. All rights reserved.
☆
Disclosure: The authors have nothing to disclose. ⁎ Correspondence: Karla M. Greco, MD, MHS, Division of Trauma Anesthesiology, Department of Anesthesiology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201. Tel.: +1 410 328 2630; fax: +1 410 328 3135. E-mail addresses: [email protected], [email protected] (K.M. Greco), [email protected] (B.M. Conti), [email protected] (C.J. Bucci), [email protected] (S.M. Galvagno). 1 Tel.: +1 410 328 2630; fax: +1 410 328 3135. http://dx.doi.org/10.1016/j.jclinane.2016.03.073 0952-8180/© 2016 Elsevier Inc. All rights reserved.
1. Introduction Reintubation after planned extubation in either the operating room or postanesthesia care unit (PACU) is an uncommon event; however, it may have a significant impact on morbidity, mortality, and cost. The incidence of reintubation rates in the PACU has been reported to be approximately 0.19% [1,2]
Rocuronium and reintubation in soft tissue infections which is lower than the failed extubation rate reported in intensive care units [3,4]. Despite the relatively rare occurrence of this event, reintubation poses a significant risk to patient safety and remains an important focus for quality improvement initiatives [5]. There are limited data regarding the risk factors for reintubation in the PACU. One case-control study identified head and neck surgery, cardiothoracic surgery, airway surgery, and operative time more than 3 hours as surgically related independent risk factors for reintubation, whereas American Society of Anesthesiologists (ASA) physical status III and administration of aminosteroid neuromuscular blockade drugs (NMBD) were found to be independent anesthetic risk factors for reintubation [6]. In a Taiwanese study, the majority of reintubations occurred within 10 minutes of extubation and was more common in patients with chronic obstructive pulmonary disease, pneumonia, ascites, or systemic inflammatory response syndrome [7]. Reintubation has been shown to be an independent risk factor for morbidity and mortality [8–13]. It is associated with the development of ventilator-associated pneumonia, need for tracheostomy, and increased hospital costs and may be associated with a risk of mortality more than 40% [8–13]. Furthermore, patients requiring reintubation are often at greater risk for having a difficult airway. In a previous study by Pronovost et al [14], for every 6 failed extubations prevented, 1 death was avoided. In the same study, the marginal cost of hospital care for a failed extubation was $10,000 per incident [14]. There are currently no well-defined risk factors associated with reintubation after planned extubation for patients in need of surgery for severe soft tissue infections. As a primary statewide referral center for patients requiring evaluation and treatment of soft tissue infections, our institution has significant experience with this distinct patient population. The primary objective of this work was to determine factors associated with reintubation in adult patients with soft tissue infections, most commonly necrotizing fasciitis of the perineum. We hypothesized that use of rocuronium in patients with soft tissue infections is an independent risk factor for extubation failure.
2. Methods 2.1. Study population, design, and outcome of interest After expedited approval by the institutional review board of the University of Maryland School of Medicine, a retrospective case-control design was devised to investigate the outcome of interest. The study was completed at a single level 1 trauma center that accepts more than 8000 direct patient admissions annually. The study population was composed of cases and controls, age 18 years or older and admitted to the trauma center from January 1, 2008, to May 21, 2015. Cases were identified using a preexisting database maintained at the institution to track patients admitted with soft tissue
187 infections in addition to a quality assurance database maintained in the Division of Trauma Anesthesiology used to identify cases of reintubation. Controls were selected as patients with nonnecrotizing soft tissue infections and matched to cases using similar distributions of the following independent variables: sex (3:1 male to female ratio), age (± 15 years), and body mass index (± 10). The primary outcome of interest for this work was the requirement for reintubation.
2.2. Anesthetic management Patients in this study were induced with propofol at 1 to 1.5 mg/kg and subsequently maintained under general anesthesia at a minimum alveolar concentration of 1 of either isoflurane or sevoflurane. Muscle relaxation was provided by either rocuronium at an intubating dose of 0.6 mg/kg or vecuronium at an intubating dose of 0.1 mg/kg based on the discretion of the provider. In the case group, 23 patients received rocuronium, and 16 patients received vecuronium. In the control group, 154 patients received rocuronium, and 63 received vecuronium. The train of four (TOF) monitoring was analyzed by Life-tech MiniStim monitor. Before extubation, the TOF was monitored at either the orbicularis oculi muscle or the adductor pollicis muscle. The site was not recorded, but it is common at our institution to monitor the orbicularis oculi muscle as the adductor pollicis muscle is often inaccessible due to arm position.
2.3. Statistical analysis Student t tests or Wilcoxon rank sum tests were used for comparison of normally and nonnormally distributed continuous variables, and the χ2 or Fisher exact test was used for comparison of end points expressed as percentages. All tests were done with a 2-sided significance of 0.05. To analyze independent variables associated with the outcome of interest (reintubation), a fixed-effect logit for panel data analysis (conditional logistic regression) was used for the matched case-control groups to determine any association with the use of rocuronium and reintubation. To further investigate relationships between measured variables and latent constructs, a structural equation modeling (SEM) approach was used. SEM is a comprehensive statistical approach to test hypotheses about relations among observed (measured) and unobserved (latent) variables [15–17]. SEM is a highly flexible multivariate technique that can help with understanding the patterns of correlation among a set of variables [17,18]. In SEM, model specification involves formulating statements about a set of variables. A pictorial representation of a model is transformed into a set of equations, and the equations are solved to test model fit and estimate parameters [17]. Relationships between independent and dependent variables can be assessed with SEM. A large direct effect is indicated by a standardized path coefficient with an absolute value greater than 0.50 [17,19].
