Predictors of weaning success from prolonged mechanical ventilation: A protocol study

doi:10.21203/rs.3.rs-5287524/v1

Objectives

To describe the outcomes of a large cohort of patients who have been on ventilation for > 14 days (extended prolonged ventilation) and identify unique predictors of weaning success within this group. We also aimed to examine the impact of diuretic therapy before weaning on the likelihood of successful weaning.

Design:

A retrospective study.

Setting:

The computerized database of Soroka University Medical Center, a tertiary 1191-bed medical center serving a population of 1.2 million residents.

Participants:

Overall, 88 patients were included in our study cohort. Forty patients (45%) were successfully weaned off mechanical ventilation and subsequently discharged either to rehabilitation facilities or directly to their homes.

Main outcome measures:

We analyzed the weaning success rate from extended prolonged mechanical ventilation and explored potential predictors for success using multivariate logistic regression.

Results

The in-hospital mortality rate was 28% (25 patients). All-cause mortality within 1 month and 1 year of discharge was 11% (10 patients) and 28% (20 patients), respectively. Hypoalbuminemia was the only significant predictor of weaning failure, with an odds ratio of 7.27. However, demographic factors such as age, comorbidities, reasons for mechanical ventilation, clinical and laboratory data at the time of admission, and diuretics treatment a few days before the initiation of weaning were not significant predictors of weaning success.

Conclusions

As patients stabilize and recover from the acute phase of illness that necessitates mechanical ventilation, rapid weaning success predictors may become less relevant in patients on long-term ventilation. Hypoalbuminemia has multiple potential mechanisms that may cause weaning failure in cases of prolonged ventilation. Therefore, interventions aimed at correcting hypoalbuminemia by improving the metabolic state may potentially enhance weaning success rates.

Mechanical ventilation

Weaning

Hypoalbuminemia

Diuretics

Weaning from mechanical ventilation is defined as the first attempt at separating the patient from a ventilator, regardless of modality, immediately after the acute condition necessitating invasive mechanical ventilation has been resolved [1, 2]. Delays in the weaning process are associated with increased complication rates, prolonged hospital stays, and reduced ICU survival rates [3–5].

In 2005, the International Consensus Conference (ICC) established criteria to classify the weaning process into three categories: simple (extubation in < 24 hrs), difficult (extubation in < 1 week), and prolonged (extubation lasting > 7 days), based on the number, timing, and success of spontaneous breathing trials (SBT). Subsequent research has demonstrated that prolonged weaning is associated with the poorest prognosis [6–11]. However, the ICC criteria do not consider factors associated with weaning failure [7, 8]. In 2017, a new definition and classification system known as Weaning Outcome according to a New Definition (WIND) was introduced, which allowed for the classification of all patients and facilitated comparisons across different ICUs.. However, the WIND classification criteria do not encompass patients who have been transferred to specialized weaning centers after unsuccessful weaning attempts in the ICU (class 3b). Notably, a few of these patients may eventually be weaned successfully after several weeks of invasive mechanical ventilation,

[9–11].

Notably, Bolles summarized that several factors predict weaning failure, including respiratory effort, cardiac function, nutritional status, and neurological condition [2]. In addition, Sellares observed chronic obstructive pulmonary disease COPD as predicting longer hospital stays, and lower survival rates in prolonged ventilated patients [13]. Upadia showed that cumulative fluid balance were independently associated with first-day weaning success [14]. Notably, fluid restriction and diuretics have been proposed to prevent and treat fluid overload in patients in the early critically ill phase. [15, 16, 17].. However, in the stabilization phase of critical care illness, usually > 1 week from mechanical ventilation initiation, the efficacy and safety of systematic diuretics have not been thoroughly investigated. [18].

Specific data regarding predictors for weaning failure in patients on ventilation for > 1 week are lacking.. Therefore, we aimed to describe the primary outcomes for this patient population, and identify the main predictors of weaning failure by comparing the successful and failed weaning groups. We also aimed to determine if diuretic treatment during the weaning process may improve the success rate among patients who require prolonged ventilation.

Study design and setting.

