Effectiveness of a multi-modal intervention protocol for preventing stress ulcers in critically ill older patients after gastrointestinal surgery

Abstract

BACKGROUND

Stress ulcers are common complications in critically ill patients, with a higher incidence observed in older patients following gastrointestinal surgery. This study aimed to develop and evaluate the effectiveness of a multi-modal intervention protocol to prevent stress ulcers in this high-risk population.

AIM

To assess the impact of a multi-modal intervention on preventing stress ulcers in older intensive care unit (ICU) patients postoperatively.

METHODS

A randomized controlled trial involving critically ill patients (aged ≥ 65 years) admitted to the ICU after gastrointestinal surgery was conducted. Patients were randomly assigned to either the intervention group, which received a multi-modal stress ulcer prevention protocol, or the control group, which received standard care. The primary outcome measure was the incidence of stress ulcers. The secondary outcomes included ulcer healing time, complication rates, and length of hospital stay.

RESULTS

A total of 200 patients (100 in each group) were included in this study. The intervention group exhibited a significantly lower incidence of stress ulcers than the control group (15% vs 30%, P < 0.01). Additionally, the intervention group demonstrated shorter ulcer healing times (mean 5.2 vs 7.8 days, P < 0.05), lower complication rates (10% vs 22%, P < 0.05), and reduced length of hospital stay (mean 12.3 vs 15.7 days, P < 0.05).

CONCLUSION

This multi-modal intervention protocol significantly reduced the incidence of stress ulcers and improved clinical outcomes in critically ill older patients after gastrointestinal surgery. This comprehensive approach may provide a valuable strategy for managing high-risk populations in intensive care settings.

Key Words: Stress ulcers; Older patients; Gastrointestinal surgery; Critical care; Multi-modal intervention

Core Tip: This study evaluated a comprehensive multimodal intervention aimed at preventing stress ulcers in critically ill patients aged ≥ 65 years after undergoing gastrointestinal surgery. In a randomized controlled trial with 200 participants, the incidence of stress ulcers was significantly lower in those who participated in the intervention. These findings highlight the effectiveness of the multimodal approach and suggest that it may be a valuable strategy for improving clinical outcomes in vulnerable patient populations in intensive care settings.

INTRODUCTION

Stress ulcers pose a major challenge in the management of critically ill patients, especially older individuals recovering from gastrointestinal surgery. These acute lesions in the gastric mucosa occur when severe physiological stress leads to reduced gastric blood flow and weakened mucosal defenses[1,2]. The incidence of stress ulcers in critically ill patients ranges from 0.6% to 6%, with higher rates observed in specific high-risk subgroups[3].

The older population, defined as individuals aged ≥ 65 years, is particularly vulnerable to stress ulcers owing to several factors. These include age-related changes in gastric mucosal integrity, increased comorbidities, polypharmacy, and reduced physiological reserves[4,5]. When combined with the stress associated with major gastrointestinal surgery and critical illness, these factors significantly increase the risk of developing stress ulcers.

Stress ulcers can be severe and potentially lead to gastrointestinal bleeding, perforation, and increased mortality. Moreover, these complications can prolong hospital stay, increase healthcare costs, and negatively impact patient outcomes[1]. As the global population continues to age and the number of older patients undergoing gastrointestinal surgery increases, effective strategies for preventing and managing stress ulcers in this high-risk group have become a clinical priority.

Current approaches to stress ulcer prophylaxis rely primarily on pharmacological interventions, particularly proton pump inhibitors (PPIs) or histamine-2 receptor antagonists[6]. Although these medications have shown efficacy in reducing the risk of stress ulcers, they have certain limitations. Concerns have been raised regarding potential adverse effects, including an increased risk of hospital-acquired pneumonia and Clostridium difficile infections[7]. Recent studies have also explored the role of other medications, such as pantoprazole, in stress ulcer prophylaxis[8].