188 Table 1
K.M. Greco et al. Table 2
Demographics
Neuromuscular blockade data
Variable
Cases (n = 39)
Controls (n = 222)
P
Variable
Age (SD) BMI (SD) Sex (%) Male Female Smoker (%) ASA class (%) I II III IV Emergent case (%) Mean creatinine (SD) Mean hemoglobin (SD) Mean lactate (SD) Transfusion Yes No SOFA, median (IQR)
55.4 (14.6) 31.3 (9.3)
50.5 (15.1) 31.4 (9.4)
.06 .98
30 (76.9) 9 (23.1) 17 (43.6)
143 (64.7) 78 (35.3) 94 (42.7)
.14 .92
0 4 (10.3) 27 (69.2) 8 (20.5) 9 (23.1) 1.61 (1.3) 10.2 (2.2) 2.07 (2.8)
4 (1.8) 62 (27.9) 137 (61.7) 19 (8.6) 37 (16.7) 1.22 (1.03) 11.2 (6.1) 1.6 (0.6)
11 (28.2) 28 (71.8) 1 (0-3)
50 (22.5) 172 (77.5) 0 (0-2)
Agent Rocuronium Vecuronium Succinylcholine Cisatracurium Vecuronium + rocuronium TOF⁎ 0 1 2 3 4 Tetany Not recorded Neuromuscular blockade reversed Yes No
.02 .33 .09 .07 .39
.44 .09
Cases Controls P (n = 39) (n = 222) 23 (59) 16 (41) 0 0 0
154 (69.4) 63 (28.4) 1 (0.45) 2 (0.9) 2 (0.9)
.79
0 0 3 (7.6) 1 (2.6) 24 (61.5) 2 (5.1) 9 (23)
7 (3.2) 2 (0.9) 2 (0.9) 7 (3.2) 102 (46) 71 (32) 31 (14)
.004
30 (76.9) 196 (88.3) 9 (23.1) 26 (11.7) b .008
TOF = train of four.
IQR = interquartile range.
The SEM used the maximum likelihood method with missing values and calculation of robust SEs. Standardized coefficients were approximated by calculation of Yule's Q [20]. The standardized coefficients were transformed to odds ratios via (1 + Q)/(1 − Q) [20]. All tests, including SEM, were performed in Stata v.12.1 (Stata Corp, College Station, TX).
3. Results Thirty-nine cases (reintubated soft tissue infection patients) and 222 controls were identified for this study. The distribution of cases and controls was similar with regard to age, body mass index (BMI), sex, smoking status, and laboratory values (Table 1). A higher proportion of cases were ASA physical status IV compared to controls (20.5% vs 8.6%; P = .02). Median Sequential Organ Failure Assessment (SOFA) scores were not statistically significantly different between the 2 groups. Similar proportions of neuromuscular blockers were given between the groups (Table 2). Reintubated patients had a significantly higher TOF ratio (TOFR) compared to control patients (61.5% vs 46%; P = .004), but neuromuscular blockade was more commonly reversed in control patients compared to cases (P b .008). Conditional logistic regression demonstrated higher odds of reintubation among patients who had an elevated creatinine (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.1-2.4; P = .02). In the fully fitted regression model, no other covariates were independently associated with reintubation (Table 3).
SEM modeling revealed several weak to moderate correlations between covariates and the risk for reintubation (Table 4). Weakness was modeled as a latent variable and was associated with an increased risk for reintubation (OR, 4.71; 95% CI, 3.54-6.4; P b .001). This variable was created by combining 3 observed variables: administration of reversal agents for neuromuscular blockade (categorical), TOFR (continuous), and type of neuromuscular blocker (categorical). In the SEM model, creatinine was associated with an increased risk for reintubation, but this association was not statistically significant. The use of rocuronium was independently associated with increased odds of reintubation (OR, 1.22; 95% CI, 1.2-1.44; P = .03).
Table 3
Conditional logistic regression results
Variable
Unadjusted 95% CI OR
Age
1.02
0.99-1.05 1.01
Male sex BMI
1.82 1.00
0.82-4.02 0.92 0.96-1.04 0.98
Emergent case Creatinine
1.5
0.66-3.42 –
1.3 0.86 0.53
1.0031.62 1.68 0.73-1.02 – 0.22-1.26 0.37
– – 0.11-1.3 .12
0.71 3.64
0.39-1.3 – 1.72-7.72 –
– –
Hemoglobin Reversal given Smoker SOFA score
Adjusted 95% CI OR
P
0.981.04 0.35-2.4 0.931.04 –
.49
–
1.1-2.4
.02
.87 .53
– –
Rocuronium and reintubation in soft tissue infections Table 4
Results of structural equation modeling
Variable
Correlation 95% CI coefficient
Weakness a Age
0.65 0.05
BMI
−0.02
Emergency case Sex
−0.02 0.05
Creatinine
0.18
SOFA score
0.03
Rocuronium used
0.10
0.56-0.73 −0.06 to 0.16 −0.12 to 0.09 −0.14 to 0.10 −0.06 to 0.15 −0.01 to 0.37 −0.17 to 0.24 0.09-0.18
OR
95% CI
P
4.71 3.54-6.4 b .001 1.11 0.89-1.38 .38 0.96
0.79-1.2
.74
0.96 0.75-1.22
.78
1.11 0.89-1.35
.41
1.44 0.98-2.17
.07
1.06 0.71-1.63
.75
1.22
.03
1.2-1.44
Dependent variable: reintubation. a Weakness was modeled as a latent variable based on the following observed variables: train-of-four, type of neuromuscular blocker administered, and administration of a neuromuscular blocker reversal agent (neostigmine).
Among patients requiring reintubation, patients in the rocuronium failed a trial of extubation more rapidly compared to patients in the vecuronium group (Fig. 1).