This was a retrospective cohort study of patients on continuous, prolonged ventilation (≥ 14

days) that had at least one weaning attempt at Soroka University Medical Center (SUMC) between 2014 and 2023. This study was performed using the computerized database of the SUMC, a single center serving a population of 1.2 million residents in Southern Israel.

Study population

Our study included patients aged ≥ 18 years who were hospitalized in a respiratory rehabilitation unit inside the internal

medicine ward or the ICU, with the above inclusion criteria. Patients were excluded from the study if they had been on ventilation for < 14 days, were designated as do not resuscitate, had severe dementia, were bedridden, had end-stage lung or liver disease, or had active malignancies. Our study followed the principles of the Declaration of Helsinki and was approved by the Institutional Review Board at SUMC (#0164-23-SOR). The need for informed consent was waived as all data were retrospectively collected, and participants’ identities were kept strictly anonymous.

Study objectives

In this study, we primarily aimed to establish the success rate of weaning patients from mechanical ventilation after extended prolonged intubation and explore characteristics associated with weaning success or failure. Our primary outcomes were mortality and ventilation-free success rates. The secondary outcome was hospitalization LOS.

Data sources

Computerized data was extracted from the SUMC database, including demographic characteristics, diagnoses from hospitalizations, chronic illnesses, laboratory data, intubation

parameters, treatments administered, and clinical outcomes.

Statistical analysis

A descriptive analysis was initially performed, including the central tendency and distribution of the different variables of patient demographics, clinical background, laboratory findings, medications administered, and clinical outcomes. A univariate analysis was then conducted.

Pearson’s chi-square test or Fisher’s exact test, t-test, and Wilcoxson rank-sum test were performed to compare categorical variables, normally distributed continuous variables, and non-normally distributed continuous variables, respectively. Subsequently, multivariate logistic regression was performed while evaluating variation inflation factors. Variables were included in the regression based on domain expertise and univariate analysis. Notably, all statistical analyses were ‎conducted using R software version 4.2.0.

In our study, a cohort of 88 patients who required prolonged mechanical ventilation (defined as > 14 days) were subjected to weaning trials within the respiratory rehabilitation unit inside the Internal Medicine department. The cohort population was divided into two groups based on the success of the weaning process [success (SW) and failure (FW) groups]. Table 1 presents the baseline demographic characteristics of both groups, and the main reasons for intubation among patients of both groups are summarized in Table 2. Notably, no significant differences were identified regarding sex or social status, background diseases, or reasons for intubation in the SW and FW groups. However, the SW group was younger, with a median age of 64 years (range: 57−76), than the FW group, with a median age of 77 years (range: 67−82). Comparing the ventilation data between the two groups revealed that hypertension did not quite reach significance as a factor for weaning failure (P = 0.07). Other comorbidities, such as COPD, obesity, diabetes, and chronic ischemic heart disease, did not affect outcomes.

Table 3 presents the main outcomes among study individuals. Forty patients (45%) were successfully weaned off mechanical ventilation and subsequently discharged to rehabilitation facilities or directly to their residences. The mean length of hospitalization and duration of mechanical ventilation were 45 days (interquartile range: 32−59 days) and 31 days (interquartile range: 19−41 days), respectively. Notably, most patients in both groups underwent tracheostomy (78% and 79%).

The in-hospital mortality rate was 28% (25 patients). However, the all-cause mortality within 1 month and 1 year of discharge was 11% (10 patients) and 28% (20 patients), respectively. Furthermore, the length of mechanical ventilation was inversely associated with weaning outcomes, with the FW group requiring a median of 35 days of ventilation compared with 28 days in the SW group (P = 0.04).

