Acta Anaesthesiol Scand 2014; 58: 942–947 Printed in Singapore. All rights reserved
© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12373
Impact of malnutrition on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery X. Tian1, Y. Xiang2, Y. Fan3, H. Bu1, H. Yang1, A. Manyande4, F. Gao1 and Y. Tian1 1
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, 2Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, 3Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and 4School of Psychology, Social Work and Human Sciences, University of West London, London, UK
Background: Malnutrition is a major health problem, especially in hospitalized patients as it can be closely related to many post-operative complications. However, research on malnutrition and its effect on the outcome of general anesthesia have been largely neglected. Here we investigated malnutrition status on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery under general anesthesia. Methods: One hundred and one patients were recruited between January and June 2012 at Tongji Hospital and assigned into three groups according to Nutritional Risk Screening Tool 2002 score. A standard combined general anesthesia procedure was performed under regular monitoring. The dosage of propofol needed for induction, consumption during maintenance and recovery time were recorded. Results: When compared with normal nutritional status individuals, the propofol dosage at induction was significantly decreased about 4.3% in moderate malnutritional status patients (P < 0.01) and about 16.8% in severely malnutritional status
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alnutrition affects many aspects of patients’ lives: leading to increased complications and mortality, length of hospital stay, costs and decreased quality of life.1–6 It has been reported that 30–50% of patients in hospital suffer malnutrition.7–9 In order to diagnose malnutrition in hospital, several methods have been proposed, such as the Nutritional Risk Screening Tool 2002 (NRS-2002),10 Nutritional Risk Index,11 Malnutrition Universal Screening Tool12 and the Subjective Global Assessment.13 Each has its advantages and disadvantages. However, none of them was specially designed for pre-anesthesia assessment. To the best of our knowledge, malnutrition and its effects on general anesthesia were not previously studied either.
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patients (P < 0.01). The average consumption of propofol was also significantly lower in malnourished individuals; for moderate malnutritional, the decrease was about 20% (P < 0.01) while for the severely malnutritional, it was 30% (P < 0.01) when compared with normal nutritional status individuals. For the recovery time of propofol anesthesia, the patients with severe malnutritional status awoke average 6.8 min later than those normally nourished (P < 0.01), but those patients with moderate malnutrition status did not (P = 0.885). Conclusion: The present results indicate that the dosage and recovery time of propofol does change in malnourished individuals. Therefore, malnutrition may somehow affect the outcome of general anesthesia. Accepted for publication 26 June 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Usually, anesthesiologists use the American Society of Anesthesiologists (ASA) score system to evaluate the physical status of patients. Unfortunately, there is no nutritional factor in ASA score evaluation system. The NRS-2002 was developed by the Danish Association of Parenteral and Enteral Nutrition and recommended by the European Society for Parenteral and Enteral Nutrition (ESPEN). It has an objective scoring system that allows one to follow the patient’s nutritional status and age; clinical data plus anthropometric measurements are included. Although this score was created on the basis of its power to predict therapeutic effect, NRS-2002 has also been used increasingly for pre-operative classification and risk assessment. It is a validated tech-
Malnutrition affects the outcome of general anesthesia
nique that has gained wide acceptance in clinical practice.14–18 The score system is easy to use and is based on selecting core indicators that reflect nutritional risk. These indicators were derived from randomized controlled trials deemed suitable for nutritional risk screening in patients. Although the notion that malnutrition can affect outcomes in surgical patients was first reported in 1936,19 it has since been extensively studied and is well documented.20–22 Further evidence suggests that optimization of nutritional status prior to major surgery leads to improved surgical outcome.23–25 As far as we know, there is no study to date that has investigated the effect of nutritional status on the outcome of general anesthesia. In this preliminary study, we aimed to compare propofol dosage and recovery time between different nutritional status patients who undergo selective abdominal surgery.
Methods After obtaining the approval from the local institute’s Ethical Committee (Huazhong University of Science and Technology, IRB ID: 20111202, 2011/ 12/04) and written informed consent, 101 patients were recruited to the study between 1 January and 30 June 2012 at Tongji Hospital. The sample was formed of patients of both sex who fulfilled the ASA I and II criteria and were scheduled for elective endoscopic gastrointestinal surgical procedures (Table 1). Patients were excluded from the study for the following reasons: allergy to anesthetics (propofol, vecuronium and opioids); if they had any neurological, cardiovascular or cerebrovascular disease; or other chronic disease such as renal failure and muscular diseases; previous history of difficult intubation or anticipated difficult
intubation; daily alcohol consumption; obesity [defined as a body mass index (BMI) 30 kg/m2]; taking drugs which interact with the metabolism of anesthetics such as loop diuretics, magnesium and lithium salts; history of abdominal surgery; or a poor quality signal on the Narcotrend monitor. Those without written informed consent were also excluded.
Grouped by nutrition risk screening Patients were assessed in the pre-operative period within 48 h of admission. Age, ASA physical status and sex were recorded. Trained nutritionists used NRS-2002 to evaluate nutritional status of patients. The NRS-2002 consists of a nutrition score, a severity of disease score and an age adjustment for patients above 70 years of age (+ 1). A scoring method was applied to assess the nutritional status. Patients who got NRS score < 3 were considered with normal nutritional status and assigned to group I. Patients who got score ≥ 3 < 5 were considered with moderate malnutritional status and assigned to group II. And those who got a total score ≥ 5 were considered with severe malnutritional status relevantly as group III.