4. Discussion This case-control study sought to ascertain risk factors for reintubation after planned extubation in a subset of patients requiring surgery for soft tissue infections. Using 2 robust
Fig. 1
189 analytical techniques to control for known confounders, we determined that rocuronium and renal failure were associated with increased odds of reintubation in this specific population. Most data regarding reintubation originate from the intensive care unit setting, not immediately after anesthesia recovery in the PACU. Reintubation is typically defined as reinstituting ventilator support after a planned extubation within 24 to 72 hours. In our study, reintubation rates were considered within 2 hours of extubation. The 2 neuromuscular blockade drugs administered that were studied, rocuronium and vecuronium, are aminosteroid compounds. These drugs are deacetylated by the liver and then excreted in the urine [21]. Our result that patients with impaired renal function are more likely to be reintubated despite hepatic breakdown is consistent with the reported data in the literature. Rujirojindakul et al [6] found an independent association between reintubations in patients with renal failure and those who received an aminosteroid neuromuscular blocking drug. In a small study published by Robertson, patients with renal failure had increased clinical duration and time to recovery of the TOF to 70% after administration of rocuronium [22]. Further research is necessary to explain why those with renal impairment suffer a higher incidence of reintubations if a drug that is metabolized by the liver is used. An interesting finding in our study is the higher recorded TOFR in reintubated patients compared to controls. We speculate that these patients were less likely to have been administered neuromuscular blockade reversal, and indeed, when examined in the unadjusted analysis, 23.1% of cases did not receive reversal compared with 11.7% of controls (P b .0008). It is conceivable that providers may have been lulled into a false sense of security with a higher TOFR. Alternatively, nonquantitative TOF testing by anesthesiologists is fraught with interpretative error [23]. In a study by Eikermann
Time to reintubation in cases: vecuronium vs rocuronium (n = 39).
190 et al [23], with repeated dosing of NMBD despite a TOFR equal to 0.9, the maximum force of the adductor pollicis remains weak. Before 1996, a TOFR of 0.7 was accepted as a marker for muscle strength and the ability to extubate. More recent studies have shown that a TOFR less than 0.7 impairs the hypoxic ventilatory response [24,25], and the response does not normalize until the ratio exceeds 0.9 [25,26]. Even with an established TOFR of less than 0.9, volunteers were found to have pharyngeal dysfunction and an increased risk of aspiration [27,28]. In an observational study using a single intubating dose of an intermediate acting NMBD, residual paralysis occurred in the PACU more than 2 hours after administration implying that a long duration between initial administration of muscle relaxant and arrival to the PACU does not guarantee a full recovery. Among patients requiring reintubation in the study by Debaene et al [29], 16% of patients arriving in the PACU had a TOFR less than 0.7 and 45% had a TOFR less than 0.9. This study is subject to all of the limitations inherent with observational study designs. Given the rare occurrence of the outcome of interest (reintubation), it is likely that this study was underpowered to generate reliable effect estimates. Indeed, presumably due to the relatively low number of cases, many of the calculated CIs were quite wide in this study. Advanced statistical techniques, including conditional logistic regression and SEM, were used to control for known confounders. Nevertheless, it is possible that residual confounders may be responsible for the outcome of reintubation. Future studies, including additional patient data derived from automated continuous vital signs and enhanced electronic perioperative documentation, are underway. Serious soft tissue infections are relatively rare but associated with a very high morbidity and mortality. Our study, although modest in size, represents the largest study to our knowledge examining the anesthetic management of these patients. In previous studies, reintubation after planned extubation is associated with an increased risk of death, prolonged intensive care unit stay, and need for long term care [10]. Reintubation is likely less a marker of a poor outcome and more likely an indicator for underappreciated severe illness. This observation is supported by the relatively low, nonsignificantly different SOFA scores observed in both cases and controls. Our study has additional limitations that merit discussion. Data on total volatile anesthetic dose and total opioid dose were not recorded for this study. At our institution, isoflurane is titrated to a minimum alveolar concentration of 0.9 to 1.1 end-expired % in 40% to 50% oxygen, fentanyl administered at a dose of 10 to 20 μg/kg in divided doses, and hydromorphone given in 0.2 mg doses, titrated for analgesia and a respiratory rate greater than 12. Although practices regarding titration of volatile anesthetics and opioids are highly consistent among our group of anesthesiologists who provide general anesthesia for this patient population, it is possible that effect modification, as a result of statistical interaction between neuromuscular blockers, volatile anesthetics, and opioids, may partially explain differences between cases and controls. At
K.M. Greco et al. our institution, a trial of an evidence-based pre-extubation checklist was implemented [30]. This intervention by Howie and Dutton [30] was conducted between 2009 and 2010, which coincided with the inclusion period for this study. This study involved a performance improvement project and was associated with a significant decrease in extubation failures [30]. Finally, additional outcomes, such as inhospital mortality and discharge status, were not examined. In summary, we advise caution when extubating patients with soft tissue infections who receive rocuronium. Clinicians should be particularly cautious when extubating patients with soft tissue infections and renal failure. The results from this study support reversal of neuromuscular blockade in this patient population because TOFR was not reliable in this study. Although large randomized studies are likely impractical for this patient population, larger, well-designed observational studies, including studies using quantitative TOF monitoring, are indicated to better understand risk factors for reintubation in patients with soft tissue infections.
Acknowledgments We would like to thank Josie Armiger and Betsy Burcham for their assistance in accessing data from the Shock Trauma Database and Dr Fouche-Weber for her guidance and support.