Analysis of mechanical ventilation parameters during ventilation initiation (Table 4) indicated that higher average positive end-expiratory pressure values at admission were significantly associated with weaning failure [5.37 cmH₂O, standard deviation (SD) = 0.7, vs. 5.04 cmH₂O, SD = 0.54]. Furthermore, oxygen levels at any stage during hospitalization did not impact the outcomes. Regarding laboratory values upon admission, patients with anemia had significantly higher rates of weaning failure. The average hemoglobin level in the SW group was 10.1 g/dL (SD = 1.41) compared with 9.4 g/dL (SD = 1.39) in the FW group. However, renal function was significantly worse in the FW group, with an average creatinine level of 1.36 mg/dL (SD = 1.21) compared with 0.8 mg/dL (SD = 0.61) in the SW group. A significant difference in the serum albumin levels of both groups at admission (P < 0.005) was observed. Patients in the SW group had higher albumin levels, averaging 2.78 g/dL (SD = 0.4), compared with 2.36 g/dL (SD = 0.4) in the FW group (Table 2).Diuretic or anti-hypertensive treatment did not have an impact on the success rate of the weaning process; however, slightly better success rates (P = 0.09) with higher and prolonged use of diuretics during weaning trials were observed (Table 5).Table 6 and Figure 1 present logistic regression analysis data focused on parameters showing significant group differences to assess their predictive value for weaning outcomes. The findings indicated that low serum albumin levels were the sole parameter with a significant negative predictive value for weaning failure (OR = 7.27, P < 0.005). Age, renal function during early hospitalization, hypertension, anemia on admission, and diuretic treatment during the weaning process, which showed significant differences between both groups, did not show any independent significant association with the success of the weaning process after logistic regression analysis.

Prolonged weaning from mechanical ventilation is a complex problem associated with extreme consequences for patient health and quality of life. The inability to properly wean leads to complete reliance on long-term tracheostomy-assisted ventilation in a healthcare facility or at home, which is associated with a considerable decline in quality of life and reduced life expectancy. Patients who could not be weaned from mechanical ventilation had a 1-year mortality rate of approximately 75%, compared with a 15% rate among successfully weaned individuals. Notably, the weaning of approximately 25% of critically ill patients from mechanical ventilation exceeds 1 week. Moreover, 10% of patients still require ventilation 30 days after initiation [19]. This subgroup of patients accounts for approximately half of the resources used in the ICU. Therefore, many of these patients are subsequently transferred to specialized long-term care facilities designed for patients who need extended periods of prolonged ventilation. Within these dedicated institutions, weaning efforts persist, and success rates can sometimes be as high as 64% [20]. However, 20% of patients requiring prolonged ventilation remained dependent on non-invasive mechanical ventilation [21].

The current definition of prolonged mechanical ventilation, as delineated by the WIND study in 2016, is ventilation extending beyond 7 days [12]. Notably, we could not find any studies investigating this unique population (class 3B, according to the WIND classification). Therefore, our study population included patients who were on ventilation for at least 2 weeks and subsequently failed weaning from ventilation. Patients require tracheostomy after 2 weeks of mechanical ventilation to continue ventilation owing to the increased risk of prolonged oro-tracheal intubation. Notably, most patients who require mechanical ventilation through tracheostomy have poor weaning chances; therefore, most ICUs transfer such patients to respiratory rehabilitation units. Subsequently, these patients experience a chronic phase of illness after stabilization of their baseline medical reason for ICU hospitalization. Therefore, the focus on this long-weaning population could explain why the success rate of weaning was lower than that reported in other literature, as it included patients classified based on the 3B category according to the WIND criteria. This group differs from the patients described by Lago in Brazil [12] and Windisch in Germany [21].

In 2002 [2], Esteban demonstrated that specific underlying conditions, such as severe sepsis and multi-organ failure, particularly ARDS, necessitate prolonged mechanical ventilation. In addition, Boles, in his 2007 review, identified several predictors that impede successful weaning from mechanical ventilation. These predictors include respiratory diseases, neuromuscular disorders, cardiac function, nutritional status (low body mass), psychological state (presence of delirium), diaphragm function, hyperglycemia, anemia, metabolic acidosis, renal failure, and electrolyte imbalances [18, 22–24]. Pilcher et al. showed that the probability of successful weaning from extended mechanical ventilation was lower in patients with neuromuscular disorders or compromised chest wall integrity than in those with COPD. However, an inverse relationship was identified regarding mortality, and significantly higher mortality rates were observed in individuals with prolonged ventilation due to COPD than in those with neuromuscular disorders [3].