Monitoring Perioperatively, hypnosis was monitored using a Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany, version 4.0). Electrode impedance was checked and confirmed to be below 6 kΩ. Neuromuscular transmission was measured by an accelerometer using a commercial device incorporating a pulse generator and a piezoelectric motion sensor placed at the tip of the thumb (TOF-watch SX; Organon, Dublin, Ireland). Skin temperature over the thumb was monitored and maintained above
Table 1 Patient characteristics. Age (year) Gender (m/f) Height (cm) Weight (kg) Surgery (gastric/colorectal resection) ASA physical status (I/II) BMI (< 20.5) Monthly loss of body weight (> 5%)
Group I (n = 30)
Group II (n = 44)
Group III (n = 23)
57 (46–68) 15/15 169 (11.3) 65.5 (3.8) 12/18 13/17 0 0
55 (44–65) 24/20 167 (8.7) 63.1 (6.4) 15/29 20/24 28 34
59 (49–74) 11/12 168 (9.4) 56.9 (6.9) 8/15 9/14 18 21
Note: Patients were grouped based on their NRS-2002 score. Those patients who got NRS score < 3 were considered with normal nutritional status and assigned to group I, ≥ 3 < 5 were considered with moderate malnutritional status and as group II, relevantly score ≥ 5 were considered with severe malnutritional status as group III. Data are presented as mean (SD), mean (range), or frequency. ASA, American Society of Anesthesiologists; BMI, body mass index.
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32°C. The ulnar nerve was stimulated supramaximally at the wrist with train-of-four stimuli (60 mA for 200 μs) at 15-s intervals and the acceleration of the thumb was measured. Baseline twitch amplitude was established before induction of anesthesia. Other standard monitoring methods were used, including pulse oximetry, temperature, electrocardiograph, capnography and non-invasive blood pressure monitoring.
Induction Once a 16-G intravenous catheter with a valve was placed in one arm, all patients then received 0.04 mg/kg midazolam intravenously. Anesthesia was induced by fentanyl (5 μg/kg); 3 min later, propofol (Diprivan, ASTRA-Zeneca, Cheshire, UK) was infused via infusion pump at the rate of 1 mg/ kg/min. The end point of hypnosis was when the Narcotrend value reached to D0 and patients were ventilated with 50% oxygen during face mask ventilation. One minute later after end point of hypnosis, vecuronium bromide dose of 0.1 mg/kg was administered. The trachea was intubated 2 min after the administration of vecuronium. The cuff of endotracheal tube was covered by 1–2 g compound lidocaine cream. The lungs were mechanically ventilated in a volume-control mode with settings aimed at achieving an end-tidal carbon dioxide concentration of 35 mmHg.
Maintenance Muscle relaxation. For muscle relaxation monitoring during anesthetic maintenance, the first twitch response in relation to the baseline values (T1/Tc) as well as the fourth twitch in relation to the first one of each train (T1/T4) were monitored. When recovery from the initial bolus dose was evident by a single twitch depression (T1/Tc) of more than 0.1, continuous infusion of vecuronium was started. Target neuromuscular relaxation was defined as maintaining T1/Tc of 0.1 during the operation. The infusion rate was started as 1 μg/kg/min and manually adjusted every 15 min. The rate was increased by 10% if T1/Tc was more than 0.1, and decreased by 10% if T1/Tc was 0.
Anesthesia Anesthesia was administered with a continuous infusion of propofol started at 10 mg/kg/h. During the maintenance phase, propofol infusion was adjusted to maintain the Narcotrend to a target value of D0. If the Narcotrend value was outside this
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range for longer than 10 s, the concentration of propofol was increased or decreased by 0.5 mg/ kg/h steps to bring the Narcotrend value to D0. A lower limit threshold of 5 mg/kg/h for the propofol effect-site level was defined to prevent the risk of awareness.
Analgesia Immediately after induction, an infusion of remifentanil 0.3 μg/kg/min was started. This was maintained unchanged throughout surgery, except in the presence of tachycardia, hypertension or any other indirect sign of inadequate analgesia, when the doses were changed in 0.05 μg/kg/min steps within the limits of 0.1 and 0.5 μg/kg/min. Hypotension, defined as a systolic blood pressure below 85 mmHg for more than 5 min, was treated by increasing the rate of crystalloid fluid infusion and administration of phenylephrine 40 μg boluses intravenously. If hypotension persisted, then the remifentanil infusion was reduced in steps of 0.05 μg/kg/min. Bradycardia, defined as a heart rate below 40 beats/min, was treated with atropine 0.01 mg/kg combined with a reduction in the rate of the remifentanil infusion.