References [1] Mathew JP, Rosenbaum SH, O'Connor T, Barash PG. Emergency tracheal intubation in the postanesthesia care unit: physician error or patient disease? Anesth Analg 1990;71:691-7. [2] Rose DK, Cohen MM, Wigglesworth DF, DeBoer DP. Critical respiratory events in the postanesthesia care unit. Patient, surgical, and anesthetic factors. Anesthesiology 1994;81:410-8. [3] de Lassence A, Alberti C, Azoulay E, Le Miere E, Cheval C, Vincent F, et al. Impact of unplanned extubation and reintubation after weaning on nosocomial pneumonia risk in the intensive care unit: a prospective multicenter study. Anesthesiology 2002;97:148-56. [4] Johnson RG, Arozullah AM, Neumayer L, Henderson WG, Hosokawa P, Khuri SF. Multivariable predictors of postoperative respiratory failure after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007;204:1188-98. [5] Pronovost PJ, Jenckes M, To M, Dorman T, Lipsett PA, Berenholtz S, et al. Reducing failed extubations in the intensive care unit. Jt Comm J Qual Improv 2002;28:595-604. [6] Rujirojindakul P, Geater AF, McNeil EB, Vasinanukorn P, Prathep S, Asim W, et al. Risk factors for reintubation in the post-anaesthetic care unit: a case-control study. Br J Anaesth 2012;109:636-42. [7] Ting PC, Chou AH, Yang MW, Ho AC, Chang CJ, Chang SC. Postoperative reintubation after planned extubation: a review of 137,866 general anesthetics from 2005 to 2007 in a Medical Center of Taiwan. Acta Anaesthesiol Taiwan 2010;48:167-71. [8] Menon N, Joffe AM, Deem S, Yanez ND, Grabinsky A, Dagal AH, et al. Occurrence and complications of tracheal reintubation in critically ill adults. Respir Care 2012;57:1555-63.
Rocuronium and reintubation in soft tissue infections [9] Demling RH, Read T, Lind LJ, Flanagan HL. Incidence and morbidity of extubation failure in surgical intensive care patients. Crit Care Med 1988; 16:573-7. [10] Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest 1997;112:186-92. [11] Rashkin MC, Davis T. Acute complications of endotracheal intubation. Relationship to reintubation, route, urgency, and duration. Chest 1986; 89:165-7. [12] Daley BJ, Garcia -Perez F, Ross SE. Reintubation as an outcome predictor in trauma patients. Chest 1996;110:1577-80. [13] Epstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med 1998;158:489-93. [14] Pronovost P, Garrett E, Dorman T, Jenckes M, Webb III TH, Breslow M, et al. Variations in complication rates and opportunities for improvement in quality of care for patients having abdominal aortic surgery. Langenbecks Arch Surg 2001;386:249-56. [15] Hoyle R. The structural equation modeling approach: basic concepts and fundamental issues. In: Hoyle R, editor. Structural equation modeling: concepts, issues, and applications. Thousand Oaks, CA: Sage Publications, Inc.; 1995. p. 1-15. [16] Acock A. Discovering structural equation modeling using Stata. College Station, TX: Stata Press; 2013. [17] The basics of structural equation modeling. 2010 Accessed 5 August 2015, at http://www.lexjansen.com/wuss/2006/tutorials/TUT-Shr.pdf. [18] Kline R. Principles and practice of structural equation modeling. New York, NY: The Guilford Press; 1998. [19] Grace JB, Bollen KA. Interpreting the results from multiple regression and structural equation models. Bull Ecol Soc Am 2005;283–95. [20] Kupek E. Beyond logistic regression: structural equation s modeling for binary variables and its application to investigating unobserved confounders. BMC Med Res Methodol 2006;6:13.
191 [21] Hunter JM. New neuromuscular blocking drugs. N Engl J Med 1995; 332:1691-9. [22] Robertson EN, Driessen JJ, Booij LH. Pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure. Eur J Anaesthesiol 2005;22:4-10. [23] Eikermann M, Gerwig M, Hasselmann C, Fiedler G, Peters J. Impaired neuromuscular transmission after recovery of the train-of-four ratio. Acta Anaesthesiol Scand 2007;51:226-34. [24] Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993;78:693-9. [25] Eriksson LI. Reduced hypoxic chemosensitivity in partially paralysed man. A new property of muscle relaxants? Acta Anaesthesiol Scand 1996;40:520-3. [26] Eriksson LI. The effects of residual neuromuscular blockade and volatile anesthetics on the control of ventilation. Anesth Analg 1999;89:243-51. [27] Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997;87: 1035-43. [28] Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 2000; 92:977-84. [29] Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042-8. [30] Howie W, Dutton R. Implementaton of an evidence-based extubation checklist to reduce extubation failure in patients with trauma: a pilot study. AANA J 2012;80:179-84.
Original contribution
Rocuronium is associated with an increased risk of reintubation in patients with soft tissue infections☆ Karla M. Greco MD, MHS (Assistant Professor)a,⁎, Bianca M. Conti MD (Assistant Professor, Director of Education)a,1 , Cynthia J. Bucci MD (Assistant Professor)a,1 , Samuel M. Galvagno Jr. DO, PhD (Associate Professor)a,b,1 a
Division of Trauma Anesthesiology, Department of Anesthesiology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD 21201 b Division of Critical Care Medicine University of Maryland School of Medicine, Baltimore, MD 21201 Received 7 January 2016; revised 22 February 2016; accepted 29 March 2016
Keywords: Reintubation; Rocuronium; Soft tissue infection; Extubation failure; Structural equation modeling; Neuromuscular blockade drugs
Abstract Study Objective: To determine risk factors associated with reintubations in adult patients with soft tissue infections. Design: A retrospective case-control design. Setting: Operating room and postoperative recovery area. Patients: There were 39 patients who presented for surgical intervention of their soft tissue infection and 222 controls having general surgery who were matched for age, sex, and body mass index. All patients were older than the age of 18 years and mostly American Society of Anesthesiologists physical status of III to IV and presented to our level 1 trauma center. Interventions: Reintubation within 2 hours after planned extubation. Measurements: The following data were collected: reintubation rates, train of four ratio, reversal agents, age, sex, creatinine, smoking history, transfusion requirements, Sequential Organ Failure Assessment score, hemoglobin, and lactate. Main Results: The use of rocuronium was independently associated with increased odds of reintubation. Patients with a higher train of four ratio were more likely to be reintubated and less likely to be reversed as compared to those with a lower train of four ratio. Conclusions: Soft tissue patients who have received rocuronium are at increased risk for reintubation, particularly those with renal failure. In addition, this article supports the use of neuromuscular blockade reversals, even in patients with a strong train of four ratio. © 2016 Elsevier Inc. All rights reserved.