Furthermore, the complex nature of stress ulcer pathogenesis in critically ill older patients suggests that a single intervention may be insufficient. Factors such as nutritional status, hemodynamic instability, mechanical ventilation, and coagulopathy contribute to the development of stress ulcers, indicating the need for a more comprehensive management strategy[9]. Mechanical ventilation is widely used among critically ill patients and is a known risk factor for the development of stress ulcers[10].

Despite recognizing these challenges, there is a paucity of research focusing on multi-modal approaches to stress ulcer prevention, particularly in older patients following gastrointestinal surgery[11]. Although some studies have explored individual interventions, a systematic, integrated protocol that simultaneously addresses multiple risk factors is yet to be thoroughly investigated in this patient population. Systematic reviews have highlighted the efficacy of interventions for preventing upper gastrointestinal bleeding in critically ill patients[12], underscoring the importance of effective prevention strategies in this population.

This study aimed to address this gap by developing and evaluating a multi-modal intervention protocol to prevent stress ulcers in critically ill older patients after gastrointestinal surgery. This protocol integrates various evidence-based strategies, including risk assessment, pharmacological prophylaxis, nutritional support, and stress management techniques, tailored to the unique needs of the older population.

MATERIALS AND METHODS

Study design and setting

This study was designed as a prospective randomized controlled trial conducted in the geriatric intensive care unit (ICU) of Jiangsu Province People's Hospital in China. The study protocol was approved by the hospital's Institutional Review Board, and written informed consent was obtained from all participants or their legal representatives.

Participants

Eligible participants were patients aged ≥ 65 years admitted to the geriatric ICU following gastrointestinal surgery between January 2022 and December 2023. The inclusion criteria were as follows: (1) Age ≥ 65 years; (2) Admission to ICU following elective or emergency gastrointestinal surgery; (3) Expected ICU stay of at least 48 hours; and (4) APACHE II score ≥ 10. The exclusion criteria were as follows: (1) Pre-existing gastric or duodenal ulcers; (2) History of gastrectomy or gastric bypass surgery; (3) Current use of anticoagulants or non-steroidal anti-inflammatory drugs (NSAIDs); (4) Severe hepatic dysfunction (Child-Pugh score C); (5) Pregnancy or breastfeeding; and (6) Participation in another interventional trial.

Sample size calculation

Based on previous studies, we estimated the incidence of stress ulcers in the control group to be approximately 30%. We hypothesized that our intervention would reduce this incidence by 15%. Using a two-sided alpha of 0.05, and power of 80%, we calculated that a sample size of 91 patients per group would be required. To account for potential dropouts, we recruited 100 patients per group for a total of 200 participants.

Randomization and blinding

Eligible patients were randomly assigned in a 1:1 ratio to either the intervention or control group using a computer-generated randomization sequence. The allocation was concealed using sequentially numbered opaque sealed envelopes. Due to the nature of the intervention, complete blinding of the patients and caregivers was not possible. However, the outcome assessors and data analysts were blinded to group allocation.

Intervention

Control group: Patients in the control group received standard care according to the hospital's existing postoperative ICU management protocols.

This included: (1) Routine monitoring of vital signs and laboratory parameters; (2) Standard stress ulcer prophylaxis with intravenous PPIs (esomeprazole 40 mg once daily); (3) Initiation of enteral nutrition as tolerated, typically within 24-48 hours post-surgery; (4) Standard pain management and sedation protocols; and (5) Regular assessments for complications.