Recovery Thirty minutes before the end of surgery (when the surgeon begins to close the abdominal wall), vecuronium infusion was stopped. After skin incision was closed and the TOF ratio was more than 25%, 0.2 mg/kg pyridostigmine and 0.05 mg glycopyrrolate per 1 mg pyridostigmine were administered. Then propofol and remifentanil were discontinued. The time from discontinuation of anesthesia to spontaneous opening of eyes were recorded. When consciousness was restored and TOF ratio was more than 90%, extubation was done. Post-operative pain management (analgesia) was executed by a special post-operative analgesia group of Tongji hospital.
Quality control Researchers were trained before conducting the study; a unified nutritional assessment questionnaire was adopted for screening and assessment by one researcher; the height and weight of patients with ward clothes on were measured without shoes at fasting; and the surgeons involved in this study were equally distributed among three groups. The anesthetists were blinded to nutrition status assessment.
Malnutrition affects the outcome of general anesthesia Table 2 Anesthesia requirement. Anaesthesia time (min) Surgical time (min) Propofol induction dose (mg/kg) Propofol maintenance dose (mg/kg/h) Propofol recover time (min)
Group I (n = 30)
Group II (n = 44)
Group III (n = 23)
307 (24) 253 (21) 1.84 (0.14) 8.63 (0.70) 8.3 (1.1)
320 (32) 272 (28) 1.76 (0.09)* 7.04 (0.59)* 8.4 (2.4)
299 (21) 250 (25) 1.53 (0.16)* 6.16 (0.76)* 15.1 (3.4)*
Compared with group I, *P < 0.01. Values are presented as mean (SD). SD, standard deviation.
Statistical analysis SPSS statistical software version 19.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Based on our preliminary clinical experience, a sample size of 21 patients in each group was deemed to be sufficient to characterize the outcome variables. Measurement data were expressed as mean ± standard deviation (SD). Enumeration data were expressed as percentage. The differences of enumeration data, such as sex, were compared by χ2 test, while the differences of numerical data were analyzed by one-way analysis of variance followed by pairwise comparisons using least squares difference test. P < 0.05 was considered statistically significant.
Results Groups’ equivalence Out of a total of 101 patients assessed for eligibility, 97 were screened and subsequently enrolled to the study. One was excluded because of severe hypotension during surgery and three for poor Narcotrend signal. Based on NRS-2002, body nutrition reserves, BMI, body weight and nutritional status evaluation, 30 patients were assigned to group I, 44 to group II and 23 to group III. The groups were similar with respect to other characteristics (e.g. type and length of surgical incision). Table 1 shows the characteristics of the patient groups.
Propofol requirement Propofol dosage and recovery time are presented in Table 2. Statistical analyses revealed a significant effect of nutrition status on propofol induction dose (F = 48.17, P < 0.01), propofol maintenance (F = 95.01, P < 0.01) and propofol recover time (F = 69.84, P < 0.01). The propofol dosage for induction in group I was 1.84 ± 0.14 (SD) mg/kg, while in group II was 1.76 ± 0.09 (SD) mg/kg and in group
III was 1.53 ± 0.16 (SD) mg/kg. When compared with group I, the propofol dosage for induction was significantly decreased in group II (P < 0.01) and group III (P < 0.01). The average maintenance dose of propofol was also significantly lower in malnourished individuals; for group II, the decrease was about 20% (P < 0.01) and for group III, 30% (P < 0.01) in comparison to group I. For the recovery time from propofol, there were no significant differences between group I and II (P = 0.885). However, the patients with severe nutritional status (group III) awoke much latter than those normally nourished (group I) (P < 0.01).
Discussion The aim of this preliminary study was to compare propofol dosage and recovery time between different nutritional status patients who had undergone selective abdominal surgery. Based on NRS-2002, we found that the dosage of propofol decreased in those patients with moderate malnutrition status when compared with better nutritional individuals both during induction and maintenance, but the recovery time did not change in these patients, whereas in patients with severe malnutritional status, the dosage decreased more significantly. In addition awakening from propofol anesthesia was significantly delayed in severely malnourished patients. Most importantly, our results showed that malnutrition is somehow correlated with the outcome of general anesthesia. Although the exact mechanism as to why the dosage and recovery time from propofol changed in malnourished individuals is not investigated in this study, we speculate that this presumably occurred through two pathways. Firstly, the pharmacokinetics and metabolism parameter of propofol may be altered in malnourished individuals. Although there is no such kind of data available for propofol, malnutrition and its effect on drug
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pharmacokinetics and metabolism has been well documented. For example, the evidence that protein binding and clearance is significantly reduced in several drugs has been reported in malnourished people.26–30 Furthermore, it has been demonstrated that malnutrition results in reduction of body fat which could alter the distribution of highly lipidsoluble drugs.31 The consequence of the elevation of unbounded drug concentration in plasma could delay clearance and change the distribution which is likely to result in lowering the dosage required in some drugs. Furthermore, malnutrition could lead to decrease in cytochrome P450 enzyme activity,32,33 impairing drug biotransformation and conjugation reactions.34–36 Thus, drug metabolism also changes a lot in malnourished individuals compared with normal people. Malnutrition may also have an effect on propofol’s protein binding, clearance, distribution, biotransformation and conjugation which then contribute to lowering the dosage needed and delays the recovery time from propofol. Secondly, malnutrition may cause the sensitivity to propofol to change in the central nervous system (CNS). Moreover, although propofol is primarily a hypnotic, the exact mechanism of its action has not yet been fully elucidated. It has been proposed to have several mechanisms of action, most probably through the potentiation of GABAA receptor activity,37,38 which thereby slow the channel-closing time. Recent research has also suggested that the endocannabinoid system,39 N-Methyl-D-aspartate (NMDA) subtype receptor40,41 and sodium channel42,43 may contribute significantly to propofol’s anesthetic action. However, only sporadic reports focus on the effect of malnutrition on mature CNS. Research using animal models showed that prolonged malnutrition in adult rats produces marked loss of hippocampal neurons and synapses accompanied by substantial impairments of hippocampaldependent behaviors.44,45 Furthermore, malnutrition has been reported to exert negative influence on structural and functional state of brain neurons.46 Because we did not find any direct evidence that malnutrition can affect the expression or/and sensitivity of those propofol related receptors, further studies are required that focus on this area, in order to examine in more detail the mechanism involved. In conclusion, the present results indicate that firstly, the dosage and recovery time from propofol does change in malnutrition individuals. Secondly, that malnutrition may somehow affect the outcome of general anesthesia. Therefore, for pre-anesthesia
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evaluation, the nutritional factor should also be considered and more related research conducted.
