The effect of different doses of neostigmine plus metoclopramide on the gastric residual volume in patients under enteral nutrition in intensive care unit

Mohammadrea Moshari1, Zahra Tahmasebi2, Mastaneh Dahi3, Maryam Vosoughian4, Shideh Dabir5, Firoozeh Madadi6, Soudeh Tabashi7, Mohsen Ariannik8, Mohammad Ali Khabiri Khatiri9
Author affiliations:
  1. Mohammadrea Moshari, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: rmoshari@yahoo.com
  2. Zahra Tahmasebi, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: drzahra.tah@gmail.com
  3. Mastaneh Dahi, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: ma_dahi@yahoo.com
  4. Maryam Vosoughian, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: maryam.vosoghian@yahoo.com
  5. Shideh Dabir, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: shdabir@yahoo.com
  6. Firoozeh Madadi, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: fmadadi33@gmail.com
  7. soudeh tabashi, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: soodeh.tabashi@yahoo.com
  8. mohsen Ariannik, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: mnamnak@yahoo.com
  9. Mohammad Ali Khabiri Khatiri, Department of Anesthesiology, Shahid Beheshti University of Medical Sciences. Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, Iran; E-mail: firoozehmendeley@gmail.com
Correspondence: Mohammad Ali Khabiri Khatiri; E-mail: firoozehmendeley@gmail.com; Phone: +98 9203613840

 

ABSTRACT

 

Background & Objective: Gastric motility disorder is common in patients admitted to an intensive care unit (ICU), leading to increased morbidity and mortality. We investigated the effects of different doses of neostigmine in combination with metoclopramide on gastric residual volume (GRV) in ICU patients on enteral feeding.

Methods: In this double-blind clinical trial, 144 patients hospitalized in the ICU who were under enteral nutrition through nasogastric (NGT) or orogastric (OG) tube were randomly allocated to four groups. In all four groups, 20 mg of metoclopramide was prescribed IV slowly within one minute. In groups A, B, and C, 1, 1.5, and 2 mg of neostigmine were injected IV, respectively. Group D received only 20 mg of metoclopramide. All patients were gavaged every 4 h with 300 ml. The patient's head was kept at a 45° angle. To determine GRV, aspiration was done through NG tube or OG tube before the start of infusion and then at 3, 6, 9, and 12 h after the end of infusion.

Results: There was no significant difference between the studied groups in terms of demographic variables such as age, blood pressure, heart rate and BMI (P > 0.05). The average difference of SOFA and APACHE and laboratory factors between the groups was not significant. The results of the comparison of the marginal averages of the residual volume of the stomach at different hours of the day showed that the amount of the residual volume at all hours had a significant average difference with each other. The addition of different doses of neostigmine had a significant effect on the residual volume of the stomach after 3 and 6 h (P < 0.05). Meanwhile, a dose of 2.0 mg of neostigmine had the most of the change 3 h after administration.

Conclusion: Administration of neostigmine in combination with metoclopramide in ICU patients on enteral feeding significantly reduces the residual volume of the stomach within 12 hours after the treatment.

Abbreviations: APACHE- Acute Physiology And Chronic Health Evaluation; GRV - Gastric Residual Volume; NG – Nasogastric; OG - Orogastric; SOFA- Sequential Organ Failure Assessment; VAP - ventilator-associated pneumonia

Key words: APACHE; Enteral Nutrition; ICU; Metoclopramide; Neostigmine; SOFA

Citation: Moshari M, Tahmasebi Z, Dahi M, Vosoughian M, Dabir S, Madadi F, Tabashi S, Ariannik M, Khatiri MAK. The effect of different doses of neostigmine plus metoclopramide on the gastric residual volume in patients under enteral nutrition in intensive care unit. Anaesth. pain intensive care 2024;28(1):33-38.

DOI: 10.35975/apic.v28i1.2378
Received: August 06, 2023; Reviewed: September 11, 2023; Accepted: September 21, 2023

 

1. INTRODUCTION

 

One of the major problems in intensive care unit (ICU) patients under mechanical ventilation is delayed gastric emptying.1-3 Evidence shows that more than 50% of patients in the ICU have gastric motility disorder, which leads to slow gastric emptying and high gastric residual volume (GRV) which is associated with increased mortality in these patients.4-7 Delayed gastric emptying can lead to several problems, including insufficient caloric intake. In addition, nausea, regurgitation, and aspiration can increase the risk of ventilator-associated pneumonia (VAP) and thus increase the length of hospital stay.8-12 Therefore, monitoring of GRV is recommended to reduce the incidence of these complications.

