Oral Hygiene and Prophylactic Antibiotics to Prevent Intracerebral Hemorrhage Associated Pneumonia

Обзор

Project Name: Randomized Controlled Clinical Study on oral hygiene and prophylactic antibiotics to prevent Intracerebral Hemorrhage associated pneumonia Research Objectives: To evaluate the effectiveness, safety and health economics value of enhanced oral hygiene combined with antibiotics in preventing post-cerebral hemorrhage pneumonia. 1. To clarify the effectiveness of enhanced oral hygiene combined with antibiotics in preventing post-cerebral hemorrhage pneumonia. 2. To clarify the safety of enhanced oral hygiene combined with antibiotics in preventing post-cerebral hemorrhage pneumonia. 3. To clarify the health economics value of low-intensity enhanced oral hygiene combined with antibiotics in preventing post-cerebral hemorrhage pneumonia. Research Design: Research Type: Multicenter, Randomized, Controlled, Open Label, Blinded Endpoint Research Design Research Hypothesis: Intensive oral hygiene combined with antibiotic treatment is beneficial in reducing the incidence of pulmonary infections related to cerebral hemorrhage.

Подробное описание

Research Background:

The era of evidence-based medicine has been entered. For acute ischemic stroke within the 4.5-hour time window, intravenous thrombolysis, mechanical thrombectomy within 24 hours of onset, and stroke units all have clear evidence-based medical support for their intervention methods. However, for cerebral hemorrhage, which has higher disability and mortality rates, treatment methods currently lack evidence-based medical support, with management more often being supportive. In this context, exploring new targets, methods, and strategies to improve the prognosis of cerebrovascular diseases has become a hot topic in global research.

Stroke-associated pneumonia (SAP) is one of the most common complications after stroke. Substantial evidence shows that the occurrence of SAP not only increases patient length of hospital stay and medical expenses but also significantly elevates the risk of death and severe disability post-stroke. Based on data from the China National Stroke Registry (CNSR), the composition and distribution of various complications after cerebral infarction and cerebral hemorrhage in Chinese patients were first systematically reported. Among them, SAP is the most common complication for both major stroke subtypes: cerebral infarction and cerebral hemorrhage. Concurrently, it was also found that SAP not only increases the risk of adverse stroke prognosis but is also an important risk factor for the increase of various non-pneumonia complications. For example, in the sub-cohort of acute cerebral infarction patients (N=14,702), the occurrence of SAP increased the risk of gastrointestinal bleeding by 8-fold (adjusted OR=8.35; 95% CI=6.27-11.1; P\<0.001), pressure ulcers by 5-fold (OR=5.31; 95% CI=3.39-8.31; P\<0.001), deep vein thrombosis by 4-fold (OR=4.27; 95% CI=2.41-7.59; P\<0.001), symptomatic epilepsy by 4-fold (OR=3.96; 95% CI=2.67-5.88; P\<0.001), urinary tract infection by 3-fold (OR=3.34; 95% CI=2.73-4.10; P\<0.001), atrial fibrillation by 3-fold (OR=3.17; 95% CI=2.58-3.90; P\<0.001), and stroke recurrence by 2-fold (OR=2.65; 95% CI=2.07-3.40; P\<0.001).

The same phenomenon was also confirmed in the cerebral hemorrhage cohort (N=5,221). The effective prevention and control of SAP will become a new target for improving stroke prognosis, as clearly reflected in multiple domestic and international expert consensuses and guidelines on SAP.

Similar related studies have been conducted abroad. In 2015, the UK STROKE-INF study, for patients hospitalized within 48 hours after stroke onset, administered prophylactic antibiotics for 7 days plus standard stroke ward care or standard stroke ward care alone, finally including 1,217 patients from 37 units (615 in the antibiotic group, 602 in the control group). No difference was found in the diagnosis of post-stroke pneumonia between the two groups (101 of 615 patients \[16%\] in the antibiotic treatment group vs. 91 of 602 patients \[15%\] in the non-antibiotic treatment group; adjusted OR = 1.01 \[95% CI 0.61-1.68\], p = 0.957). In 2015, the Dutch PASS study randomly assigned acute stroke patients in a 1:1 ratio to an antibiotic treatment group (ceftriaxone) or a non-antibiotic treatment group (control) within 24 hours after onset. The control group received standardized stroke treatment; the ceftriaxone group received standardized treatment plus intravenous application of 2g ceftriaxone once daily for 4 days. Finally, 2,538 patients were included for treatment analysis (ceftriaxone group: 1,268; control group: 1,270). The study results showed that prophylactic use of ceftriaxone was safe, mainly manifested by a significantly lower incidence of urinary tract infections in the ceftriaxone group, with no significant difference in the incidence of infections at other sites between the two groups. Prophylactic ceftriaxone did not affect the distribution of 3-month modified Rankin Scale (mRS) scores (OR = 0.95 \[95% CI 0.81-1.09\], p = 0.46). Both these trials yielded negative results. This study aims to explore the relationship between the preventive use of antibiotics combined with oral care and the incidence of SAP in the Chinese population.