Acknowledgements This work was supported by Natural Science Foundation of China (30901395 to X. Tian) and the Doctoral Fund of Ministry of Education of China (20090142120012 to X. Tian, 20110142120021 to Y. Xiang). Conflicts of interest: Authors declare no conflicts of interest.
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Malnutrition affects the outcome of general anesthesia 14. Karateke F, Ikiz GZ, Kuvvetli A, Menekse E, Das K, Ozyazici S, Atalay BG, Ozdogan M. Evaluation of nutritional risk screening-2002 and subjective global assessment for general surgery patients: a prospective study. J Pak Med Assoc 2013; 63: 1405–8. 15. Gheorghe C, Pascu O, Iacob R, Vadan R, Iacob S, Goldis A, Tantau M, Dumitru E, Dobru D, Miutescu E, Saftoiu A, Fraticiu A, Tomescu D, Gheorghe L. Nutritional risk screening and prevalence of malnutrition on admission to gastroenterology departments: a multicentric study. Chirurgia (Bucur) 2013; 108: 535–41. 16. van Bokhorst-de van der Schueren MA, Guaitoli PR, Jansma EP, de Vet HC. Nutrition screening tools: does one size fit all? A systematic review of screening tools for the hospital setting. Clin Nutr 2014; 33: 39–58. 17. Kuppinger D, Hartl WH, Bertok M, Hoffmann JM, Cederbaum J, Bender A, Kuchenhoff H, Rittler P. Nutritional screening for risk prediction in patients scheduled for extraabdominal surgery. Nutrition 2013; 29: 399–404. 18. Kuppinger D, Hartl WH, Bertok M, Hoffmann JM, Cederbaum J, Kuchenhoff H, Jauch KW, Rittler P. Nutritional screening for risk prediction in patients scheduled for abdominal operations. Br J Surg 2012; 99: 728–37. 19. Studley HO. Percentage of weight loss: a basic indicator of surgical risk in patients with chronic peptic ulcer. JAMA 1936; 458–60. 20. Beau P, Kull E, Kaffy F, Matrat S, Ingrand P. [Malnutrition is an independent risk factor of early complications following percutaneous endoscopic gastrostomy]. Gastroenterol Clin Biol 2001; 25: 891–5. 21. Bozzetti F, Gianotti L, Braga M, Di Carlo V, Mariani L. Postoperative complications in gastrointestinal cancer patients: the joint role of the nutritional status and the nutritional support. Clin Nutr 2007; 26: 698–709. 22. Giner M, Laviano A, Meguid MM, Gleason JR. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition 1996; 12: 23–9. 23. Ljungqvist O, Soreide E. Preoperative fasting. Br J Surg 2003; 90: 400–6. 24. Miller KR, Wischmeyer PE, Taylor B, McClave SA. An evidence-based approach to perioperative nutrition support in the elective surgery patient. JPEN J Parenter Enteral Nutr 2013; 37: 39S–50S. 25. Pronio A, Di Filippo A, Aguzzi D, Laviano A, Narilli P, Piroli S, Vestri A, Montesani C. [Treatment of mild malnutrition and reduction of morbidity in major abdominal surgery: randomized trial on 153 patients]. Clin Ter 2008; 159: 13–8. 26. Oshikoya KA, Sammons HM, Choonara I. A systematic review of pharmacokinetics studies in children with proteinenergy malnutrition. Eur J Clin Pharmacol 2010; 66: 1025–35. 27. Idoipe Tomas A. [Pharmacokinetics of antibiotics in malnutrition]. Nutr Hosp 1990; 5: 77–84. 28. Jung D, Prasad PP. Influence of nutritional status on the pharmacokinetics and pharmacodynamics of pentobarbital. Drug Metab Dispos 1989; 17: 365–8. 29. Krishnaswamy K, Ushasri V, Naidu NA. The effect of malnutrition on the pharmacokinetics of phenylbutazone. Clin Pharmacokinet 1981; 6: 152–9. 30. Buchanan N. Drug-protein binding and protein energy malnutrition. S Afr Med J 1977; 52: 733–7. 31. Boullata JI. Drug disposition in obesity and protein-energy malnutrition. Proc Nutr Soc 2010; 69: 543–50. 32. Motawi TK, Abd-Elgawad HM, Shahin NN. Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach. Food Chem Toxicol 2013; 56: 467–82.