☆
Disclosure: The authors have nothing to disclose. ⁎ Correspondence: Karla M. Greco, MD, MHS, Division of Trauma Anesthesiology, Department of Anesthesiology, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201. Tel.: +1 410 328 2630; fax: +1 410 328 3135. E-mail addresses: [email protected], [email protected] (K.M. Greco), [email protected] (B.M. Conti), [email protected] (C.J. Bucci), [email protected] (S.M. Galvagno). 1 Tel.: +1 410 328 2630; fax: +1 410 328 3135. http://dx.doi.org/10.1016/j.jclinane.2016.03.073 0952-8180/© 2016 Elsevier Inc. All rights reserved.
1. Introduction Reintubation after planned extubation in either the operating room or postanesthesia care unit (PACU) is an uncommon event; however, it may have a significant impact on morbidity, mortality, and cost. The incidence of reintubation rates in the PACU has been reported to be approximately 0.19% [1,2]
Rocuronium and reintubation in soft tissue infections which is lower than the failed extubation rate reported in intensive care units [3,4]. Despite the relatively rare occurrence of this event, reintubation poses a significant risk to patient safety and remains an important focus for quality improvement initiatives [5]. There are limited data regarding the risk factors for reintubation in the PACU. One case-control study identified head and neck surgery, cardiothoracic surgery, airway surgery, and operative time more than 3 hours as surgically related independent risk factors for reintubation, whereas American Society of Anesthesiologists (ASA) physical status III and administration of aminosteroid neuromuscular blockade drugs (NMBD) were found to be independent anesthetic risk factors for reintubation [6]. In a Taiwanese study, the majority of reintubations occurred within 10 minutes of extubation and was more common in patients with chronic obstructive pulmonary disease, pneumonia, ascites, or systemic inflammatory response syndrome [7]. Reintubation has been shown to be an independent risk factor for morbidity and mortality [8–13]. It is associated with the development of ventilator-associated pneumonia, need for tracheostomy, and increased hospital costs and may be associated with a risk of mortality more than 40% [8–13]. Furthermore, patients requiring reintubation are often at greater risk for having a difficult airway. In a previous study by Pronovost et al [14], for every 6 failed extubations prevented, 1 death was avoided. In the same study, the marginal cost of hospital care for a failed extubation was $10,000 per incident [14]. There are currently no well-defined risk factors associated with reintubation after planned extubation for patients in need of surgery for severe soft tissue infections. As a primary statewide referral center for patients requiring evaluation and treatment of soft tissue infections, our institution has significant experience with this distinct patient population. The primary objective of this work was to determine factors associated with reintubation in adult patients with soft tissue infections, most commonly necrotizing fasciitis of the perineum. We hypothesized that use of rocuronium in patients with soft tissue infections is an independent risk factor for extubation failure.
2. Methods 2.1. Study population, design, and outcome of interest After expedited approval by the institutional review board of the University of Maryland School of Medicine, a retrospective case-control design was devised to investigate the outcome of interest. The study was completed at a single level 1 trauma center that accepts more than 8000 direct patient admissions annually. The study population was composed of cases and controls, age 18 years or older and admitted to the trauma center from January 1, 2008, to May 21, 2015. Cases were identified using a preexisting database maintained at the institution to track patients admitted with soft tissue
187 infections in addition to a quality assurance database maintained in the Division of Trauma Anesthesiology used to identify cases of reintubation. Controls were selected as patients with nonnecrotizing soft tissue infections and matched to cases using similar distributions of the following independent variables: sex (3:1 male to female ratio), age (± 15 years), and body mass index (± 10). The primary outcome of interest for this work was the requirement for reintubation.
2.2. Anesthetic management Patients in this study were induced with propofol at 1 to 1.5 mg/kg and subsequently maintained under general anesthesia at a minimum alveolar concentration of 1 of either isoflurane or sevoflurane. Muscle relaxation was provided by either rocuronium at an intubating dose of 0.6 mg/kg or vecuronium at an intubating dose of 0.1 mg/kg based on the discretion of the provider. In the case group, 23 patients received rocuronium, and 16 patients received vecuronium. In the control group, 154 patients received rocuronium, and 63 received vecuronium. The train of four (TOF) monitoring was analyzed by Life-tech MiniStim monitor. Before extubation, the TOF was monitored at either the orbicularis oculi muscle or the adductor pollicis muscle. The site was not recorded, but it is common at our institution to monitor the orbicularis oculi muscle as the adductor pollicis muscle is often inaccessible due to arm position.