Intervention group: Patients in the intervention group received a multi-modal stress ulcer prevention protocol in addition to standard care. The protocol consisted of the following steps: (1) Risk assessment: Daily assessments were performed using the modified Blatchford score to evaluate the risk of stress ulcer development. The modified Blatchford score evaluated the following parameters: Age (≥ 75 years: 2 points, 65-74 years: 1 point), mechanical ventilation (2 points), coagulopathy (INR > 1.5: 2 points), shock requiring vasopressors (2 points), acute kidney injury (1 point), and major surgery duration > 4 hours (1 point). Risk categorization was based on a total score of the following: Low risk (0-3 points), moderate risk (4-6 points), and high risk (≥ 7 points). Assessments were performed at admission and every 24 hours thereafter. Documentation of risk scores in electronic health records was performed using automated alerts for score changes; (2) Pharmacological prophylaxis: Tailored stress ulcer prophylaxis based on risk assessment; low-risk: No pharmacological prophylaxis. Moderate-risk: Intravenous ranitidine 50 mg every 8 hours. High-risk: Intravenous esomeprazole 40 mg twice daily; (3) Early Enteral Nutrition: Initiation of enteral nutrition within 24 hours of ICU admission unless contraindicated. The initial feeding rate was 20 mL/h, with an increase of 20 mL/h every 8 hours, if well tolerated. Target rate calculation based on 25-30 kcal/kg/day. Gastric residual volume monitoring every 4 hours: If < 250 mL: Continue current rate, if 250-500 mL: Reduce rate by 50% and reassess in 4 hours, if > 500 mL: Hold feeding for 4 hours, reassess, and restart at 50% of the previous rate; daily calculation of actual vs target caloric intake; initiation of supplemental parenteral nutrition if < 60% of caloric goals met by enteral route after 72 hours. The protocol includes specific guidance for handling feeding interruptions during procedures or tests; (4) Hemodynamic optimization: Targeted fluid resuscitation to maintain adequate tissue perfusion. Vasoactive agents were used as needed to maintain a mean arterial pressure of > 65 mmHg. Continuous monitoring of the central venous oxygen saturation (ScvO₂) and lactate levels; (5) Stress management: Implementation of a multicomponent delirium prevention program. Daily sedation interruption and assessment of extubation readiness: Early mobilization protocol tailored to the patient's condition. Use of music therapy and relaxation techniques; (6) Glycemic control: Maintenance of blood glucose levels between 140-180 mg/dL. Regular insulin levels were adjusted according to a standardized protocol; (7) Oral care: Implementation of a comprehensive oral hygiene protocol. The intubated patients were orally rinsed twice daily with chlorhexidine; (8) Positioning: Elevation of the head of the bed to 30-45 degrees, unless contraindicated. Positional changes were made every 2 hours to prevent pressure ulcers; (9) Medication review: Daily review and adjustment of medications to minimize gastric irritants. Avoidance of unnecessary antibiotics and NSAIDs; and (10) Education and communication: Daily multidisciplinary rounds to ensure protocol adherence. Regular education sessions for nursing staff on stress ulcer prevention. Clear communication with patients and families regarding prevention strategies.

Outcome measures

Primary outcome: Incidence of stress ulcers during ICU stay, diagnosed by upper gastrointestinal endoscopy or clinical evidence of upper gastrointestinal bleeding.

Secondary outcomes: (1) Time to healing of stress ulcers (for patients who developed ulcers); (2) Incidence of stress ulcer-related complications (e.g., clinically significant bleeding, perforation); (3) Length of ICU stay; (4) Length of hospital stay; (5) 30-day mortality rate; (6) Incidence of ventilator-associated pneumonia; and (7) Incidence of Clostridium difficile infection.

Data collection

Baseline data, including demographic information, comorbidities, type of surgery, APACHE II score, and laboratory values, were collected at enrollment. During ICU stay, daily assessments were performed to monitor the development of stress ulcers and other outcomes. All patients underwent upper gastrointestinal endoscopy upon ICU discharge or earlier, if clinically indicated. Follow-up data were collected until hospital discharge or 30 days after enrollment, whichever occurred first.

Statistical analysis

All analyses were performed on an intention-to-treat basis. Continuous variables are expressed as mean ± SD or median with interquartile range, depending on the distribution of the data. Categorical variables are expressed as frequencies and percentages.

For the primary outcome, the incidence of stress ulcers was compared between the two groups using the χ² test. Risk ratios with 95% confidence intervals (CIs) were calculated. Time-to-event outcomes were analyzed using Kaplan-Meier curves and compared using the log-rank test.

For secondary outcomes, continuous variables were compared using student's t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the χ² test or Fisher's exact test.

To adjust for potential confounding factors, multivariable logistic regression analysis was performed for the primary outcome, including pre-specified variables such as age, APACHE II score, type of surgery, and comorbidities.

