What is the evidence for using for subcutaneous neostigmine acute colonic pseudo-obstruction? Does it require ICU level of monitoring?

Comment by InpharmD Researcher

Available evidence indicates that subcutaneous neostigmine is a reasonable alternative to intravenous dosing for acute colonic pseudo-obstruction (ACPO), demonstrating effective decompression with low rates of bradycardia and other cholinergic adverse effects. Although guidelines do not provide route-specific recommendations or require ICU-level monitoring for subcutaneous administration, they consistently emphasize that neostigmine therapy, in general, should occur in a setting equipped for continuous cardiac and respiratory monitoring with immediate access to agents such as glycopyrrolate or atropine.

Background

The 2020 guideline from the American Society for Gastrointestinal Endoscopy and the 2021 guideline from the American Society of Colon and Rectal surgeons provide a comprehensive review on management of acute colonic pseudo-obstruction (ACPO) and colonic volvulus. Traditionally administered intravenously in bolus doses for ACPO, neostigmine has also demonstrated success through alternative administration routes. A 2018 multicenter, retrospective, observational study involving 182 patients with ileus, ACPO, or refractory constipation showed that subcutaneous administration of neostigmine led to stool passage within a median time of 29 hours (Table 1). Therefore the panel suggests that for patients with ACPO who do not respond to bolus dosing of neostigmine, it is suggested to consider alternative methods of administering neostigmine. These alternatives include subcutaneous administration or continuous intravenous infusion. Although the panel does not provide route-specific recommendations for subcutaneous administration and does not call for ICU-level monitoring, both guidelines emphasize that neostigmine should be given in a setting equipped for cardiopulmonary monitoring and rapid intervention. Continuous cardiac-rhythm and respiratory monitoring are required, and glycopyrrolate or atropine must be readily available to manage bronchospasm or bradycardia should they occur. [1], [2]

A 2024 review article explored the intravenous and subcutaneous administration of neostigmine for ACPO, also known as Ogilvie’s Syndrome, emphasizing safety and efficacy in patients. A particularly noteworthy feature of the condition is the acute dilation of the colon without anatomical obstruction, primarily affecting elderly males who have undergone surgical procedures. Neostigmine, an acetylcholinesterase inhibitor, has become an essential pharmacological intervention when conservative treatments fail. Historically, intravenous neostigmine has been the preferred method due to its rapid action and pronounced efficacy, though it necessitates intensive cardiac monitoring due to potential adverse events such as bradycardia (5-12% across studies). The review highlighted emerging clinical acceptance of subcutaneous neostigmine, which offers a more gradual absorption, reducing the intensity of cardiovascular complications and requiring less monitoring. Comparative analysis across multiple studies on intravenous and subcutaneous neostigmine administration revealed distinct differences in response times and adverse events. For instance, findings from a 2018 multicenter, retrospective study showed subcutaneous neostigmine having a median time to first bowel movement of 29.19 hours, compared with minutes to hours for intravenous dosing, albeit with a minimal incidence of bradycardia. In contrast, a 1999 prospective, double-blind trial demonstrated a median response time of four minutes for intravenous neostigmine, however, this was accompanied by a higher rate of bradycardia. Despite the absence of direct randomized controlled trials comparing the two routes, current evidence supports that both forms have legitimate clinical applications based on patient-specific factors, urgency, and facility capabilities. However, the article underscores the necessity for prospective studies to further define optimal administration protocols and dosage guidelines, especially for subcutaneous use in this vulnerable patient population. [3]

References:

[1] Naveed M, Jamil LH, Fujii-Lau LL, et al. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in the management of acute colonic pseudo-obstruction and colonic volvulus. Gastrointest Endosc. 2020;91(2):228-235. doi:10.1016/j.gie.2019.09.007
[2] Alavi K, Poylin V, Davids JS, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colonic Volvulus and Acute Colonic Pseudo-Obstruction. Dis Colon Rectum. 2021;64(9):1046-1057. doi:10.1097/DCR.0000000000002159
[3] Y Lu L. Intravenous and Subcutaneous Administration of Neostigmine for Acute Colonic Pseudo Obstruction A Short Review. Journal on Surgery. 2024;4(2). doi:https://doi.org/10.52768/2691-7785/1172