2.3. Statistical analysis Student t tests or Wilcoxon rank sum tests were used for comparison of normally and nonnormally distributed continuous variables, and the χ2 or Fisher exact test was used for comparison of end points expressed as percentages. All tests were done with a 2-sided significance of 0.05. To analyze independent variables associated with the outcome of interest (reintubation), a fixed-effect logit for panel data analysis (conditional logistic regression) was used for the matched case-control groups to determine any association with the use of rocuronium and reintubation. To further investigate relationships between measured variables and latent constructs, a structural equation modeling (SEM) approach was used. SEM is a comprehensive statistical approach to test hypotheses about relations among observed (measured) and unobserved (latent) variables [15–17]. SEM is a highly flexible multivariate technique that can help with understanding the patterns of correlation among a set of variables [17,18]. In SEM, model specification involves formulating statements about a set of variables. A pictorial representation of a model is transformed into a set of equations, and the equations are solved to test model fit and estimate parameters [17]. Relationships between independent and dependent variables can be assessed with SEM. A large direct effect is indicated by a standardized path coefficient with an absolute value greater than 0.50 [17,19].
188 Table 1
K.M. Greco et al. Table 2
Demographics
Neuromuscular blockade data
Variable
Cases (n = 39)
Controls (n = 222)
P
Variable
Age (SD) BMI (SD) Sex (%) Male Female Smoker (%) ASA class (%) I II III IV Emergent case (%) Mean creatinine (SD) Mean hemoglobin (SD) Mean lactate (SD) Transfusion Yes No SOFA, median (IQR)
55.4 (14.6) 31.3 (9.3)
50.5 (15.1) 31.4 (9.4)
.06 .98
30 (76.9) 9 (23.1) 17 (43.6)
143 (64.7) 78 (35.3) 94 (42.7)
.14 .92
0 4 (10.3) 27 (69.2) 8 (20.5) 9 (23.1) 1.61 (1.3) 10.2 (2.2) 2.07 (2.8)
4 (1.8) 62 (27.9) 137 (61.7) 19 (8.6) 37 (16.7) 1.22 (1.03) 11.2 (6.1) 1.6 (0.6)
11 (28.2) 28 (71.8) 1 (0-3)
50 (22.5) 172 (77.5) 0 (0-2)
Agent Rocuronium Vecuronium Succinylcholine Cisatracurium Vecuronium + rocuronium TOF⁎ 0 1 2 3 4 Tetany Not recorded Neuromuscular blockade reversed Yes No
.02 .33 .09 .07 .39
.44 .09
Cases Controls P (n = 39) (n = 222) 23 (59) 16 (41) 0 0 0
154 (69.4) 63 (28.4) 1 (0.45) 2 (0.9) 2 (0.9)
.79
0 0 3 (7.6) 1 (2.6) 24 (61.5) 2 (5.1) 9 (23)
7 (3.2) 2 (0.9) 2 (0.9) 7 (3.2) 102 (46) 71 (32) 31 (14)
.004
30 (76.9) 196 (88.3) 9 (23.1) 26 (11.7) b .008
TOF = train of four.
IQR = interquartile range.
The SEM used the maximum likelihood method with missing values and calculation of robust SEs. Standardized coefficients were approximated by calculation of Yule's Q [20]. The standardized coefficients were transformed to odds ratios via (1 + Q)/(1 − Q) [20]. All tests, including SEM, were performed in Stata v.12.1 (Stata Corp, College Station, TX).
3. Results Thirty-nine cases (reintubated soft tissue infection patients) and 222 controls were identified for this study. The distribution of cases and controls was similar with regard to age, body mass index (BMI), sex, smoking status, and laboratory values (Table 1). A higher proportion of cases were ASA physical status IV compared to controls (20.5% vs 8.6%; P = .02). Median Sequential Organ Failure Assessment (SOFA) scores were not statistically significantly different between the 2 groups. Similar proportions of neuromuscular blockers were given between the groups (Table 2). Reintubated patients had a significantly higher TOF ratio (TOFR) compared to control patients (61.5% vs 46%; P = .004), but neuromuscular blockade was more commonly reversed in control patients compared to cases (P b .008). Conditional logistic regression demonstrated higher odds of reintubation among patients who had an elevated creatinine (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.1-2.4; P = .02). In the fully fitted regression model, no other covariates were independently associated with reintubation (Table 3).
SEM modeling revealed several weak to moderate correlations between covariates and the risk for reintubation (Table 4). Weakness was modeled as a latent variable and was associated with an increased risk for reintubation (OR, 4.71; 95% CI, 3.54-6.4; P b .001). This variable was created by combining 3 observed variables: administration of reversal agents for neuromuscular blockade (categorical), TOFR (continuous), and type of neuromuscular blocker (categorical). In the SEM model, creatinine was associated with an increased risk for reintubation, but this association was not statistically significant. The use of rocuronium was independently associated with increased odds of reintubation (OR, 1.22; 95% CI, 1.2-1.44; P = .03).
Table 3
Conditional logistic regression results
Variable
Unadjusted 95% CI OR
Age
1.02
0.99-1.05 1.01
Male sex BMI
1.82 1.00
0.82-4.02 0.92 0.96-1.04 0.98
Emergent case Creatinine
1.5
0.66-3.42 –
1.3 0.86 0.53
1.0031.62 1.68 0.73-1.02 – 0.22-1.26 0.37
– – 0.11-1.3 .12
0.71 3.64
0.39-1.3 – 1.72-7.72 –
– –
Hemoglobin Reversal given Smoker SOFA score
Adjusted 95% CI OR
P
0.981.04 0.35-2.4 0.931.04 –
.49
–
1.1-2.4
.02
.87 .53
– –
Rocuronium and reintubation in soft tissue infections Table 4
Results of structural equation modeling
Variable
Correlation 95% CI coefficient
Weakness a Age
0.65 0.05
BMI
−0.02
Emergency case Sex
−0.02 0.05
Creatinine
0.18
SOFA score
0.03
Rocuronium used
0.10
0.56-0.73 −0.06 to 0.16 −0.12 to 0.09 −0.14 to 0.10 −0.06 to 0.15 −0.01 to 0.37 −0.17 to 0.24 0.09-0.18
OR
95% CI
P
4.71 3.54-6.4 b .001 1.11 0.89-1.38 .38 0.96
0.79-1.2
.74
0.96 0.75-1.22
.78
1.11 0.89-1.35
.41
1.44 0.98-2.17
.07
1.06 0.71-1.63
.75
1.22
.03
1.2-1.44
Dependent variable: reintubation. a Weakness was modeled as a latent variable based on the following observed variables: train-of-four, type of neuromuscular blocker administered, and administration of a neuromuscular blocker reversal agent (neostigmine).