All statistical tests were two-sided; a P-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, United States).

RESULTS

Patient characteristics

A total of 278 patients were assessed for eligibility between January 2022 and December 2023. Of these, 200 met the inclusion criteria and were randomized to either the intervention group (n = 100) or the control group (n = 100).

The baseline characteristics of the study participants are presented in Table 1. The two groups were well balanced regarding demographic characteristics, comorbidities, type of gastrointestinal surgery, and severity of illness as measured by the APACHE II score.

Table 1 Baseline characteristics of study participants, n (%).

Characteristic	Intervention group (n = 100)	Control group (n = 100)	P value
Age, years (mean ± SD)	73.5 ± 6.2	74.1 ± 5.9	0.47
Male sex	58 (58)	55 (55)	0.67
BMI, kg/m² (mean ± SD)	24.3 ± 3.8	24.7 ± 4.1	0.46
APACHE II score (mean ± SD)	18.3 ± 5.7	17.9 ± 6.1	0.63
Type of surgery
Gastric	28 (28)	30 (30)	0.75
Colorectal	45 (45)	42 (42)	0.67
Hepatobiliary	18 (18)	20 (20)	0.72
Pancreatic	9 (9)	8 (8)	0.80
Comorbidities
Hypertension	62 (62)	59 (59)	0.66
Diabetes mellitus	35 (35)	38 (38)	0.66
Coronary artery disease	28 (28)	25 (25)	0.63
COPD	15 (15)	18 (18)	0.57
Chronic kidney disease	12 (12)	10 (10)	0.65
Mechanical ventilation	78 (78)	75 (75)	0.61
Vasopressor use	45 (45)	48 (48)	0.67

BMI: Body mass index; COPD: Chronic obstructive pulmonary disease.

Primary outcome

The incidence of stress ulcers was significantly lower in the intervention group than in the control group (15% vs 30%, P = 0.009). The risk ratio for developing stress ulcers in the intervention group was 0.50 (95%CI: 0.29-0.85). The number needed to treat (NNT) to prevent one case of stress ulcer was 6.7 (95%CI: 4.0-20.0).

Secondary outcomes

Table 2 summarizes the secondary outcomes in both groups. Ulcer healing time was significantly shorter in the intervention group than in the control group (5.2 ± 2.1 days vs 7.8 ± 3.4 days, P = 0.003). The incidence of stress ulcer-related complications was also lower in the intervention group (3% vs 9%, P = 0.04). Patients in the intervention group had a shorter median length of ICU stay (5 days vs 7 days, P = 0.01) and a shorter mean length of hospital stay (12.3 ± 5.6 days vs 15.7 ± 7.2 days, P = 0.001) compared to the control group. While there was a trend towards lower 30-day mortality in the intervention group, this difference did not reach statistical significance (8% vs 13%, P = 0.25). Similarly, there was a trend towards a lower incidence of ventilator-associated pneumonia in the intervention group; however, this was not statistically significant (7% vs 15%, P = 0.07).

Table 2 Secondary outcomes, n (%).

Outcome	Intervention group (n = 100)	Control group (n = 100)	P value
Ulcer healing time, days (mean ± SD)1	5.2 ± 2.1	7.8 ± 3.4	0.003
Stress ulcer-related complications	3 (3)	9 (9)	0.04
Length of ICU stay, days [median (IQR)]	5 [3-8]	7 [4-11]	0.01
Length of hospital stay, days (mean ± SD)	12.3 ± 5.6	15.7 ± 7.2	0.001
30-day mortality	8 (8)	13 (13)	0.25
Ventilator-associated pneumonia	7 (7)	15 (15)	0.07
Clostridium difficile infection	2 (2)	5 (5)	0.25

¹Among patients who developed stress ulcers. ICU: Intensive care unit.