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the evidence for using for subcutaneous neostigmine acute colonic pseudo-obstruction? Does it require ICU level of monitoring?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Efficacy and Safety of Subcutaneous Neostigmine for Ileus, Acute Colonic Pseudo-obstruction, or Refractory Constipation
Design

Multicenter, retrospective observational study

N= 182

Objective To evaluate whether an alternative route of administration for neostigmine via subcutaneous (SQ) delivery is safe and effective in a broad cohort of medical and surgical patients
Study Groups

Surgical (n= 155)

Medical (n= 27)

Inclusion Criteria Patients 18 years or older who received at least 1 dose of SQ neostigmine between June 1, 2014, and June 1, 2016, for ileus, acute colonic pseudo-obstruction (ACPO), or refractory constipation
Exclusion Criteria Incomplete documentation or SQ neostigmine administered for an indication other than ileus, ACPO, or refractory constipation
Methods Patients received SQ neostigmine with the most common dose being 0.25 mg SQ 4 times daily. Efficacy was measured by time to first bowel movement (BM), total dose administered before BM, and need for rescue intervention. Safety was assessed by monitoring for cardiac arrest, bradycardia, bronchospasm, nausea, or severe salivation, lacrimation, or diarrhea. 
Duration June 1, 2014, to June 1, 2016
Outcome Measures Time to BM following initiation of SQ neostigmine, number of doses administered before BM, total SQ neostigmine dose administered before BM
Baseline Characteristics   Cohort (n = 182) Surgical (n = 155) Medical (n = 27)
Age, years  61.02 ± 15.86 61.45 ± 15.13 58.55 ± 19.69
Gender, male 120 (65.93) 103 (66.45) 17 (62.96)
Height, cm  172.66 ± 10 172.78 ± 9.93 171.95 ± 10.54
Weight, kg  88.59 ± 21.86 88.67 ± 20.45 88.1 ± 29.14
Telemetry 86 (47.25%) 64 (41.29%) 22 (81.48%)
Abdominal imaging 108 (59.34%) 83 (52.23%) 25 (92.6%)

Diagnosis

Postoperative ileus

ACPO

Refractory constipation

Ileus (noncharacterized)

 

139 (76.37%)

20 (10.99%)

10 (5.49%)

13 (7.14%)

 

139 (89.68%)

11 (7.1%)

5 (3.23%)

0

 

0

9 (33.33%)

5 (18.52%)

13 (48.15%)

Results   Cohort (n = 182) Surgical (n = 155) Medical (n = 27)
Time to BM following initiation of SQ neostigmine, hours  29.19 (12.18-56.84) 26.97 (9.58-57) 33.97 (21.7-59.92)
Additional laxative or intestinal stimulant to produce BM 44 (24.18%) 38 (24.52%) 6 (22.22%)

Number of doses administered before BM  

1

5+

 

49 (26.92%)

85 (46.7%)

 

47 (30.32%)

68 (43.87%)

 

2 (7.4%)

17 (62.96%)

Total neostigmine dose administered before BM, mg 1.25 (0.5-2.25) 1 (0.5-2.5) 1.25 (1-2)
Adverse Events Bradycardia (1.09%), nausea (11.54%), severe diarrhea (0.55%)
Study Author Conclusions SQ neostigmine may be reasonable for management of ileus, ACPO, or refractory constipation, though use should be avoided in patients with new-onset heart block, a history of second-degree heart block, or following bowel resection with primary anastomosis. Monitoring for bradycardia with telemetry may be considered. 
Critique The study provides valuable insights into the use of SQ neostigmine as an alternative to IV administration, showing a lower incidence of adverse events. However, the retrospective design and lack of a comparator arm limit the ability to draw definitive conclusions. The study's reliance on provider documentation and the absence of standardized management protocols may affect the accuracy of the findings. Additionally, the study's generalizability to medical or oncological patients is limited due to the predominance of surgical patients in the cohort. 