Among patients requiring reintubation, patients in the rocuronium failed a trial of extubation more rapidly compared to patients in the vecuronium group (Fig. 1).
4. Discussion This case-control study sought to ascertain risk factors for reintubation after planned extubation in a subset of patients requiring surgery for soft tissue infections. Using 2 robust
Fig. 1
189 analytical techniques to control for known confounders, we determined that rocuronium and renal failure were associated with increased odds of reintubation in this specific population. Most data regarding reintubation originate from the intensive care unit setting, not immediately after anesthesia recovery in the PACU. Reintubation is typically defined as reinstituting ventilator support after a planned extubation within 24 to 72 hours. In our study, reintubation rates were considered within 2 hours of extubation. The 2 neuromuscular blockade drugs administered that were studied, rocuronium and vecuronium, are aminosteroid compounds. These drugs are deacetylated by the liver and then excreted in the urine [21]. Our result that patients with impaired renal function are more likely to be reintubated despite hepatic breakdown is consistent with the reported data in the literature. Rujirojindakul et al [6] found an independent association between reintubations in patients with renal failure and those who received an aminosteroid neuromuscular blocking drug. In a small study published by Robertson, patients with renal failure had increased clinical duration and time to recovery of the TOF to 70% after administration of rocuronium [22]. Further research is necessary to explain why those with renal impairment suffer a higher incidence of reintubations if a drug that is metabolized by the liver is used. An interesting finding in our study is the higher recorded TOFR in reintubated patients compared to controls. We speculate that these patients were less likely to have been administered neuromuscular blockade reversal, and indeed, when examined in the unadjusted analysis, 23.1% of cases did not receive reversal compared with 11.7% of controls (P b .0008). It is conceivable that providers may have been lulled into a false sense of security with a higher TOFR. Alternatively, nonquantitative TOF testing by anesthesiologists is fraught with interpretative error [23]. In a study by Eikermann
Time to reintubation in cases: vecuronium vs rocuronium (n = 39).
190 et al [23], with repeated dosing of NMBD despite a TOFR equal to 0.9, the maximum force of the adductor pollicis remains weak. Before 1996, a TOFR of 0.7 was accepted as a marker for muscle strength and the ability to extubate. More recent studies have shown that a TOFR less than 0.7 impairs the hypoxic ventilatory response [24,25], and the response does not normalize until the ratio exceeds 0.9 [25,26]. Even with an established TOFR of less than 0.9, volunteers were found to have pharyngeal dysfunction and an increased risk of aspiration [27,28]. In an observational study using a single intubating dose of an intermediate acting NMBD, residual paralysis occurred in the PACU more than 2 hours after administration implying that a long duration between initial administration of muscle relaxant and arrival to the PACU does not guarantee a full recovery. Among patients requiring reintubation in the study by Debaene et al [29], 16% of patients arriving in the PACU had a TOFR less than 0.7 and 45% had a TOFR less than 0.9. This study is subject to all of the limitations inherent with observational study designs. Given the rare occurrence of the outcome of interest (reintubation), it is likely that this study was underpowered to generate reliable effect estimates. Indeed, presumably due to the relatively low number of cases, many of the calculated CIs were quite wide in this study. Advanced statistical techniques, including conditional logistic regression and SEM, were used to control for known confounders. Nevertheless, it is possible that residual confounders may be responsible for the outcome of reintubation. Future studies, including additional patient data derived from automated continuous vital signs and enhanced electronic perioperative documentation, are underway. Serious soft tissue infections are relatively rare but associated with a very high morbidity and mortality. Our study, although modest in size, represents the largest study to our knowledge examining the anesthetic management of these patients. In previous studies, reintubation after planned extubation is associated with an increased risk of death, prolonged intensive care unit stay, and need for long term care [10]. Reintubation is likely less a marker of a poor outcome and more likely an indicator for underappreciated severe illness. This observation is supported by the relatively low, nonsignificantly different SOFA scores observed in both cases and controls. Our study has additional limitations that merit discussion. Data on total volatile anesthetic dose and total opioid dose were not recorded for this study. At our institution, isoflurane is titrated to a minimum alveolar concentration of 0.9 to 1.1 end-expired % in 40% to 50% oxygen, fentanyl administered at a dose of 10 to 20 μg/kg in divided doses, and hydromorphone given in 0.2 mg doses, titrated for analgesia and a respiratory rate greater than 12. Although practices regarding titration of volatile anesthetics and opioids are highly consistent among our group of anesthesiologists who provide general anesthesia for this patient population, it is possible that effect modification, as a result of statistical interaction between neuromuscular blockers, volatile anesthetics, and opioids, may partially explain differences between cases and controls. At
K.M. Greco et al. our institution, a trial of an evidence-based pre-extubation checklist was implemented [30]. This intervention by Howie and Dutton [30] was conducted between 2009 and 2010, which coincided with the inclusion period for this study. This study involved a performance improvement project and was associated with a significant decrease in extubation failures [30]. Finally, additional outcomes, such as inhospital mortality and discharge status, were not examined. In summary, we advise caution when extubating patients with soft tissue infections who receive rocuronium. Clinicians should be particularly cautious when extubating patients with soft tissue infections and renal failure. The results from this study support reversal of neuromuscular blockade in this patient population because TOFR was not reliable in this study. Although large randomized studies are likely impractical for this patient population, larger, well-designed observational studies, including studies using quantitative TOF monitoring, are indicated to better understand risk factors for reintubation in patients with soft tissue infections.