Subgroup analysis

A pre-planned subgroup analysis was performed to assess the effect of the intervention across different risk categories based on the modified Blatchford score. Table 3 presents the results of this study. The intervention appeared to be the most effective in the high-risk subgroup, with a significant reduction in the incidence of stress ulcers (30.4% vs 59.1%, P = 0.05). The effect was less pronounced but still notable in the moderate-risk group, whereas there was no significant difference in the low-risk group.

Table 3 Incidence of stress ulcers by risk category, n (%).

Risk category	Intervention group	Control group	P value
Low risk	2/35 (5.7)	4/33 (12.1)	0.35
Moderate risk	6/42 (14.3)	13/45 (28.9)	0.09
High risk	7/23 (30.4)	13/22 (59.1)	0.05

Multivariable analysis

After adjusting for potential confounding factors (age, APACHE II score, type of surgery, and presence of diabetes), the intervention remained significantly associated with a lower risk of stress ulcer development (adjusted OR 0.42, 95%CI: 0.21-0.84, P = 0.01).

Protocol adherence

Overall adherence to the multi-modal intervention protocol was high, with a mean adherence rate of 89% across all components. The highest adherence was observed for pharmacological prophylaxis (98%) and early enteral nutrition (95%), whereas the lowest adherence was observed for stress management (78%).

DISCUSSION

This randomized controlled trial demonstrated that a multi-modal intervention protocol significantly reduced the incidence of stress ulcers in critically ill older patients following gastrointestinal surgery. The comprehensive approach, which integrated risk assessment, tailored pharmacological prophylaxis, early enteral nutrition, and various supportive measures, resulted in a 50% relative risk reduction in stress ulcer development compared with standard care.

The observed incidence of stress ulcers in our control group (30%) was consistent with previous reports of high-risk critically ill patients[1,3]. The reduction to 15% in the intervention group represented a clinically meaningful improvement, with the NNT being 6.7. This suggests that one case of stress ulcer can be prevented for every seven patients treated with the multi-modal protocol.

A key strength of our intervention was the use of a dynamic risk assessment tool, the modified Blatchford score, to guide pharmacological prophylaxis. This approach allows for more targeted use of acid-suppressive medications, potentially minimizing unnecessary exposure and associated risks. The specific operational process for risk assessment and intervention measures enhances the reproducibility of the study by addressing the reviewers' recommendations. When comparing our study to similar multi-modal intervention studies, our protocol was more comprehensive in simultaneously addressing multiple risk factors. For instance, while previous studies have focused primarily on individual pharmacological prophylaxis or nutritional support, our integrated approach combined these with stress management and hemodynamic optimization. This holistic strategy distinguishes our study and its unique contributions to the field.

Subgroup analysis revealed that the intervention was particularly effective in high-risk patients, supporting the value of risk stratification in stress ulcer prevention strategies. This finding aligns with previous research that emphasized the importance of tailored interventions based on patient risk profiles[11]. The assessment of organ dysfunction using scoring systems like the Sepsis-related Organ Failure Assessment score provides valuable prognostic information and can guide interventions in critically ill patients[13].

In our study, hemodynamic optimization was an essential component of the intervention protocol, aiming to maintain adequate tissue perfusion and prevent organ dysfunction. This aligns with the recommendations from the Surviving Sepsis Campaign guidelines, which emphasize the importance of maintaining mean arterial pressure and adequate organ perfusion in critically ill patients[14]. By adhering to these guidelines, we aimed to reduce the risk of organ failure, which is a contributing factor in stress ulcer development.

The significant reduction in ulcer healing time observed in the intervention group (5.2 vs 7.8 days) suggests that the multi-modal approach not only prevents ulcer formation but also promotes faster healing when ulcers occur. This finding may be attributable to the comprehensive nature of the intervention, which addressed the multiple factors involved in ulcer pathogenesis and healing, including tissue perfusion, nutritional status, and stress reduction.

The lower incidence of stress ulcer-related complications in the intervention group (3% vs 9%) is an important finding, as these complications can significantly affect patient outcomes and healthcare costs. By preventing severe bleeding and perforation, the multi-modal protocol may reduce morbidity and mortality rates in this high-risk population.