Consequently, the probability of predictors of weaning failure in patients on ventilation for > 14 days remaining consistent after such an extended weaning period remains unclear. Therefore, we primarily aimed to identify predictors of successful or unsuccessful weaning in patients undergoing prolonged mechanical ventilation. In a 2019 meta-analysis by Ghauri, COPD and renal insufficiency were identified as predictors of prolonged ventilation. Furthermore, similar findings were observed among patients who were on mechanical ventilation following neurovascular events and endovascular treatments. [22, 23, 25]

In our study, predictors of weaning failure included advanced age, duration of ventilation in the ICU, renal insufficiency at admission, and hypoalbuminemia, aligning with other reported findings [2, 21, 22]. However, logistic regression analysis revealed that hypoalbuminemia on admission was the only independent predictor of prolonged weaning failure with an OR of 7.27. Baseline renal function did not predict weaning outcomes as described in earlier studies. This finding may imply that underlying conditions may become less crucial in determining weaning outcomes for patients on mechanical ventilation for > 2 weeks.

Hypoalbuminemia has been recognized as a pivotal predictor of mortality in patients with shock undergoing extracorporeal membrane oxygenation (ECMO) therapy [26]. Nutritional status is a typical but crucial factor influencing weaning ability from mechanical ventilation. Furthermore, low body mass has been associated with weaning failure, a finding that aligns with the observation of hypoalbuminemia in our study. Therefore, the reason why hypoalbuminemia is the most significant predictor of weaning failure from mechanical ventilation may result from a multifactorial pathophysiology [27].

Increased risk of infections: Hypoalbuminemia elevates the risk of infections, sepsis, and multi-organ failure, particularly increasing the likelihood of ventilator-associated pneumonia. Conde's 2008 study [28] identified hypoalbuminemia as a predictor of postoperative pulmonary infections.

Altered pharmacokinetics and pharmacodynamics: The effectiveness of targeted antibiotic therapy is compromised due to hypoalbuminemia, affecting treatment efficacy [20].

Negative protein balance: Hypoalbuminemia leads to muscle breakdown and weakening of the respiratory muscles.

Increased thromboembolic events: Hypoalbuminemia increases the risk of thromboembolic events, including large arterial and venous events such as deep vein thrombosis and pulmonary embolism.

Indication of poor nutritional status: Hypoalbuminemia signifies poor caloric balance and malnutrition, often due to chronic illness.

Critical for wound healing: Albumin is essential for wound healing. The presence of pressure ulcers in patients with hypoalbuminemia reduces healing potential and worsens prognosis.

Therefore, a prospective follow-up study would be necessary to assess whether active treatment with albumin, either through jejunostomy feeding or daily intravenous administration, can improve weaning success rates.

In our investigation, we also aimed to examine whether diuretic treatment before the initiation of the weaning process enhances the weaning success rate. The weaning process in our institute includes diuretic treatment a few days before weaning efforts begin. Patients were treated with low doses of diuretics 3 days before initiating the weaning process. The rationale for this strategy was to decrease the light fluid overload accumulating in the lungs and soft tissues of the chest during prolonged ventilation. However, our statistical analysis completely dismissed the implications of diuretic use for improving the weaning success rate.

Our study has some limitations. It is a single-center, retrospective study; therefore, not all potential predictors of successful weaning from prolonged mechanical ventilation were examined. For example, diaphragm function is typically recognized as a significant factor in weaning success; however, we could not obtain comprehensive data on this parameter for all patients on ventilation.

Nevertheless, our study possessed notable strengths. The weaning process was standardized, as it was conducted at the same center by the same physicians using consistent protocols. Additionally, our study cohort was relatively large and particularly focused on patients who have been on ventilation for > 14 days, compared with other studies where prolonged ventilation was only one of several subgroups examined.

Hypoalbuminemia was the primary predictor of weaning failure in patients who were on ventilation for > 2 weeks, with at least two failed weaning attempts. However, the importance of predictors such as age and background diseases was diminished by prolonged intubation. Diuretic treatment before weaning initiation did not show improvement in the weaning success rate. Therefore, our study has significant therapeutic implications since daily albumin supplementation and a high-protein diet could be studied to determine whether they enhance weaning rates in a prospective study.

Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding:

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contribution

All authors reviewed the manuscript A.B - wrote the manuscript , O.M- collect data, statistical analysis, figures and tables . T.S- wrote the manuscript and collect data I.P-Statistical analysis and trial designing consultation N.P- collect dataC.B - designing, Treating all patients include in the trial.

Acknowledgement

Acknowledgments: We would like to thank Editage for the English-language editing.

Data sharing statement

Data supporting this study are available from the “Camilion” patient database system used in our hospital. Access to data is restricted to hospital medical staff only due to Israeli patient rights law. No new data were created or analyzed during this study. Data sharing is not applicable to this article.

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Table 1. Baseline demographic characteristics

	Overall, N = 88¹	Failure (N = 48)¹	Success (N = 40)¹	P-value²
Age	73 (63, 80)	77 (67, 82)	64 (57, 76)	0.002
Sex - Male	44 (50%)	24 (50%)	20 (50%)	>0.9
Weaning attempts	3.00 (1.00, 3.50)	3.00 (2.00, 4.00)	2.00 (1.00, 3.00)	0.026
Hypertension	51 (58%)	32 (67%)	19 (48%)	0.070
Dyslipidemia	43 (49%)	24 (50%)	19 (48%)	0.8
Ischemic Heart Disease	34 (39%)	22 (46%)	12 (30%)	0.13
Diabetes Mellitus	32 (36%)	18 (38%)	14 (35%)	0.8
COPD	23 (26%)	14 (29%)	9 (23%)	0.5
Obesity	22 (25%)	15 (31%)	7 (18%)	0.14
CKD	13 (15%)	7 (15%)	6 (15%)	>0.9
Malignancy	13 (15%)	9 (19%)	4 (10 %)	0.08
Pulmonary Hypertension	9 (10%)	6 (13%)	3 (7.5%)	0.5
Thyroid Dysfunction	7 (8.0%)	3 (6.3%)	4 (10%)	0.7
OSA	5 (5.7%)	2 (4.2%)	3 (7.5%)	0.7
Dementia	5 (5.7%)	4 (8.3%)	1 (2.5%)	0.4
Smoking	17 (19%)	7 (15%)	10 (25%)	0.2
Alcohol	9 (10%)	5 (10%)	4 (10%)	>0.9
Drug use	6 (6.8%)	2 (4.2%)	4 (10%)	0.4
Chronic steroid use	1 (1.1%)	0 (0%)	1 (2.5%)	0.5
¹ Median (IQR); n (%)
² Wilcoxon rank sum exact test; Pearson’s Chi-square test; Wilcoxon rank sum test; Fisher’s exact test

COPD: chronic obstructive pulmonary disease, CKD: chronic kidney disease, OSA: obstructive sleep apnea, IQR: interquartile range

Table 2. Main reasons for intubation

Characteristic	Overall, N = 88¹	Failure, N = 48¹	Success, N = 40¹	P-value²
Intubation Main Reason				0.036
Other	16 (18%)	9 (19%)	7 (18%)
Sepsis	15 (17%)	9 (19%)	6 (15%)
Pneumonia	14 (16%)	6 (13%)	8 (20%)
Respiratory Failure	9 (10%)	9 (19%)	0 (0%)
CVA	7 (8.0%)	2 (4.2%)	5 (13%)
Myocardial infarction	6 (6.8%)	4 (8.3%)	2 (5.0%)
Traumatic brain injury	6 (6.8%)	3 (6.3%)	3 (7.5%)
COPD Exacerbation	5 (5.7%)	1 (2.1%)	4 (10%)
Cardiac Arrest	4 (4.5%)	3 (6.3%)	1 (2.5%)
COVID-19	3 (3.4%)	2 (4.2%)	1 (2.5%)
Suicide	3 (3.4%)	0 (0%)	3 (7.5%)
¹ n (%)
² Fisher’s exact test

CVA: cerebrovascular accident, COPD: chronic obstructive pulmonary disease, COVID-19: coronavirus disease 2019

