Probiotics Can Reduce Ventilator-Associated Pneumonia in Mechanically Ventilated Children
Neveen El Sayed Ibrahim Boraey(1), Tarek Abd El-Rahman Atiyyah(1), Rania Ahmed Ghonaim(2), RaghdaHamed A. Deraz(3)andDalia Abdullatif Abdulrahman(1)
(1)Department of Pediatrics, Faculty of Medicine – Zagazig University, Egypt.
(2)Department of Clinical Pathology, Faculty of Medicine – Zagazig University, Egypt.
(3)Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine – Zagazig University, Egypt.
Corresponding Author Name: RaghdaHamed Abdel Aziz Deraz Phone Number: 00201061237598 Email:[email protected]
Abstract
Background:Ventilator-Associated Pneumonia (VAP) is a common nosocomial infection in ICU patients, regardless of the admission or ventilation cause.Objective: This study aims to assess probiotics role in VAP prevention in the pediatric intensive care unit (PICU). Methods: The clinical trial included eighty critically ill children of different morbidities that were categorized into two groups: Probiotic group (forty children) and Non-probiotic group (forty children), who did not receive probiotics. All subjects in the study received full assessment and proper management according to their original illness. Results: The incidence of VAP among the studied eighty patients was 44 cases (55%). The incidence was significantly higher in the non-probiotic group (72.5%) than in the probiotic group. Weaning failure, complications, and mortality showed non-significant differences between groups, regardless of the cause of ventilation. Conclusion:
Using probiotics is safe and effective in the prevention of VAP but does not affect the general prognosis of different cases.
Keywords: Probiotics, ventilator association pneumonia, poisoned children, ICU- acquired infection, ventilated children.
Introduction
Even though the prevalence of ventilator-associated pneumonia (VAP) has reduced in recent years, it remains a significant source of morbidity and death in mechanically ventilated patients.
VAP is thought to be responsible for between 27 and 47% of infections acquired in intensive care units (ICUs). The clinical and economic cost of VAP continues to be high, and current VAP preventive efforts are variable but unsatisfactory [1].
Despite the complex etiology of VAP, it generally includes pathogenic bacteria colonizing the upper aerodigestive tract and contaminated oropharyngeal secretions leaking into the lung[2].
Numerous preventative approaches have been suggested to mitigate VAP, either by pharmacologic or non-pharmacologic interventions. However, the efficacy evidence for each measure is too unreliable to use solely in clinical practice. Instead, care providers should consider a multidisciplinary strategy [3].
One novel intervention, which has been studied in adults, is the administration of prophylactic probiotics to restore non-pathogenic flora that competes with pathogens, modulates local and systemic immunity, and reduces intestinal permeability, thereby preventing nosocomial infections in critically ill patients[4].
Compared to other strategies, probiotics are considered a new intervention that is orally administered to prevent VAP [5,6]. However, its efficacy in reducing the VAP rate in critically ill patients and particularly in childrenis still controversial [7].
While probiotics have been studied in various pediatric diseases such as antibiotic- associated diarrhea, acute infectious diarrhea,and necrotizing enterocolitis[8], research on their effect on VAP in pediatric patients is still lacking.[9].
This study aims to assess probiotics role in ventilator-associated pneumonia prevention in ventilated children due to different causes of admission and whether the response to probiotics differs according to the original cause of illnesses indicating ventilation.
Patients and Methods
This randomized controlled trial was performed in the Pediatric intensive care unit (PICU) and clinical pathology department at Zagazig University Hospitals during the period from May 2019 to January 2020. The study included eighty critically ill ventilated children, the need for mechanical ventilation in those children was due to neurological causes; 53 cases [66.25%] (e.g., status epilepticus, Guilain Barre syndrome, cerebral palsy, cerebral hemorrhage, and neurological anomalies), complicated renal failure with pulmonary edema or combined acute lung injury (ALI) and acute kidney injury (AKI); 17cases [21.25%], and 10 cases [12.50%] were severely poisoned (carbon monoxide, aluminum phosphide, and organophosphorus pesticides).The institutional research board approved the study (IRB No: 5427/9/6/2019).