Until now, there have been surgical methods and pharmacological methods to facilitate gastric emptying and reduce GRV in patients, but each of them has its limitations.13,14 A variety of drugs have been used, including metoclopramide, erythromycin, and cisapride; however, there is no conclusive evidence for any of these to have superior effects over one another.15 One of the recently used drugs in this field is neostigmine.18 Studies have reported mixed results regarding the effectiveness of neostigmine on enteral feeding tolerance, especially in patients admitted to the ICU.16,17 While the effect of neostigmine on postoperative ileus has been evaluated in several studies, very few studies have evaluated the effect of neostigmine on GRV in ICU patients.19-21 In addition, complications such as dysrhythmias and extrapyramidal side effects limit the use of these drugs.22-24 Considering the above information and the high potential risk of GRV in mortality in ICU patients and few studies to compare the effect of neostigmine and metoclopramide on gastrointestinal feeding tolerance in critically ill patients, this study was conducted with the aim of comparing the effects of neostigmine and metoclopramide on gastric residual volume of patient under enteral nutrition in ICU.

 

2. METHODOLOGY

 

The present study was a double-blind clinical trial which was performed with the approval of the Ethics Committee in Biomedical Research, on patients admitted to ICU of Aiatolla Taleghani Hospital, who were candidate of enteral nutrition through nasogastric (NG) tube or orogastric (OG) tube.

Inclusion criteria included patients aged 20 to 60 y, feeding through a NG or OG tube, gastric residual volume > 120 ml, absence of previous underlying diseases, such as diabetes, arrhythmia and heart block, renal failure, asthma etc., HR > 60 beats/min and SBP > 90 mmHg, absence of known allergy to neostigmine and metoclopramide.

Exclusion criteria was new-onset arrhythmias and heart blocks, SBP < 60 mmHg during study, hypothermia, renal failure (serum creatinine greater than 1.5 in two consecutive tests), use of prokinetic drugs within 8 h before intervention, gastric or digestive system surgery within the past 10 days, clinical evidence of obstruction of the digestive system, pregnancy and breastfeeding, occurrence of extrapyramidal complications, active bronchospasm requiring medication, hypokalemia (potassium level less than 3 meq/L) and active gastrointestinal bleeding.

The clinical caregiver and the patient were kept blind to the drug grouping. After the patients signed the written consent form, 144 eligible patients were randomly divided into 4 groups via sealed envelopes (Figure 1). In all 4 groups, 20 mg of metoclopramide was prescribed IV slowly within one minute. In groups A, B, and C, 1 mg, 1.5 mg, and 2 mg of neostigmine were administered intravenously, respectively. Group D received placebo instead. Thereafter all patients were fed with the same formula every 3 h in the amount of 300 ml via NG or OG tube, while the patients were head-up at a 45-degree angle. To determine GRV, aspiration was done through NG or OG tube before the next entral feeding. During the study, clinical and para-clinical NG   parameters of the patients were recorded in a pre-designed questionnaire and analyzed using SPSS 25 software.

 



 

3. RESULTS

 

In this double-blind clinical trial, the average age of the patients was 59 ± 19.8 y (range 21-96 y). No significant difference was observed between demographic indicators and prognostic indicators of patients admitted to the ICU (Table 1).

The results of Table 2 show that there is no significant difference between the laboratory indicators in the four studied groups.

 

Table 1: Comparative study of demographic indicators and prognostic indicators of the patients
Index Group A Group B Group C Group D P-value
Age 59.5 ± 20.8 58.2 ± 21.4 57.8 ± 17.00 60.7 ± 20.3 0.903
BMI 25.3 ± 4.87 24.6 ± 4.22 24.5 ± 3.87 24.7 ± 3.9 0.920
BP 77.1 ± 14.2 81.9 ± 14.8 82.00 ± 14.5 79.5 ± 12 0.330
HR 90.70 ± 15.00 82.20 ± 18.90 83.90 ± 17.30 87.00 ± 15.00 0.111
SOFA score 4.31 ± 3.6 4.78 ± 3.4 4.92 ± 3.24 4.68 ± 3.58 0.613
APACHE score 15.600 ± 5.75 15.6 ± 4.77 16.7 ± 5.47 15.3 ± 5.00 0.681
Data presented as mean ± SD; P < 0.05 considered as significant
 

The results of Table 3 show the results of the four drug groups on the residual stomach volume, which has a significance level of 0.0001. As a result, it can be stated that the present model has a significant mean difference.