References:

Kram B, Greenland M, Grant M, Campbell ME, Wells C, Sommer C. Efficacy and Safety of Subcutaneous Neostigmine for Ileus, Acute Colonic Pseudo-obstruction, or Refractory Constipation. Ann Pharmacother. 2018;52(6):505-512. doi:10.1177/1060028018754302

Neostigmine for Treating Acute Colonic Pseudo-Obstruction in Neurocritically Ill Patients

Design

Retrospective study

N= 31

Objective

To investigate the effectiveness and adverse events when using neostigmine to manage ACPO in neurocritically ill patients

Study Groups

All patients (n= 31)

Inclusion Criteria

Patients with ACPO treated using neostigmine in the NeuroICU at two centers between March 2017 and August 2020

Exclusion Criteria

Not specified

Methods

Neostigmine was administered intravenously (IV) or subcutaneously (SC) at doses ranging from 0.25 mg to 2 mg. Outcomes were bowel movements (BM) and changes in colon diameters on abdominal radiographs. Safety events such as bradycardia, vomiting, salivation, and sweating were evaluated.

Duration

March 2017 to August 2020

Outcome Measures

Primary: BM following neostigmine injection

Secondary: Changes in colon diameter, success of initiating enteral feeding, need for endoscopic or surgical decompression

Baseline Characteristics  

All patients (n= 31)

Age, years

46.8 ± 19.5

Male

20 (65.4%)

Diagnosis at admission

Stroke (ischemic and hemorrhagic)

Status epilepticus

Anti-NMDA-receptor encephalitis

Traumatic brain injury

Traumatic spinal cord injury

Cardiac arrest

Astrocytoma

 

11 (35.5%)

7 (22.6%)

4 (12.9%)

4 (12.9%)

3 (9.7%)

1 (3.2%)

1 (3.2%)

Route

IV

SC

IV and SC

 

28 (90.3%)

2 (6.5%)

1 (3.2%)

Results

 

All patients (n= 31)

Time to BM following initiation of neostigmine, minutes (IQR)

120 (60–210) 

Change in colon diameter, mm

-17.5 (-12.8 to -26.3)

BM following neostigmine injection

31 (100.0%)

Enteral feeding after neostigmine

28 (90.3%)

Abbreviations: IQR, interquartile range

Adverse Events

Hypersalivation, sweating, bradycardia, and vomiting occurred in 12.9% of patients. Bradycardia occurred in 3.2% and was managed with atropine.

Study Author Conclusions

Neostigmine injection is a safe and effective treatment option for ACPO in neurocritically ill patients who fail to respond to conservative management.

Critique

The study's retrospective design and small sample size limit the generalizability of the findings. The lack of a control group makes it difficult to compare the effect of neostigmine with other treatments. However, the study provides valuable insights into the use of neostigmine in a specific patient population.

 

References:

Kim TJ, Torres L, Paz A, et al. Neostigmine for Treating Acute Colonic Pseudo-Obstruction in Neurocritically Ill Patients. J Clin Neurol. 2021;17(4):563-569. doi:10.3988/jcn.2021.17.4.563

 

Subcutaneous neostigmine appears safe and effective for acute colonic pseudo-obstruction (Ogilvie’s syndrome)
Design