The ventilated children were randomly divided into two groups: Probiotics and Non- probiotics (control) groups; each was furtherly divided into categories according to the original cause of admission and ventilation to study whether the original illness influences the responsiveness to probiotic treatment and whether the treatment with probiotics can significantly affect the general prognosis and outcome of those cases. Inclusion criteria were mechanically ventilated children for ≥48 hrs., aged from one month to 12 years, and admitted to the PICU due to any cause rather than respiratory infection. Exclusion criteria were Immunosuppression patients, cancer patients, short bowel syndrome, and primary respiratory infections.
The probiotics group (40 children divided as 25 neurological, 9 combined ALI and AKI, and six poisoned patients) received Lactobacillus (LB) corresponding to Lactobacillus delbrueckii and Lactobacillus fermentum as commercial sachets twice daily. Each sachet contained 10 billion Lactobacillus and was suspended in sterile water and given using the nasogastric tube.Patients had active intervention until they were extubated, a tracheostomy was placed, or they died. The non-
probiotics group (forty children: 28 neurological, 8 combined ALI and AKI, and 4 poisoned patients) did not receive probiotics prevention nor placebo.
Throughout the study, patients have received all routine and specific care, antibiotic therapy when needed under their admitting pediatrician's supervision, and the specific treatment of poisoned children as recommended by the admitting clinical toxicologist. Throughout the study period, institutional VAP preventive methods were maintained, as detailed in the online supplement.
Patients were subjected, as well, to complete history taking including (age, sex, cause of PICU admission, cause of mechanical ventilation (MV), then the duration of MV and total PICU stay (Days) was assessed. Comprehensive laboratory investigations [complete blood count (CBC), C reactive protein (CRP), total bilirubin, serum albumin, liver and kidney functions, electrolytes, arterial blood gases (ABG), and bleeding profile] were performed as well. Chest x.ray is done routinely to ensure lung ventilation and prober tubal position. Tracheal aspirates andthroat swabs were taken for culture and sensitivity 5-7 days after MV.
VAP incidence density was calculated as follows: (Number of cases with VAP/Number of ventilator days) x 1000= VAP rate per 1000 ventilator days.
Statistical Analysis
Data analysis was performed using the software SPSS (Statistical Package for the Social Sciences) version 20. The level of statistical significance was set at 5% (P < 0.05). A highly significant difference was present if p ≤ 0.001.
Results
Table 1shows a statistically significant difference between study groups regarding the presence of non-sterile tracheal aspirate and Klebsiella pneumonia.
Table (1)Comparison between the studied groups regarding tracheal aspirate:
Tracheal aspirate groups Test
Probiotic group
Non-probiotic group
χ2 p
N=40 (%) N=40 (%)
Sterile 25 (62.5) 11 (27.5) 9.899 0.002*
Non-sterile Acinetobacter E. coli
Klebseilla pneumonia Pseudomonas
15 (37.5) 3 (7.5) 2 (5) 10 (25) 0 (0)
29 (72.5) 6 (15) 5 (12.5) 16 (40) 2 (5)
Fisher Fisher 5.895 Fisher
0.063 0.082 0.015*
0.111
*p<0.05 is statistically significant
Figure (1) shows VAP distribution in both groups, with lower incidence in the probiotic group and a significant difference.
Figure (1) Combined bar chart showing a comparison between the studied groups regarding the incidence of VAP
VAP incidence density in probiotic group= 15/359 X 1000= 41.78 VAP rate per 1000 ventilator days. VAP incidence density in Non-probiotic group= 29/363 X 1000= 79.89 VAP rate per 1000 ventilator days
Ventilated cases who received probiotics in different etiological categories showed a significantly lower VAP incidence, denoting a good response to probiotic treatment whatever the cause of ventilation (figure 2).
Figure (2): Lower frequency of VAP among probiotic ventilated patients of different causal categories
The ICU stay duration and mechanical ventilation showed non-significant differences between both groups (Table 2).