The results of Lon's test show (Table 4) that the residual volume of the stomach immediately after drug injection and after 6 h had a significance level of less than 0.05. As a result, the assumption of equal variance of the groups in these two dependent variables is not confirmed. While the significance level of other times is higher than 0.05, which confirms the assumption of equal variance of the groups in the other three dependent times.

The results of the marginal averages of the effect of drugs on the residual volume of the stomach show that metoclopramide drug alone did not cause an average difference in the residual volume of the stomach at different hours because the averages are almost the same. But with the addition of different doses of neostigmine had a significant effect on the residual volume of the stomach. The average volume of the residual volume immediately after the injection with metoclopramide and neostigmine (1 mg) became 62.286 and 3 h after the injection it was 42.571. But 6 h after injection, the average residual volume of the stomach increased by 55.714 units, and after 9 and 12 h, the residual volume of the stomach also increased (Figure 2).

 

4. DISCUSSION

 

The purpose of this study was to investigate the effect of different doses of neostigmine in combination with metoclopramide on the gastric residual volume of ICU patients under enteral nutrition. Based on the results obtained from this study, there was no significant difference between the studied groups in terms of demographic variables such as age, blood pressure, heart rate, and BMI. Also, the average difference of SOFA and APACHE scores and laboratory factors between groups was not significant.

 



 

Previously, Rahat-Dahmardeh et al. investigated the effect of neostigmine and metoclopramide on the residual volume of the stomach of mechanically ventilated patients in the ICU. These researchers showed that the effect of treatment with neostigmine by adjusting the effect of age, sex, and SOFA increases the chance of improving GRV compared to the metoclopramide group.25
In the present study, the comparison of the marginal averages of the residual volume of the stomach in different hours of the day in each group separately shows that the amount of the residual volume of the stomach in all hours has a significant average difference with each other. This is expected due to the prokinetic properties of metoclopramide and neostigmine.

On the other hand, the comparison of the averages of the residual volume of the stomach as a two-by-two comparison of the groups without considering the time factor showed that there is no significant difference between the effects of drugs on the amount of the residual volume of the stomach. In other words, the average residual stomach volume of all 4 groups in 12 h was not significantly different from each other,and a decrease in the average residual volume was observed in all groups within 12 h.

 

Table 2: Comparative laboratory results in different groups
Index Group A Group B Group C Group D P value
Hb 10.1 ± 2.53 10.5 ± 2.48 10.4 ± 2.38 10.9 ± 2.44 0.527
Mg 1.89 ± 0.37 1.90 ± 0.30 1.88 ± 0.37 1.98 ± 0.22 0.351
k 4.00 ± 62.00 4.2 ± 0.72 4.2 ± 0.57 4.08 ± 0.63 0.289
Na 136.1 ± 3.17 137.5 ± 3.15 136.5 ± 3.9 137.7 ± 2.87 0.085
Data presented as mean ± SD; P < 0.05 considered as significant
 

Table 3: Multivariate tests and investigation of four drug groups on the remaining stomach volume
Indexes Value f Hypothesis df P.value
The rest of the stomach volume Pillai's Trace 0.738 95.721 136 <.00001
Wilks' Lambda 0.262 95.721 136 <.00001
Hoteling's Trace 2.185 95.721 136 <.00001
Roy's Largest Root 2.185 95.721 136 <.00001
The rest of the volume of the stomach and the group Pillai's Trace 0.567 8.033 414 <.00001
Wilks' Lambda 0.473 9.828 360.14 <.00001
Hoteling's Trace 1.034 11.605 404 <.00001
Roy's Largest Root 0.95 32.775 138 <.00001
P < 0.05 considered as significant
 

Table 4: Examination of the remaining volume in the stomach at different time periods
Times Levene Df1 Df2 P value
Immediately after injection 3.132 3 139 0.028
After 3 h 3.172 3 139 0.036
After 6 h 1.847 3 139 0.142
After 9 h 1.168 3 139 0.324
After 12 h 0.934 3 139 0.426
 

But the results of the marginal averages of the residual volume of the stomach at different hours of the day show that the amount of the residual volume of the stomach at all hours has a significant average difference from each other. The high difference is related to the residual volume of the stomach immediately after injection and 3 h after injection, and the lowest difference related to the residual volume of the stomach immediately after injection and 12 h after injection is 3.645.