Acknowledgments We would like to thank Josie Armiger and Betsy Burcham for their assistance in accessing data from the Shock Trauma Database and Dr Fouche-Weber for her guidance and support.
References [1] Mathew JP, Rosenbaum SH, O'Connor T, Barash PG. Emergency tracheal intubation in the postanesthesia care unit: physician error or patient disease? Anesth Analg 1990;71:691-7. [2] Rose DK, Cohen MM, Wigglesworth DF, DeBoer DP. Critical respiratory events in the postanesthesia care unit. Patient, surgical, and anesthetic factors. Anesthesiology 1994;81:410-8. [3] de Lassence A, Alberti C, Azoulay E, Le Miere E, Cheval C, Vincent F, et al. Impact of unplanned extubation and reintubation after weaning on nosocomial pneumonia risk in the intensive care unit: a prospective multicenter study. Anesthesiology 2002;97:148-56. [4] Johnson RG, Arozullah AM, Neumayer L, Henderson WG, Hosokawa P, Khuri SF. Multivariable predictors of postoperative respiratory failure after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007;204:1188-98. [5] Pronovost PJ, Jenckes M, To M, Dorman T, Lipsett PA, Berenholtz S, et al. Reducing failed extubations in the intensive care unit. Jt Comm J Qual Improv 2002;28:595-604. [6] Rujirojindakul P, Geater AF, McNeil EB, Vasinanukorn P, Prathep S, Asim W, et al. Risk factors for reintubation in the post-anaesthetic care unit: a case-control study. Br J Anaesth 2012;109:636-42. [7] Ting PC, Chou AH, Yang MW, Ho AC, Chang CJ, Chang SC. Postoperative reintubation after planned extubation: a review of 137,866 general anesthetics from 2005 to 2007 in a Medical Center of Taiwan. Acta Anaesthesiol Taiwan 2010;48:167-71. [8] Menon N, Joffe AM, Deem S, Yanez ND, Grabinsky A, Dagal AH, et al. Occurrence and complications of tracheal reintubation in critically ill adults. Respir Care 2012;57:1555-63.
Rocuronium and reintubation in soft tissue infections [9] Demling RH, Read T, Lind LJ, Flanagan HL. Incidence and morbidity of extubation failure in surgical intensive care patients. Crit Care Med 1988; 16:573-7. [10] Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest 1997;112:186-92. [11] Rashkin MC, Davis T. Acute complications of endotracheal intubation. Relationship to reintubation, route, urgency, and duration. Chest 1986; 89:165-7. [12] Daley BJ, Garcia -Perez F, Ross SE. Reintubation as an outcome predictor in trauma patients. Chest 1996;110:1577-80. [13] Epstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med 1998;158:489-93. [14] Pronovost P, Garrett E, Dorman T, Jenckes M, Webb III TH, Breslow M, et al. Variations in complication rates and opportunities for improvement in quality of care for patients having abdominal aortic surgery. Langenbecks Arch Surg 2001;386:249-56. [15] Hoyle R. The structural equation modeling approach: basic concepts and fundamental issues. In: Hoyle R, editor. Structural equation modeling: concepts, issues, and applications. Thousand Oaks, CA: Sage Publications, Inc.; 1995. p. 1-15. [16] Acock A. Discovering structural equation modeling using Stata. College Station, TX: Stata Press; 2013. [17] The basics of structural equation modeling. 2010 Accessed 5 August 2015, at http://www.lexjansen.com/wuss/2006/tutorials/TUT-Shr.pdf. [18] Kline R. Principles and practice of structural equation modeling. New York, NY: The Guilford Press; 1998. [19] Grace JB, Bollen KA. Interpreting the results from multiple regression and structural equation models. Bull Ecol Soc Am 2005;283–95. [20] Kupek E. Beyond logistic regression: structural equation s modeling for binary variables and its application to investigating unobserved confounders. BMC Med Res Methodol 2006;6:13.
191 [21] Hunter JM. New neuromuscular blocking drugs. N Engl J Med 1995; 332:1691-9. [22] Robertson EN, Driessen JJ, Booij LH. Pharmacokinetics and pharmacodynamics of rocuronium in patients with and without renal failure. Eur J Anaesthesiol 2005;22:4-10. [23] Eikermann M, Gerwig M, Hasselmann C, Fiedler G, Peters J. Impaired neuromuscular transmission after recovery of the train-of-four ratio. Acta Anaesthesiol Scand 2007;51:226-34. [24] Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993;78:693-9. [25] Eriksson LI. Reduced hypoxic chemosensitivity in partially paralysed man. A new property of muscle relaxants? Acta Anaesthesiol Scand 1996;40:520-3. [26] Eriksson LI. The effects of residual neuromuscular blockade and volatile anesthetics on the control of ventilation. Anesth Analg 1999;89:243-51. [27] Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997;87: 1035-43. [28] Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 2000; 92:977-84. [29] Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042-8. [30] Howie W, Dutton R. Implementaton of an evidence-based extubation checklist to reduce extubation failure in patients with trauma: a pilot study. AANA J 2012;80:179-84.