Table (2) Comparison between the studied groups regarding duration of mechanical ventilation and ICU stay:
Duration (days) Groups Test
Probiotic group Non-probiotic group Z/t p
0.0
% 10.0
% 20.0
% 30.0
% 40.0
% 50.0
% 60.0
% 70.0
% 80.0
%
Absent Present
Probiotic group Non-probiotic group
N=40 (%) N=40 (%) ICU stay
Mean ± SD Median (Range)
14.85 ± 10.31 13.5 (8 - 73)
12.05 ± 3.96 12 (7 – 22)
-1.563 0.118
Mechanical ventilation:
Mean ± SD Range
8.98 ± 2.02 7 - 14
9.08 ± 2.01 7 – 14
-0.222¥ 0.825
Z Mann Whitney test ¥t independent sample t-test
The probiotic group showed lower mortality but with no significant difference. (Figure 3).
Figure (3) Combined bar chart showing a comparison between the studied groups regarding the outcome
This was furtherly confirmed by a non-significant decrease in the rate of developed complications, weaning failure, and the overall mortality within the three etiological categories of the probiotic group compared with the same categories of the non-probiotic group. The original cause of admission non significantly influenced these parameters within the etiological categories of the same group (table 3).
Table (3): Differential statistical analysis of the two studied groups showing the relation between the cause of admission and the patient outcome:
The group Prognostic parameters
Neurological (n=53)
[66.25%]
Combined ALI & AKI (n=17) [21.25%]
Poisoned (n= 10) [12. 5%]
Total (%) P
Probiotics group
- Weaning failure - Developed
complications
11 15
6 9
0 1
17 (42.5%)
25 0.88
0.0
% 10.0
% 20.0
% 30.0
% 40.0
% 50.0
% 60.0
% 70.0
% 80.0
% 90.0
% 100.0
%
Death Discharge
Probiotic group Non-probiotic group
- Death
15 6 1
(62.5%) 22(55%)
NS Non-
probiotics group
- Weaning failure - Developed
complications - Death
13 22 17
8 10
6
1 1 2
22(55%) 33(82.5%) 25(62.5%)
0.83 NS
P 0.85 NS 0.93 NS 0.69 NS
Discussion
This study showed that the probiotic use significantly protects against the development of VAP with a non-significant difference between the studied groups regarding developed complications and the overall mortality regardless of the cause of admission and ventilation.
Thesefindings are in agreement with Mahmoodpoor et al.[10],who found a non-significant difference between the studied groups regarding the cause of admission or other causes of ventilation.
This study showed also a non-significant difference between the studied groups regarding the duration of ICU stay. This agreed with Bo et al. [6],who also concluded no significant differences in ICU length of stay and mechanical ventilation duration. Furthermore, Zeng et al.
[11]found that probiotics administration was not associated with any improvement in mechanical ventilation duration and length of hospital stay. These results were in disagreement with Mahmoodpoor et al. [10],who found that probiotics use can reduce ICU admission time and hospitalization time in VAP patients.
In this study, regarding microorganisms associated with tracheal aspirate in all the studied groups, Klebsiella was the most common organism.Galal et al. [12] discovered that the majority of VAP patients (75.7 percent) had gram-negative bacteria, with Pseudomonas aeruginosa and Acinetobacter predominating, whereas Methicillin-Resistant Staphylococcus aureus (MRSA) caused most of the gram-positive infections.
This study showed a significant difference between the studied groups regarding the presence of Klebsiella pneumonia; It was reduced in the probiotics group. VAP caused by Klebsiella was significantly lower in the probiotics group (25%) than the control group (40.0%);
the P-value was 0.01. This was consistent with Morrow et al. [15],who showed a significant reduction in the incidence of VAP caused by Klebsiella in the probiotics group.
The current study showed a VAP incidence among all the studied 80 patients of 55%. This result was in agreement with Khattab et al. [16],who aimed to study VAP characteristics and risk factors in critically ill patients. Amanati et al. [17]studiedVAP incidence and mortality rate in PICU. They found that VAP developed in 22.9% of critically ill children undergoing mechanical ventilation.