Retrospective case series

N= 30

Objective To assess the safety of subcutaneous neostigmine on ward inpatients with acute colonic pseudo-obstruction (ACPO) monitored with standard nursing care
Study Groups All patients (n= 30)
Inclusion Criteria Patients diagnosed with ACPO using clinical examination and radiology, treated with subcutaneous neostigmine between August 2008 and October 2012
Exclusion Criteria Contraindications to neostigmine such as known perforation, peptic ulcer disease, recent myocardial infarction, concurrent use of beta blockers, asthma, COAD, or renal failure
Methods Patients were treated with subcutaneous neostigmine on regular wards with standard nursing observations. The main outcomes were time to flatus and bowels working and complications. Data were collected prospectively. 
Duration August 2008 to October 2012
Outcome Measures Clinically successful resolution of ACPO, time to flatus and bowels working
Baseline Characteristics The cohort had a mean age of 74 years and included 19 men and 11 women. Most patients had significant comorbidities, commonly cardiac disease, psychiatric or cognitive impairment, chronic obstructive airways disease, and type 2 diabetes. Frequent admission diagnoses included urosepsis, fractured neck of femur, advanced malignancy, and COAD exacerbation, and four patients were nursing home residents. Electrolyte abnormalities were common, most notably hypokalemia (n = 10), and nearly all patients were taking medications that could contribute, especially opioids (n = 13), diuretics, and antipsychotics. Twelve patients were postoperative, primarily after orthopedic or neurosurgical procedures.
Results Duration of symptoms (days) Additional medical management Number of doses Duration of treatment (days) Time to flatus (days) Time to stool (days)
2 Docusate with senna, psyllium husk, erythromycin, sodium citrate enemas 7 4 1 1
Unknown Erythromycin 13 7 1 2
2 Erythromycin, metoclopramide 5 3 1 1
4 Erythromycin 5 3 0 0
2 Nasogastric tube, droperidol, sodium citrate enema 15 9 0 0
7 Macrogol, metoclopramide 15 17 0 2
2 Nasogastric tube, sodium citrate enema 13 14 0 0
2 Lactulose, macrogol, sodium citrate enemas 5 3 1 1
1 Nil 9 4 1 1
4 Nasogastric tube 6 3 0 0
Unknown Nil 2 2 1 1
3 Macrogol, domperidone 4 3 1 1
3 Colonoscopic decompression 6 3 1 N/A
3 Nil 4 2 1 1
5 Paraffin liquid, sodium citrate enemas 11 4 0 0
4 Nil 18 6 0 0
5 Docusate with senna, macrogol, metoclopramide 1 4 0 0
4 Macrogol 3 2 0 0
1 Nil 9 2 1 4
6 Nil 5 3 0 0
7 Lactulose 17 10 1 2
7 Macrogol 5 5 0 0
3 Nil 1 1 0 0
7 Macrogol 7 4 0 0
3 Docusate with senna, macrogol 6 2 0 0
4 Docusate with senna, macrogol, prune juice 4 3 0 0
Unknown Docusate, lactulose, macrogol, sodium phosphate enemas 9 5 2 3
4 Docusate with senna, macrogol, colonoscopic decompression 14 8 0 0
3 Docusate with senna, macrogol, sodium citrate enemas 2 1 0 0
4 Nil 2 1 0 0
Adverse Events No serious complications such as clinically evident bradycardia were encountered. Two patients (7%) developed caecal tenderness and proceeded to colonoscopic decompression, which was successful. 
Study Author Conclusions Subcutaneous neostigmine appears to be safe for the treatment of ACPO. No clinically evident serious adverse events occurred, meaning continuous cardiac monitoring as a routine may not be necessary. Similar success rates were achieved compared with intravenous neostigmine. 
Critique The study provides evidence supporting the safety and efficacy of subcutaneous neostigmine for ACPO, potentially reducing the need for continuous cardiac monitoring. However, the retrospective design and small sample size limit the generalizability of the findings. Further research with larger, controlled trials is needed to confirm these results. 
References:

Frankel A, Gillespie C, Lu CT, Hewett P, Wattchow D. Subcutaneous neostigmine appears safe and effective for acute colonic pseudo-obstruction (Ogilvie's syndrome). ANZ J Surg. 2019;89(6):700-705. doi:10.1111/ans.15265