33. Reen RK, Melo GE, Moraes-Santos T. Malnutrition sequela on the drug metabolizing enzymes in male Holtzman rats. J Nutr Biochem 1999; 10: 615–8. 34. Zhang W, Parentau H, Greenly RL, Metz CA, Aggarwal S, Wainer IW, Tracy TS. Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase. Eur J Drug Metab Pharmacokinet 1999; 24: 141–7. 35. Krishnaswamy K. Drug metabolism and pharmacokinetics in malnourished children. Clin Pharmacokinet 1989; 17 (Suppl. 1): 68–88. 36. Mehta S. Drug disposition in children with protein energy malnutrition. J Pediatr Gastroenterol Nutr 1983; 2: 407–17. 37. Krasowski MD, Hong X, Hopfinger AJ, Harrison NL. 4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor. J Med Chem 2002; 45: 3210–21. 38. Trapani G, Latrofa A, Franco M, Altomare C, Sanna E, Usala M, Biggio G, Liso G. Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors. J Med Chem 1998; 41: 1846–54. 39. Fowler CJ. Possible involvement of the endocannabinoid system in the actions of three clinically used drugs. Trends Pharmacol Sci 2004; 25: 59–61. 40. Kingston S, Mao L, Yang L, Arora A, Fibuch EE, Wang JQ. Propofol inhibits phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in neurons. Anesthesiology 2006; 104: 763–9. 41. Orser BA, Bertlik M, Wang LY, MacDonald JF. Inhibition by propofol (2,6 di-isopropylphenol) of the N-methyl-Daspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol 1995; 116: 1761–8. 42. Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, Dengler R, Leuwer M. High-affinity blockade of voltageoperated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. Br J Pharmacol 2008; 155: 265–75. 43. Haeseler G, Leuwer M. High-affinity block of voltageoperated rat IIA neuronal sodium channels by 2,6 di-tertbutylphenol, a propofol analogue. Eur J Anaesthesiol 2003; 20: 220–4. 44. Lister JP, Blatt GJ, DeBassio WA, Kemper TL, Tonkiss J, Galler JR, Rosene DL. Effect of prenatal protein malnutrition on numbers of neurons in the principal cell layers of the adult rat hippocampal formation. Hippocampus 2005; 15: 393–403. 45. Paula-Barbosa MM, Andrade JP, Castedo JL, Azevedo FP, Camoes I, Volk B, Tavares MA. Cell loss in the cerebellum and hippocampal formation of adult rats after long-term low-protein diet. Exp Neurol 1989; 103: 186–93. 46. Medvedev DI, Bogolepov NN, Eremina IZ, Savrova OB, Bogolepova IN. [Histological structure of adult mouse brain in protein-deficient nutrition]. Morfologiia 2000; 118: 17–9.
Address: Feng Gao Department of Anesthesiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Jiefang Road 1095# Wuhan, Hubei 430030 China e-mail: [email protected]
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© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12373
Impact of malnutrition on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery X. Tian1, Y. Xiang2, Y. Fan3, H. Bu1, H. Yang1, A. Manyande4, F. Gao1 and Y. Tian1 1
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, 2Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, 3Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and 4School of Psychology, Social Work and Human Sciences, University of West London, London, UK
Background: Malnutrition is a major health problem, especially in hospitalized patients as it can be closely related to many post-operative complications. However, research on malnutrition and its effect on the outcome of general anesthesia have been largely neglected. Here we investigated malnutrition status on propofol consumption and recovery time among patients undergoing laparoscopic gastrointestinal surgery under general anesthesia. Methods: One hundred and one patients were recruited between January and June 2012 at Tongji Hospital and assigned into three groups according to Nutritional Risk Screening Tool 2002 score. A standard combined general anesthesia procedure was performed under regular monitoring. The dosage of propofol needed for induction, consumption during maintenance and recovery time were recorded. Results: When compared with normal nutritional status individuals, the propofol dosage at induction was significantly decreased about 4.3% in moderate malnutritional status patients (P < 0.01) and about 16.8% in severely malnutritional status
M
alnutrition affects many aspects of patients’ lives: leading to increased complications and mortality, length of hospital stay, costs and decreased quality of life.1–6 It has been reported that 30–50% of patients in hospital suffer malnutrition.7–9 In order to diagnose malnutrition in hospital, several methods have been proposed, such as the Nutritional Risk Screening Tool 2002 (NRS-2002),10 Nutritional Risk Index,11 Malnutrition Universal Screening Tool12 and the Subjective Global Assessment.13 Each has its advantages and disadvantages. However, none of them was specially designed for pre-anesthesia assessment. To the best of our knowledge, malnutrition and its effects on general anesthesia were not previously studied either.