The results of the marginal averages of the effect of drugs on the residual volume of the stomach show that metoclopramide drug alone did not cause an average difference in the residual volume of the stomach at different hours because the averages are almost the same. However, the addition of different doses of neostigmine had a significant effect on the amount of residual volume of the stomach, and a significant decrease, especially in the 3rd and 6th hours after the injection. This reduction has been more considerable and evident in 1.5 and 2 doses of neostigmine. It should be noted that during this study, the patients were under strict monitoring and fortunately, none of the patients showed significant drug side effects and were not excluded from the study. Previous studies have shown that although neostigmine treatment significantly improved GRV in more patients within 12 h of treatment, all patients in both groups had a complete recovery. Considering that there was no significant difference between the two groups in terms of complications, it seems that both drugs are effective in improving the GRV of ICU patients. Gholipour et al aimed to compare the effect of neostigmine and metoclopramide and showed that neostigmine is effective in reducing GRV and improving gastric emptying in ICU patients under mechanical ventilation without significant complications compared to metoclopramide and this protocol can be effective in tolerating enteral feeding in ICU patients.25-27
 

5. CONCLUSION

 

In general, within 12 hours after the treatment with three different doses of neostigmine, the residual volume of the stomach of all patients in all 3 intervention groups significantly decreased compared with the control group. It was noted that higher dose of neostigmine had the most significant effect.

7. Data availability
The numerical data generated during this research is available with the authors.

8. Ethical considerations
Formal approval of the Ethics Committee in Biomedical Research of Aiatolla Taleghani Hospital was obtained.  Written consent of every patient or their next of kin was obtained. The study was conducted according to the World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects.

Acknowledgement
We gratefully thank all patients for their full cooperation in the conduct of this study, without which it could never be completed.

9. Conflict of interest
The study utilized the hospital resources only, and no external or industry funding was involved.

10. Authors’ contribution
All the authors met the standard criteria of authorship based on recommendations of the international committee of medical journals editors.

MM: concept, study design

MD, MV: manuscript writing

SD, ST: revising and editing of the manuscript

FM: statistical analysis

MA, ZT: data collection

MK, ZT: conduction of study

 