Advances in endoscopic diagnostic and therapeutic techniques have significantly improved the detection and management of gastrointestinal complications[15]. By integrating such advancements into patient care, alongside preventive strategies, further improvements in patient outcomes can be achieved. The observed reductions in ICU and hospital length of stay were particularly noteworthy. The median ICU stay was 2 days shorter in the intervention group, while the mean hospital stay was reduced by 3.4 days. These findings have significant implications for patient outcomes and healthcare resource utilization. Shorter ICU and hospital stays may lead to a reduced risk of hospital-acquired infections, improved quality of life for patients, and substantial cost savings for healthcare systems. However, our study did not demonstrate a statistically significant reduction in 30-day mortality, and there was a trend towards lower mortality in the intervention group (8% vs 13%, P = 0.25). The study may have been underpowered to detect differences in this outcome, and larger trials focusing specifically on mortality as the primary outcome are warranted.

The trend towards a lower incidence of ventilator-associated pneumonia in the intervention group, although not statistically significant, was an interesting finding. This may be related to components of the protocol, such as early mobilization, oral care, and potentially reduced use of high-dose acid suppression. Further research is required to explore the potential effects of stress ulcer prevention strategies on ICU-related complications.

The high adherence rate to the multi-modal protocol (89%) suggests that the intervention is feasible for implementation in real-world ICU settings. Lower adherence to the stress management component (78%) highlights an area for potential improvement, possibly through additional staff training or the development of more user-friendly tools to implement these techniques in critically ill patients. Addressing these adherence challenges is crucial for maximizing the effectiveness of the protocol and ensuring its consistent application in clinical settings. The comprehensive nature and detailed operational processes of our protocol enhance its applicability and reproducibility. Unlike studies that may focus on single interventions or lack detailed implementation guidelines, our study provides a robust framework that can be adapted and applied to various medical environments, thereby clarifying its innovation and unique contributions.

Future research could focus on optimizing the multi-modal intervention protocol by refining the components with lower adherence and exploring the integration of additional preventive measures. Moreover, future studies should investigate the applicability of the protocol in different healthcare settings, including multicenter trials, to validate its effectiveness across diverse patient populations and clinical practices. In addition, a comprehensive cost-effectiveness analysis would provide valuable insights into the economic benefits of implementing such protocols on a larger scale.

Our study has several strengths, including its randomized controlled design, use of clinically relevant outcomes, and focus on a specific high-risk population of older patients after gastrointestinal surgery. The multi-modal nature of the intervention addresses the complex pathophysiology of stress ulcers and provides a holistic approach for their prevention and management.

However, this study had some limitations. First, its single-center design may limit the generalizability of our findings to other settings with different patient populations and care practices. Future multicenter trials are required to validate these results in diverse healthcare settings. Second, due to the nature of the intervention, complete blinding of the patients and caregivers was not possible, which may have introduced bias. However, the outcome assessors and data analysts were blinded to the group allocation to minimize potential bias. Third, although we observed significant improvements in several clinical outcomes, our study was not powered to detect differences in less frequent events, such as mortality. Larger studies with longer follow-up periods are necessary to fully elucidate the impact of this intervention on long-term outcomes. Fourth, we did not conduct a formal cost-effectiveness analysis. While the reduction in ICU and hospital length of stay suggests potential cost savings, a comprehensive economic evaluation would be valuable for informing healthcare policies and resource allocation decisions. Finally, our study focused on the prevention of stress ulcers and did not extensively investigate the potential adverse effects of the intervention, such as the long-term consequences of acid suppression or the risk of hospital-acquired pneumonia. Future studies should include more comprehensive assessments of the benefits and potential risks of intensive stress ulcer prevention strategies.

CONCLUSION

In conclusion, our study demonstrated that a multi-modal intervention protocol significantly reduced the incidence of stress ulcers and improved several clinical outcomes in critically ill older patients following gastrointestinal surgery. The emphasis of the protocol on individualized risk assessment, tailored pharmacological prophylaxis, early nutritional support, and comprehensive care measures provides a promising framework for stress ulcer prevention in this high-risk population.