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patients (P < 0.01). The average consumption of propofol was also significantly lower in malnourished individuals; for moderate malnutritional, the decrease was about 20% (P < 0.01) while for the severely malnutritional, it was 30% (P < 0.01) when compared with normal nutritional status individuals. For the recovery time of propofol anesthesia, the patients with severe malnutritional status awoke average 6.8 min later than those normally nourished (P < 0.01), but those patients with moderate malnutrition status did not (P = 0.885). Conclusion: The present results indicate that the dosage and recovery time of propofol does change in malnourished individuals. Therefore, malnutrition may somehow affect the outcome of general anesthesia. Accepted for publication 26 June 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Usually, anesthesiologists use the American Society of Anesthesiologists (ASA) score system to evaluate the physical status of patients. Unfortunately, there is no nutritional factor in ASA score evaluation system. The NRS-2002 was developed by the Danish Association of Parenteral and Enteral Nutrition and recommended by the European Society for Parenteral and Enteral Nutrition (ESPEN). It has an objective scoring system that allows one to follow the patient’s nutritional status and age; clinical data plus anthropometric measurements are included. Although this score was created on the basis of its power to predict therapeutic effect, NRS-2002 has also been used increasingly for pre-operative classification and risk assessment. It is a validated tech-
Malnutrition affects the outcome of general anesthesia
nique that has gained wide acceptance in clinical practice.14–18 The score system is easy to use and is based on selecting core indicators that reflect nutritional risk. These indicators were derived from randomized controlled trials deemed suitable for nutritional risk screening in patients. Although the notion that malnutrition can affect outcomes in surgical patients was first reported in 1936,19 it has since been extensively studied and is well documented.20–22 Further evidence suggests that optimization of nutritional status prior to major surgery leads to improved surgical outcome.23–25 As far as we know, there is no study to date that has investigated the effect of nutritional status on the outcome of general anesthesia. In this preliminary study, we aimed to compare propofol dosage and recovery time between different nutritional status patients who undergo selective abdominal surgery.
Methods After obtaining the approval from the local institute’s Ethical Committee (Huazhong University of Science and Technology, IRB ID: 20111202, 2011/ 12/04) and written informed consent, 101 patients were recruited to the study between 1 January and 30 June 2012 at Tongji Hospital. The sample was formed of patients of both sex who fulfilled the ASA I and II criteria and were scheduled for elective endoscopic gastrointestinal surgical procedures (Table 1). Patients were excluded from the study for the following reasons: allergy to anesthetics (propofol, vecuronium and opioids); if they had any neurological, cardiovascular or cerebrovascular disease; or other chronic disease such as renal failure and muscular diseases; previous history of difficult intubation or anticipated difficult
intubation; daily alcohol consumption; obesity [defined as a body mass index (BMI) 30 kg/m2]; taking drugs which interact with the metabolism of anesthetics such as loop diuretics, magnesium and lithium salts; history of abdominal surgery; or a poor quality signal on the Narcotrend monitor. Those without written informed consent were also excluded.
Grouped by nutrition risk screening Patients were assessed in the pre-operative period within 48 h of admission. Age, ASA physical status and sex were recorded. Trained nutritionists used NRS-2002 to evaluate nutritional status of patients. The NRS-2002 consists of a nutrition score, a severity of disease score and an age adjustment for patients above 70 years of age (+ 1). A scoring method was applied to assess the nutritional status. Patients who got NRS score < 3 were considered with normal nutritional status and assigned to group I. Patients who got score ≥ 3 < 5 were considered with moderate malnutritional status and assigned to group II. And those who got a total score ≥ 5 were considered with severe malnutritional status relevantly as group III.
Monitoring Perioperatively, hypnosis was monitored using a Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany, version 4.0). Electrode impedance was checked and confirmed to be below 6 kΩ. Neuromuscular transmission was measured by an accelerometer using a commercial device incorporating a pulse generator and a piezoelectric motion sensor placed at the tip of the thumb (TOF-watch SX; Organon, Dublin, Ireland). Skin temperature over the thumb was monitored and maintained above
Table 1 Patient characteristics. Age (year) Gender (m/f) Height (cm) Weight (kg) Surgery (gastric/colorectal resection) ASA physical status (I/II) BMI (< 20.5) Monthly loss of body weight (> 5%)
Group I (n = 30)
Group II (n = 44)
Group III (n = 23)
57 (46–68) 15/15 169 (11.3) 65.5 (3.8) 12/18 13/17 0 0
55 (44–65) 24/20 167 (8.7) 63.1 (6.4) 15/29 20/24 28 34
59 (49–74) 11/12 168 (9.4) 56.9 (6.9) 8/15 9/14 18 21
Note: Patients were grouped based on their NRS-2002 score. Those patients who got NRS score < 3 were considered with normal nutritional status and assigned to group I, ≥ 3 < 5 were considered with moderate malnutritional status and as group II, relevantly score ≥ 5 were considered with severe malnutritional status as group III. Data are presented as mean (SD), mean (range), or frequency. ASA, American Society of Anesthesiologists; BMI, body mass index.