11. REFERENCES

 
  1. Mueller C, Compher C, Ellen DM; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: Nutrition screening, assessment, and intervention in adults. JPEN J Parenter Enteral Nutr. 2011 Jan;35(1):16-24. [PubMed] DOI: 1177/0148607110389335
  2. Rahimi Bashar F, Khoshraftar E, Tahmasebi R, Hajiesmaeili MR, Seifi S, Sedaghat A, et al. Comparing the effects of acupuncture and pharmacologic therapies on delayed gastric emptying: a prospective, block-randomized, single-blinded, parallel clinical trial. Iran Red Crescent Med J. 2017;19(2):e32772. DOI: 5812/ircmj.32772
  3. Grant K, Thomas R. Prokinetic drugs in the intensive care unit: reviewing the evidence. J Intensive Care Soc. 2009;10(1):34–37. DOI: 1177/1751143709010001
  4. Ashouri E, Fatehi N. A comparison of performing tube feeding with the standard procedures at selected educational and treatment centers of Isfahan University of Medical Sciences, Iran. Iran J Nurs Midwifery Res. 2012;17(2 Suppl 1):S80–S84. [PubMed] [FreeFullText]
  5. Nguyen NQ, Ng MP, Chapman M, Fraser RJ, Holloway RH. The impact of admission diagnosis on gastric emptying in critically ill patients. Crit Care. 2007;11(1):R16. [PubMed] DOI: 1186/cc5685
  6. Doherty WL, Winter B. Prokinetic agents in critical care. Crit Care. 2003 Jun;7(3):206-8. [PubMed] DOI: 1186/cc1849
  7. Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest. 2001 Apr;119(4):1222-41. [PubMed] DOI: 1378/chest.119.4.1222
  8. Hsu CW, Sun SF, Lee DL, Lin SL, Wong KF, Huang HH, et al. Impact of disease severity on gastric residual volume in critical patients. World J Gastroenterol. 2011 Apr 21;17(15):2007-12. [PubMed] DOI: 3748/wjg.v17.i15.2007
  9. Ukleja A. Altered GI motility in critically Ill patients: current understanding of pathophysiology, clinical impact, and diagnostic approach. Nutr Clin Pract. 2010 Feb;25(1):16-25. [PubMed] DOI: 1177/0884533609357568
  10. Metheny NA, Schallom L, Oliver DA, Clouse RE. Gastric residual volume and aspiration in critically ill patients receiving gastric feedings. Am J Crit Care. 2008 Nov;17(6):512-9. [PubMed]
  11. Parish M, Panahi JR, Afhami MR, Pour AM. Role for the second anesthesiologist in failed intubations. Anesth Analg. 2006 Mar;102(3):971. [PubMed] DOI: 1213/01.ANE.0000190879.76048.2D
  12. Hawkyard CV, Koerner RJ. The use of erythromycin as a gastrointestinal prokinetic agent in adult critical care: benefits versus risks. J Antimicrob Chemother. 2007 Mar;59(3):347-58. [PubMed] DOI: 1093/jac/dkl537
  13. Emirleroglu M, Ekci B, Durgun V. The effect of neostigmine on postoperative ileus and the healing of colon anastomoses. Bratisl Lek Listy. 2011;112(6):309-13. [PubMed]
  14. Caliskan E, Turkoz A, Sener M, Bozdogan N, Gulcan O, Turkoz R. A prospective randomized double-blind study to determine the effect of thoracic epidural neostigmine on postoperative ileus after abdominal aortic surgery. Anesth Analg. 2008 Mar;106(3):959-64. [PubMed] DOI: 1213/ane.0b013e318163fbfe
  15. Gholipour Baradari A, Alipour A, Firouzian A, Moarab L, Emami Zeydi A. A Double-Blind Randomized Clinical Trial Comparing the Effect of Neostigmine and Metoclopramide on Gastric Residual Volume of Mechanically Ventilated ICU Patients. Acta Inform Med. 2016 Dec;24(6):385-389. [PubMed] DOI: 5455/aim.2016.24.385-389
  16. Imai K, Kitakoji H, Chihara E, Sakita M. Effects of atropine sulfate and neostigmine on gastric electrical activity in human subjects--electrogastrographic study. Hepatogastroenterology. 2008 Jan-Feb;55(81):294-7. [PubMed]
  17. Zeinali F, Stulberg JJ, Delaney CP. Pharmacological management of postoperative ileus. Can J Surg. 2009 Apr;52(2):153-7. [PubMed]
  18. Nguyen NQ, Chapman M, Fraser RJ, Bryant LK, Burgstad C, Holloway RH. Prokinetic therapy for feed intolerance in critical illness: one drug or two? Crit Care Med. 2007 Nov;35(11):2561-7. [PubMed] DOI: 1097/01.CCM.0000286397.04815.B1
  19. Deane AM, Fraser RJ, Chapman MJ. Prokinetic drugs for feed intolerance in critical illness: current and potential therapies. Crit Care Resusc. 2009 Jun;11(2):132-43. [PubMed]
  20. Grant K, Thomas R. Prokinetic drugs in the intensive care unit: reviewing the evidence. J Intensive Care Soc. 2009;10:34–7. [FreeFullText]
  21. Lucey MA, Patil V, Girling K, Jacques T, O'Leary M. Does neostigmine increase gastric emptying in the critically ill?--results of a pilot study. Crit Care Resusc. 2003 Mar;5(1):14-9. [PubMed]
  22. Aghadavoudi O, Abbasi S, Kashefi P, Golparvar M, Habibzade M, Kazemi S. Evaluation of intravenous neostigmine infusion on tolerance of enteral nutrition in Intensive Care Unit patients. J Res Med Sci. 2013 Sep;18(9):750-4. [PubMed]
  23. Lucey MA, Patil V, Girling K, Jacques T, O'Leary M. Does neostigmine increase gastric emptying in the critically ill?--results of a pilot study. Crit Care Resusc. 2003 Mar;5(1):14-9. [PubMed]
  24. Baradari AG, Khajavi MR, Firouzian A, Alipour A, Daneshpour H, Panahi Y, et al. Effects of combined prokinetic administration on gastric emptying in critically ill patients. Arab J Gastroenterol. 2017 Mar;18(1):30-34. [PubMed] DOI: 1016/j.ajg.2017.01.007
  25. Baradari AG, Alipour A, Firouzian A, Moarab L, Emami Zeydi A. A double-blind randomized clinical trial comparing the effect of neostigmine and metoclopramide on gastric residual volume of mechanically ventilated icu patients. Acta Inform Med. 2016 Dec;24(6):385-389. [PubMed] DOI: 5455/aim.2016.24.385-389
  26. Parthasarathy G, Ravi K, Camilleri M, Andrews C, Szarka LA, Low PA, et al. Effect of neostigmine on gastroduodenal motility in patients with suspected gastrointestinal motility disorders. Neurogastroenterol Motil. 2015 Dec;27(12):1736-46. [PubMed] DOI: 1111/nmo.12669
  27. Rahat-Dahmardeh A, Saneie-Moghadam S, Khosh-Fetrat M. Comparing the Effect of Neostigmine and Metoclopramide on Gastric Residual Volume of Mechanically Ventilated Patients in Intensive Care Unit: A Double-Blind Randomized Clinical Trial. Biomed Res Int. 2021 Aug 16;2021:5550653. [PubMed] DOI: 10.1155/2021/5550653