Research Objectives:

To clarify the effectiveness of enhanced oral hygiene combined with antibiotics in preventing pneumonia after cerebral hemorrhage.

To clarify the safety of enhanced oral hygiene combined with antibiotics in preventing pneumonia after cerebral hemorrhage.

To clarify the health economics value of enhanced oral hygiene combined with antibiotics in preventing pneumonia after cerebral hemorrhage.

Вмешательства

• Биопрепарат wether apply enhanced oral care combined with prophylactic antibiotics
  Intervention group: After randomization, immediate intensive oral hygiene treatment (chlorhexidine 20 ml, three times a day) combined with antibiotics (ceftazidime 1 g, every 8 hours) was administered on the basis of the conventional standard treatment, and the treatment lasted for 3 days; Control group: Conventional standard treatment combined with routine oral care (normal saline 20 ml, twice a day), and detailed records were made of the specific measures of patient oral care, including the se

Первичные конечные точки

• The occurrence of pneumonia related to cerebral hemorrhage [Срок оценки: From enrollment to the 10th day after randomization or at the time of discharge]

Вторичные конечные точки (5)

• urinary tract infection or other systemic infection [Срок оценки: From enrollment to the 10th day after randomization or at discharge]
• Improvement in neurological dysfunction (NIHSS10d-NIHSS group) [Срок оценки: From enrollment to the 10th day after randomization or at discharge]
• Length of hospital stay [Срок оценки: From hospital admission until discharge (anticipated average 7-10 days)]
• direct medical expenses during hospitalization [Срок оценки: From hospital admission until discharge (anticipated average 7-10 days)]
• Modified Rankin Scale score [Срок оценки: From enrollment to the 90 days ± 7 days after randomization]

Критерии участия

Критерии включения

• Age 18-80 years old;
• Spontaneous intracerebral hemorrhage;
• Supratentorial intracerebral hemorrhage (ICH);
• Hematoma volume < 30 ml (calculated by ABC/2 method);
• Glasgow Coma Scale score ≥ 9 at randomization;
• Time from onset to randomization ≤ 72 hours;
• Spontaneous intracerebral hemorrhage-associated pneumonia score (ICH-APS) ≥ 8;
• Informed consent from the patient and/or their family.

Критерии исключения

• Secondary intracerebral hemorrhage, such as that resulting from cerebral aneurysms, cerebral arteriovenous malformations, brain tumors, cerebral venous system thrombosis, antithrombotic therapy (antiplatelet, anticoagulant therapy, etc.), hemorrhagic transformation after cerebral infarction, hematological diseases, etc.
• The patient's clinical symptoms and signs suggest signs of brain herniation, such as progressive decline in consciousness level, weakened or absent pupillary light reflex.
• Obvious signs of pneumonia already exist, such as fever, persistent cough or yellow purulent sputum, and imaging examinations (chest X-ray or chest CT) suggest signs of pneumonia; two consecutive measurements of body temperature ≥ 37.5℃, or one measurement of body temperature ≥ 38.0℃.
• A history of severe cardiovascular disease, meeting any of the following: 1) Heart failure (New York Heart Association functional class ≥ III); 2) Unstable angina within 3 months; 3) Any supraventricular or ventricular arrhythmia requiring treatment; 4) Prolonged QTc interval considered clinically significant by the investigator (reference range: > 450ms for men, > 470ms for women) (Note: QTc interval must be calculated according to Fridericia's formula); 5) Complete atrioventricular block and left or right bundle branch block requiring treatment; 6) Acute myocardial infarction or interventional treatment within 1 month; high-risk patients with chronic arrhythmia, such as sick sinus syndrome, second or third-degree atrioventricular block, bradycardia-related syncope without pacemaker installation, etc.
• Diagnosed with severe active liver disease, such as acute hepatitis, chronic active hepatitis, liver cirrhosis, etc.; or ALT or AST > 3 times the upper limit of normal.
• Severe renal insufficiency: such as patients undergoing dialysis, or diagnosed with severe active kidney disease, etc., or creatinine clearance rate < 50 mL/min.
• Other severe diseases that lead to an expected lifespan of less than 1 year.
• Patients scheduled for surgical intervention before the first administration, including but not limited to hematoma evacuation (including minimally invasive and conventional surgery), decompressive craniectomy, hematoma aspiration, and external ventricular drainage.
• Patients unable to understand the research procedures and/or complete follow-up due to mental illness, cognitive impairment, emotional disorders, etc.
• Pregnant or lactating women.
• Participation in other clinical studies within 3 months or currently participating in other clinical studies.
• Known allergy to cephalosporins, penicillins, or chlorhexidine compound mouthwash.