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32°C. The ulnar nerve was stimulated supramaximally at the wrist with train-of-four stimuli (60 mA for 200 μs) at 15-s intervals and the acceleration of the thumb was measured. Baseline twitch amplitude was established before induction of anesthesia. Other standard monitoring methods were used, including pulse oximetry, temperature, electrocardiograph, capnography and non-invasive blood pressure monitoring.
Induction Once a 16-G intravenous catheter with a valve was placed in one arm, all patients then received 0.04 mg/kg midazolam intravenously. Anesthesia was induced by fentanyl (5 μg/kg); 3 min later, propofol (Diprivan, ASTRA-Zeneca, Cheshire, UK) was infused via infusion pump at the rate of 1 mg/ kg/min. The end point of hypnosis was when the Narcotrend value reached to D0 and patients were ventilated with 50% oxygen during face mask ventilation. One minute later after end point of hypnosis, vecuronium bromide dose of 0.1 mg/kg was administered. The trachea was intubated 2 min after the administration of vecuronium. The cuff of endotracheal tube was covered by 1–2 g compound lidocaine cream. The lungs were mechanically ventilated in a volume-control mode with settings aimed at achieving an end-tidal carbon dioxide concentration of 35 mmHg.
Maintenance Muscle relaxation. For muscle relaxation monitoring during anesthetic maintenance, the first twitch response in relation to the baseline values (T1/Tc) as well as the fourth twitch in relation to the first one of each train (T1/T4) were monitored. When recovery from the initial bolus dose was evident by a single twitch depression (T1/Tc) of more than 0.1, continuous infusion of vecuronium was started. Target neuromuscular relaxation was defined as maintaining T1/Tc of 0.1 during the operation. The infusion rate was started as 1 μg/kg/min and manually adjusted every 15 min. The rate was increased by 10% if T1/Tc was more than 0.1, and decreased by 10% if T1/Tc was 0.
Anesthesia Anesthesia was administered with a continuous infusion of propofol started at 10 mg/kg/h. During the maintenance phase, propofol infusion was adjusted to maintain the Narcotrend to a target value of D0. If the Narcotrend value was outside this
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range for longer than 10 s, the concentration of propofol was increased or decreased by 0.5 mg/ kg/h steps to bring the Narcotrend value to D0. A lower limit threshold of 5 mg/kg/h for the propofol effect-site level was defined to prevent the risk of awareness.
Analgesia Immediately after induction, an infusion of remifentanil 0.3 μg/kg/min was started. This was maintained unchanged throughout surgery, except in the presence of tachycardia, hypertension or any other indirect sign of inadequate analgesia, when the doses were changed in 0.05 μg/kg/min steps within the limits of 0.1 and 0.5 μg/kg/min. Hypotension, defined as a systolic blood pressure below 85 mmHg for more than 5 min, was treated by increasing the rate of crystalloid fluid infusion and administration of phenylephrine 40 μg boluses intravenously. If hypotension persisted, then the remifentanil infusion was reduced in steps of 0.05 μg/kg/min. Bradycardia, defined as a heart rate below 40 beats/min, was treated with atropine 0.01 mg/kg combined with a reduction in the rate of the remifentanil infusion.
Recovery Thirty minutes before the end of surgery (when the surgeon begins to close the abdominal wall), vecuronium infusion was stopped. After skin incision was closed and the TOF ratio was more than 25%, 0.2 mg/kg pyridostigmine and 0.05 mg glycopyrrolate per 1 mg pyridostigmine were administered. Then propofol and remifentanil were discontinued. The time from discontinuation of anesthesia to spontaneous opening of eyes were recorded. When consciousness was restored and TOF ratio was more than 90%, extubation was done. Post-operative pain management (analgesia) was executed by a special post-operative analgesia group of Tongji hospital.
Quality control Researchers were trained before conducting the study; a unified nutritional assessment questionnaire was adopted for screening and assessment by one researcher; the height and weight of patients with ward clothes on were measured without shoes at fasting; and the surgeons involved in this study were equally distributed among three groups. The anesthetists were blinded to nutrition status assessment.
Malnutrition affects the outcome of general anesthesia Table 2 Anesthesia requirement. Anaesthesia time (min) Surgical time (min) Propofol induction dose (mg/kg) Propofol maintenance dose (mg/kg/h) Propofol recover time (min)
Group I (n = 30)
Group II (n = 44)
Group III (n = 23)
307 (24) 253 (21) 1.84 (0.14) 8.63 (0.70) 8.3 (1.1)
320 (32) 272 (28) 1.76 (0.09)* 7.04 (0.59)* 8.4 (2.4)
299 (21) 250 (25) 1.53 (0.16)* 6.16 (0.76)* 15.1 (3.4)*
Compared with group I, *P < 0.01. Values are presented as mean (SD). SD, standard deviation.
Statistical analysis SPSS statistical software version 19.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Based on our preliminary clinical experience, a sample size of 21 patients in each group was deemed to be sufficient to characterize the outcome variables. Measurement data were expressed as mean ± standard deviation (SD). Enumeration data were expressed as percentage. The differences of enumeration data, such as sex, were compared by χ2 test, while the differences of numerical data were analyzed by one-way analysis of variance followed by pairwise comparisons using least squares difference test. P < 0.05 was considered statistically significant.