VAP is significantly more prevalent in developing countries than it is in developed countries. The reason for this is because developing countries lack an effective VAP prevention plan.[18]
This study showed a statistically significant difference regarding VAP (lower among the probiotic group). Probiotic use significantly protects against the incidence of VAP.41.78 VAP rate per 1000 ventilator days among the Probiotic group vs. 79.89 VAP rate per 1000 ventilator days among the non-probiotic group, P = 0.002). This agreed with a study done by Banupriya et al. [9], who concluded that children who received preventive probiotics had a lower VAP incidence (17.1%) than children who did not (48.6%); 22 per 1,000 days ventilated versus 39 per 1,000 days ventilated.
Additionally, Zeng et al.[11] investigated the potential of probiotics to reduce ventilator- associated pneumonia (VAP). They discovered that the incidence of microbiologically proven VAP was significantly lower in the probiotics group than in the control group.
Branch-Elliman et al.[19] demonstrated that prophylactic probiotics and subglottic endotracheal tubes were cost-effective in preventing VAP from a societal and hospital standpoint.
Numerous research has been conducted to determine the impact of probiotics on critically ill patients[20]. They all agreed that the administration of probiotics might help lower the risk of infection, including VAP, in critically ill patients. Thus, the use of probiotics for VAP prophylaxis should be advocated in current clinical practice.
According to Morrow et al.[15], the probiotic group had a significantly lower incidence of VAP than the control group.Probiotics have been shown in previous research to decrease pathogenic bacteriacolonization of the nasal and oropharyngeal cavities[21].
This study showed that the mortality rate was (58.8%). This might be explained by the random selection of cases, late referral to our unit, and drug resistance. These results agreed withKhwannimit et al. [23],who found the overall mortality rate was 44.5%. According to Rady[24],themortality rate was 33.1%. In contrast, Taori et al. [25]found that the mortality rate was 17%.
This study showed lower mortality among the probiotic group, with no significant difference. This was consistent with Banupriya et al. [9], who discovered that probiotics had no effect on mortality. Similarly, Zeng et al.[11]concluded that probiotic treatment had no effect on mortality.
Consistent with previously reported findings. Numerous other emerging factors, such as organ failure, may lead to the mortality of critically ill patients in addition to VAP. Bekaert et al.
[26] discovered that only 4.4% of 30-days deaths and 5.9% of 60-days deaths might be attributed to VAP. Similarly, additional complications that arise during an ICU stay, such as muscular
weakness, pressure ulcers, pulmonary embolism, and hyperactive delirium, prolong mechanical ventilation duration[27].
This study correlates the cause of admission with the probability of developing VAP with and without administering probiotics and the role of probiotics on the expected outcome.
The prevalence of VAP in poisoned ventilated cases is of special concern due to the acute course of the disease in previously healthy individuals [28,29,30], so studying the preventive measures of VAP could carry a better prognosis in such cases, unlike the critically ill children with a chronic nature of the disease. However, a paucity of studies tried protective techniques and studied their role in the prevention of VAP and the expected consequent improvement.
We found that probiotics significantly protected poisoned patients from VAP without significant protection from associated complications, and this was in contrast to the clinical trial performed by Khorasani et al.[31] who didn't find a protective value of the Hi-Lo EVAC technique against VAP; and this gives value to probiotics over other previously used methods.
Conclusion:
We concluded that using probiotic therapy is effective and safe in the prevention of VAP but has no effect on the duration of MV, ICU stay, or the overall patient prognosis.
References:
1- Metersky ML, Wang Y, Klompas M, Eckenrode S, Bakullari A, Eldridge N. (2016). Trend in ventilator-associated pneumonia rates between 2005 and 2013. JAMA 316, 2427–2429. doi:
10.1001/jama.2016.16226
2- Baselski V, and Klutts JS. (2013). Quantitative cultures of bronchoscopically obtained specimens should be performed for optimal management of ventilator-associated pneumonia. J.
Clin. Microbiol. 51, 740–744. doi: 10.1128/JCM.03383-12.