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Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Профилактика

Центры проведения

Китай · 1 центр

• Beijing Tiantan Hospital — Пекин

Публикации

• Westendorp WF, Vermeij JD, Zock E, Hooijenga IJ, Kruyt ND, Bosboom HJ, Kwa VI, Weisfelt M, Remmers MJ, ten Houten R, Schreuder AH, Vermeer SE, van Dijk EJ, Dippel DW, Dijkgraaf MG, Spanjaard L, Vermeulen M, van der Poll T, Prins JM, Vermeij FH, Roos YB, Kleyweg RP, Kerkhoff H, Brouwer MC, Zwinderman AH, van de Beek D, Nederkoorn PJ; PASS investigators. The Preventive Antibiotics in Stroke Study (P PMID 25612858
• Kalra L, Irshad S, Hodsoll J, Simpson M, Gulliford M, Smithard D, Patel A, Rebollo-Mesa I; STROKE-INF Investigators. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet. 2015 Nov 7;386(10006):1835-44. doi: 10.1016/S0140-6736(15)00126-9. Epub 2015 PMID 26343840
• Vernino S, Brown RD Jr, Sejvar JJ, Sicks JD, Petty GW, O'Fallon WM. Cause-specific mortality after first cerebral infarction: a population-based study. Stroke. 2003 Aug;34(8):1828-32. doi: 10.1161/01.STR.0000080534.98416.A0. Epub 2003 Jul 10. PMID 12855836
• Saposnik G, Hill MD, O'Donnell M, Fang J, Hachinski V, Kapral MK; Registry of the Canadian Stroke Network for the Stroke Outcome Research Canada (SORCan) Working Group. Variables associated with 7-day, 30-day, and 1-year fatality after ischemic stroke. Stroke. 2008 Aug;39(8):2318-24. doi: 10.1161/STROKEAHA.107.510362. Epub 2008 Jun 19. PMID 18566303
• Katzan IL, Dawson NV, Thomas CL, Votruba ME, Cebul RD. The cost of pneumonia after acute stroke. Neurology. 2007 May 29;68(22):1938-43. doi: 10.1212/01.wnl.0000263187.08969.45. PMID 17536051
• Ingeman A, Andersen G, Hundborg HH, Svendsen ML, Johnsen SP. In-hospital medical complications, length of stay, and mortality among stroke unit patients. Stroke. 2011 Nov;42(11):3214-8. doi: 10.1161/STROKEAHA.110.610881. Epub 2011 Aug 25. PMID 21868737
• Ji R, Wang D, Shen H, Pan Y, Liu G, Wang P, Wang Y, Li H, Wang Y; China National Stroke Registry (CNSR) Investigators. Interrelationship among common medical complications after acute stroke: pneumonia plays an important role. Stroke. 2013 Dec;44(12):3436-44. doi: 10.1161/STROKEAHA.113.001931. Epub 2013 Oct 31. PMID 24178914
• Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol. 2010 Jan;9(1):105-18. doi: 10.1016/S1474-4422(09)70266-2. PMID 20083041

Идентификаторы

NCT: NCT07311343 · KY2025-105-03

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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