Results Groups’ equivalence Out of a total of 101 patients assessed for eligibility, 97 were screened and subsequently enrolled to the study. One was excluded because of severe hypotension during surgery and three for poor Narcotrend signal. Based on NRS-2002, body nutrition reserves, BMI, body weight and nutritional status evaluation, 30 patients were assigned to group I, 44 to group II and 23 to group III. The groups were similar with respect to other characteristics (e.g. type and length of surgical incision). Table 1 shows the characteristics of the patient groups.
Propofol requirement Propofol dosage and recovery time are presented in Table 2. Statistical analyses revealed a significant effect of nutrition status on propofol induction dose (F = 48.17, P < 0.01), propofol maintenance (F = 95.01, P < 0.01) and propofol recover time (F = 69.84, P < 0.01). The propofol dosage for induction in group I was 1.84 ± 0.14 (SD) mg/kg, while in group II was 1.76 ± 0.09 (SD) mg/kg and in group
III was 1.53 ± 0.16 (SD) mg/kg. When compared with group I, the propofol dosage for induction was significantly decreased in group II (P < 0.01) and group III (P < 0.01). The average maintenance dose of propofol was also significantly lower in malnourished individuals; for group II, the decrease was about 20% (P < 0.01) and for group III, 30% (P < 0.01) in comparison to group I. For the recovery time from propofol, there were no significant differences between group I and II (P = 0.885). However, the patients with severe nutritional status (group III) awoke much latter than those normally nourished (group I) (P < 0.01).
Discussion The aim of this preliminary study was to compare propofol dosage and recovery time between different nutritional status patients who had undergone selective abdominal surgery. Based on NRS-2002, we found that the dosage of propofol decreased in those patients with moderate malnutrition status when compared with better nutritional individuals both during induction and maintenance, but the recovery time did not change in these patients, whereas in patients with severe malnutritional status, the dosage decreased more significantly. In addition awakening from propofol anesthesia was significantly delayed in severely malnourished patients. Most importantly, our results showed that malnutrition is somehow correlated with the outcome of general anesthesia. Although the exact mechanism as to why the dosage and recovery time from propofol changed in malnourished individuals is not investigated in this study, we speculate that this presumably occurred through two pathways. Firstly, the pharmacokinetics and metabolism parameter of propofol may be altered in malnourished individuals. Although there is no such kind of data available for propofol, malnutrition and its effect on drug
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pharmacokinetics and metabolism has been well documented. For example, the evidence that protein binding and clearance is significantly reduced in several drugs has been reported in malnourished people.26–30 Furthermore, it has been demonstrated that malnutrition results in reduction of body fat which could alter the distribution of highly lipidsoluble drugs.31 The consequence of the elevation of unbounded drug concentration in plasma could delay clearance and change the distribution which is likely to result in lowering the dosage required in some drugs. Furthermore, malnutrition could lead to decrease in cytochrome P450 enzyme activity,32,33 impairing drug biotransformation and conjugation reactions.34–36 Thus, drug metabolism also changes a lot in malnourished individuals compared with normal people. Malnutrition may also have an effect on propofol’s protein binding, clearance, distribution, biotransformation and conjugation which then contribute to lowering the dosage needed and delays the recovery time from propofol. Secondly, malnutrition may cause the sensitivity to propofol to change in the central nervous system (CNS). Moreover, although propofol is primarily a hypnotic, the exact mechanism of its action has not yet been fully elucidated. It has been proposed to have several mechanisms of action, most probably through the potentiation of GABAA receptor activity,37,38 which thereby slow the channel-closing time. Recent research has also suggested that the endocannabinoid system,39 N-Methyl-D-aspartate (NMDA) subtype receptor40,41 and sodium channel42,43 may contribute significantly to propofol’s anesthetic action. However, only sporadic reports focus on the effect of malnutrition on mature CNS. Research using animal models showed that prolonged malnutrition in adult rats produces marked loss of hippocampal neurons and synapses accompanied by substantial impairments of hippocampaldependent behaviors.44,45 Furthermore, malnutrition has been reported to exert negative influence on structural and functional state of brain neurons.46 Because we did not find any direct evidence that malnutrition can affect the expression or/and sensitivity of those propofol related receptors, further studies are required that focus on this area, in order to examine in more detail the mechanism involved. In conclusion, the present results indicate that firstly, the dosage and recovery time from propofol does change in malnutrition individuals. Secondly, that malnutrition may somehow affect the outcome of general anesthesia. Therefore, for pre-anesthesia
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evaluation, the nutritional factor should also be considered and more related research conducted.
Acknowledgements This work was supported by Natural Science Foundation of China (30901395 to X. Tian) and the Doctoral Fund of Ministry of Education of China (20090142120012 to X. Tian, 20110142120021 to Y. Xiang). Conflicts of interest: Authors declare no conflicts of interest.
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Address: Feng Gao Department of Anesthesiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Jiefang Road 1095# Wuhan, Hubei 430030 China e-mail: [email protected]
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