3- Keyt, H., Faverio, P., &Restrepo, M. I. (2014). Prevention of ventilator-associated pneumonia in the intensive care unit: a review of the clinically relevant recent advancements. The Indian journal of medical research, 139(6), 814–821.
4- Gourbeyre P, Denery S, Bodinier M. (2011) Probiotics, prebiotics, and synbiotics: impact on the gut immune system and allergic reactions. J LeukocBiol 89:685–695. doi:
10.1189/jlb.1109753 CrossRefPubMedGoogle Scholar.
5- Siempos II, Ntaidou TK, Falagas ME. (2010): Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Crit Care Med; 38(3):954-620.
6- Theodorakopoulou M, Perros E, Giamarellos-Bourboulis EJ, Dimopoulos G. (2013).
Controversies in the management of the critically ill: the role of probiotics. Int. J. Antimicrob.
Agents 42(Suppl.), S41–S44. doi: 10.1016/j. ijantimicag.2013.04.010
7- Bo L, Li J, Tao T, Bai Y, Ye X, Hotchkiss RS, et al. (2014). Probiotics for preventing ventilator-associated pneumonia. Cochrane Database Syst. Rev. CD009066. doi:
10.1002/14651858. CD009066. pub2
8- Robinson J. (2014) Cochrane in context: probiotics for prevention of necrotizing enterocolitis in preterm infants. Evid Based Child Health 9:672–674.
9- Banupriya B, Biswal N, Srinivasaraghavan R, Narayanan P, Mandal J. (2015). Probiotic prophylaxis to prevent ventilator associated pneumonia (VAP) in children on mechanical ventilation: an open-label randomized controlled trial. Intensive Care Med. 41, 677–685. doi:
10.1007/s00134-015-3694-4
10- Mahmoodpoor A, Hamishehkar H, Asghari R, Abri R, Shadvar K, Sanaie S. (2019). Effect of a probiotic preparation on ventilator-associated pneumonia in critically ill patients admitted to the intensive care unit: a prospective double-blind randomized controlled trial. Nutr. Clin. Pract.
34, 156–162. doi: 10.1002/ ncp.10191
11- Zeng J, Wang CT, Zhang FS, Qi F, Wang SF, Ma S, et al. (2016). Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial. Intensive Care Med. 42, 1018–1028. doi: 10.1007/s00134-016-4303-x
12- Galal YS, Youssef MR, Ibrahiem SK. (2016). Ventilator-Associated Pneumonia: Incidence, Risk Factors and Outcome in Paediatric Intensive Care Units at Cairo University Hospital.
Journal of clinical and diagnostic research : JCDR, 10(6), SC06–SC11.
doi:10.7860/JCDR/2016/18570.7920.
13- Evans CR, Sharpe JP, Swanson JM, Wood GC, Fabian TC, Croce MA, et al. (2018).
Keeping it simple: impact of a restrictive antibiotic policy for ventilator-associated pneumonia in trauma patients on incidence and sensitivities of causative pathogens. Surg. Infect. 19, 672–678.
doi: 10.1089/sur.2018.087
14- Rhodes NJ, Cruce CE, O’Donnell JN, Wunderink RG, Hauser AR. (2018). Resistance trends and treatment options in gram-negative ventilator-associated pneumonia. Curr. Infect.
Dis. Rep. 20:3. doi: 10.1007/s11908-018-0609-x
15- Morrow LE, Kollef MH, Casale TB. (2010). Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am. J. Respir. Crit. Care Med. 182, 1058–
1064. doi: 10.1164/rccm.200912-1853OC
16- Khattab AA, El-Lahony DM, Soliman WF. Ventilator-associated pneumonia in the neonatal intensive care unit. Menoufia Med J 2014;27:73-7
17- Amanati A, Karimi A, Fahimzad A, Shamshiri AR, Fallah F, Mahdavi A, Talebian M.