Table 3. Laboratory tests at the initiation of the intubation period

	Failure (N = 48)¹	Success (N = 40)¹	P-value²
First P/F ratio³	89 (65, 145)	142 (67, 250)	0.052
pCO2_first (mmHg)	48 (38, 57)	47 (40, 55)	0.7
pCO2_last (mmHg)	49 (39, 54)	43 (39, 51)	0.5
pCO2_mean (mmHg)	48 (41, 56)	45 (39, 54)	0.3
WBC (10³/µL)	10.5 (8.7, 12.3)	11.5 (9.6, 13.9)	0.3
Hemoglobin (g/dL)	9.30 (8.15, 10.68)	9.75 (8.90, 11.20)	0.086
Platelets (10³/µL)	282 (217, 372)	319 (227, 412)	0.2
Glucose (mg/dL)	123 (102, 191)	133 (117, 165)	0.5
Urea (mg/dL)	74 (49, 109)	43 (33, 82)	0.008
Creatinine (mg/dL)	0.85 (0.55, 1.40)	0.74 (0.43, 1.22)	0.12
Calcium (mg/dL)	8.21 (7.70, 8.59)	8.40 (8.10, 9.08)	0.066
Albumin (g/dL)	2.40 (2.15, 2.85)	2.70 (2.50, 3.20)	0.002
INR	1.17 (1.10, 1.39)	1.12 (1.07, 1.15)	0.066
¹ Median (IQR)
² Wilcoxon rank sum test ³ P/F ratio = pO2 (mmHg) / FiO2, fraction of inspired oxygen

INR: international ratio, IQR: interquartile range; WBC: white blood cell

Table 4. Outcome table

Characteristic	Overall, N = 88¹	Failure, N = 48¹	Success, N = 40¹	p-value²
Length of stay (days)	45 (32, 59)	39 (31, 56)	52 (32, 61)	0.10
Length of intubation (days)	31 (19, 41)	35 (25, 48)	28 (18, 37)	0.040
In-hospital tracheostomy	69 (78%)	38 (79%)	31 (78%)	0.8
ICU Days	15 (9, 25), n = 59	13 (9, 23), n = 32	16 (10, 26), n = 27	0.4
Mortality during hospitalization	25 (28%)	25 (52%)	0 (0%)	<0.001
All-cause mortality within 30 days since hospital discharge	10 (11%)	3 (6.3%)	7 (18%)	0.2
All-cause mortality within 1 year since hospital discharge	25 (28%)	12 (25%)	13 (33%)	0.4
Release status				<0.001
Mechanical Ventilation	23 (37%)	23 (100%)	0 (0%)
Non -support	23 (37%)	0 (0%)	23 (58%)
Oxygen	15 (24%)	0 (0%)	15 (38%)
Oxygen + BIPAP	2 (3.2%)	0 (0%)	2 (5.0%)
¹ Median (IQR); n (%); Median (IQR), n = N
² Wilcoxon rank sum exact test; Pearson’s Chi-square test; Wilcoxon rank sum test; Fisher’s exact test

ICU: Intensive Care Unit, IQR: interquartile range

Table 5. Medications administered during the intubation period

	Failure (N = 48)¹	Success (N = 40)¹	P-value²
Total amount of diuretic agents (mg)	560 (270, 1,125), n = 39	1,015 (295, 1,176), n = 28	0.3
Duration of diuretic administration (days)	13 (5, 26)	22 (13, 32)	0.078
Daily dose of diuretics (total amount/duration)	56 (38, 100)	42 (34, 55)	0.090
Duration of anti-hypertensive agent administration (days)	12 (6, 25)	19 (9, 27)	0.4
Duration of beta-blocker agent administration (days)	18 (10, 31)	21 (16, 28)	0.4
¹ Median (IQR), n = N; Median (IQR)
² Wilcoxon rank sum test; Wilcoxon rank sum exact test

IQR: interquartile range

Table 6. Logistic regression

Characteristic	OR¹	95% CI¹	p-value
Albumin	7.27	2.00, 34.6	0.006
Diuretic daily dose	0.98	0.96, 1.00	0.052
Urea	1.00	0.99, 1.01	0.8
First P/F ratio	1.00	1.00, 1.01	0.14
¹ OR: Odds Ratio, CI: Confidence Interval

No competing interests reported.

Predictors of weaning success from prolonged mechanical ventilation: A protocol study

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Main outcome measures:

Results

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Funding:

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Data sharing statement

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