(2017). Incidence of Ventilator-Associated Pneumonia in Critically Ill Children Undergoing Mechanical Ventilation in Pediatric Intensive Care Unit. Children (Basel, Switzerland), 4(7), 56.
doi:10.3390/children4070056
18- Xie J, Yang Y, Huang Y, Kang Y, Xu Y, Ma X, et al. (2018). The current epidemiological landscape of ventilator-associated pneumonia in the intensive care unit: a multicenter prospective observational study in China. Clin. Infect. Dis. 67, S153–S161. doi: 10.1093/cid/ciy692
19- Branch-Elliman W, Wright SB, Howell MD. (2015). Determining the ideal strategy for ventilator-associated pneumonia prevention. Cost-benefit analysis. Am. J. Respir. Crit. Care Med. 192, 57–63. doi: 10.1164/rccm.201412-2316OC
20- Manzanares W, Lemieux M, Langlois PL, Wischmeyer PE. (2016). Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit. Care 19:262. doi:
10.1186/s13054-016-1434-y
21- Chapman CMC, Gibson GR, Rowland I. (2012) In vitro evaluation of single- and multi- strain probiotics: inter-species inhibition between probiotic strains, and inhibition of pathogens.
Anaerobe 18:405–413. doi: 10.1016/j.anaerobe. 2012.05. 004 CrossRefPubMedGoogle Scholar 22- Simakachorn N, Bibiloni R, Yimyaem P et al (2011) Tolerance, safety, and effect on the
faecal microbiota of an enteral formula supplemented with pre- and probiotics in critically ill children. J PediatrGastroenterolNutr 53:174–181. doi: 10.1097/MPG.0b013e318216f1ec CrossRefPubMedGoogle Scholar
23- Khwannimit B, Bhurayanontachai R, Vattanavanit V (2018) Comparison of the performance of SOFA, qSOFA and SIRS for predicting mortality and organ failure among sepsis patients admitted to the intensive care unit in a middle-income country. J Crit Care 44:156–160 24- Rady HI. Profile of patients admitted to pediatric intensive care unit, Cairo University Hospital:
1-year study. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2019 Jan 12];7:500-3.
25- Taori RN, Lahiri KR, Tullu MS.(2010). Performance of PRISM (Pediatric Risk of Mortality) score and PIM (Pediatric Index of Mortality) score in a tertiary care pediatric ICU. Indian J Pediatr; 77:267-271.
26- Bekaert M, Timsit JF, Vansteelandt S, Depuydt P, Vésin A, Garrouste-Orgeas M et al (2011) Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis. Am J RespirCrit Care Med 184:1133–1139. doi:10.1164/rccm.201105-0867OC
27- Loss SH, de Oliveira RP, Maccari JG, Savi A, Boniatti MM, Hetzel MP et al (2015) The reality of patients requiring prolonged mechanical ventilation: a multicenter study. Rev Bras TerIntensiva 27:26–35. doi:10.5935/0103-507X.20150006
28- H. Talaie S, Sabeti A, Mahdavinejad B, Barari B, and Kamalbeik S (2010) A survey on microorganisms and their sensitivity by E-test in ventilator-associated pneumonia at toxicological-intensive care unit of Loghman-Hakim hospital. ActaBiomedica, 81(3): 210–216.
29- Raphael M, Karimzad SH, Agarwal J, Bhandakar AA, Thunga G, Shreedhar N et al.
(2015) Prevalence of Ventilator Acquired Pneumonia in Organophosphorus Poisoning Patients in Tertiary Care Hospital. International Journal of Drug Development and ResearchVolume 7(4):
005-008.
30-Hashemian M, Kamalbeik S, Haji SeyedRazi P, Barari B, Salimi A, Talaie H, Mahdavinejad A.
VAP or poisoning; which one has more effect on patients' outcomes in toxicological ICU? Acta Biomed. 2015 Apr 27;86(1):63-8. PMID: 25948030.
31- Khorasani AG, Shadnia S, Mashayekhian M, Rahimi M, Aghabiklooei A (2016) Efficacy of Hi-Lo Evac Endotracheal Tube in Prevention of Ventilator-Associated Pneumonia in Mechanically Ventilated Poisoned Patients. Scientifica, 2016: 1-5.
https://doi.org/10.1155/2016/4901026