Metabolic and hemodynamic responses to early passive range of motion in sedated critically ill adults

Abstract

Background

Passive range of motion (PROM) is a common early mobilization technique in intensive care, especially for sedated, mechanically ventilated patients. This study aimed to evaluate the effect of early PROM on oxygen consumption (VO₂) and carbon dioxide production (VCO₂) in mechanically ventilated critically ill adults.

Methods

A prospective observational cohort study was conducted in the tertiary ICU of a university hospital between May and September 2023. PROM was initiated within 24–48 hours of admission in hemodynamically stable, sedated patients (RASS: -2 to -4). A physiotherapist performed a standardized 10-minute PROM protocol. VO₂ and VCO₂ were measured via indirect calorimetry before, during, and after the intervention. Statistical analyses were conducted using a repeated-measures ANOVA, with the average level before and after the measurement, as well as the peak level of VCO₂ during the intervention. Cardiovascular parameters were also recorded.

Results

Twenty-three patients were included. PROM exercises showed a significant quadratic trend in VCO₂; F = 6.686, p = 0.017 and a borderline quadratic trend in VO₂ (F = 4.320, p = 0.050). Heart rate decreased significantly compared to baseline (P = 0.043). No significant change in blood pressure levels was observed.

Conclusion

Early PROM exercises in sedated, mechanically ventilated ICU patients induced a quadratic trend in VCO₂ and VO₂, indicating a temporary and reversible metabolic response. PROM does not cause any hemodynamic instability. It accelerates the elimination of metabolic waste and can be used as part of early rehabilitation protocols.

Background

Individuals with critical illness are at risk of developing a variety of complications due to the severity of their condition and extended stays in intensive care units (ICUs) [1]. These complications often include physical, cognitive, and psychological impairments that may persist long after hospital discharge, collectively known as post-intensive care syndrome (PICS) [2]. Approximately 50% of ICU survivors develop at least one symptom of PICS, posing significant challenges to long-term recovery [3]. As survival rates improve, minimizing the burden of PICS has become a key priority for clinicians, researchers, and families [4]. In response to these challenges, multidisciplinary teams have implemented evidence-based protocols such as the ABCDEF bundle to promote functional recovery and reduce adverse outcomes without increasing risk [5, 6]. Within this bundle, the letter “E” highlights the importance of early mobilization and exercise as a non-pharmacological intervention to improve patient outcomes in ICU settings [1, 7, 8].

Early mobilization includes a continuum of activities ranging from a passive range of motion (PROM) exercises to active ambulation [9]. PROM refers to joint movement conducted without patient participation and is often the primary intervention in sedated and mechanically ventilated individuals [10]. Although it is widely used in ICUs, the physiological responses it induces, particularly cardiorespiratory changes, remain insufficiently explored. Previous research on early mobilization has primarily assessed physiological parameters, such as blood pressure, heart rate, oxygen saturation, and respiratory rate [11]. Yet, PROM exercises may also impact metabolic variables like oxygen consumption and carbon dioxide production, which are vital for caloric estimation and understanding cardiopulmonary stress [12].

Despite its frequent use, limited evidence exists on how PROM affects dynamic cardiorespiratory parameters in critically ill adults. This gap in knowledge restricts our ability to individualize PROM protocols and ensure cardiopulmonary stability during interventions. Therefore, this study aimed to evaluate the cardiorespiratory responses to early PROM in mechanically ventilated adults in the ICU. A secondary aim was to determine whether these parameters remain within stable physiological limits.

Methods

Study design

This prospective observational cohort study was conducted in the tertiary intensive care unit (ICU) of Karadeniz Technical University, Farabi Hospital, between May and September 2023. Our ICU is a tertiary, mixed medical intensive care unit with a particular specialization in respiratory and critical care medicine. Most admissions consist of patients with acute respiratory failure, sepsis/septic shock, chronic obstructive pulmonary disease (COPD) exacerbations, pneumonia, mechanical ventilation–dependent respiratory disorders, and postoperative pulmonary complications. In addition, our unit routinely manages patients with multiple organ failure, neurological impairment requiring ventilation, and hemodynamic instability typical of a tertiary referral center. An observational design was chosen to examine the feasibility and physiological effects of early passive range of motion (PROM) exercises in critically ill adults prior to conducting large-scale randomized controlled trials (RCTs). A single-center structure ensured procedural consistency and real-time physiological data acquisition.

The study protocol was approved by the Ethics Committee of the Faculty of Medicine, Karadeniz Technical University (approval number: 2023/27), and written informed consent was obtained from all participants’ legally authorized representatives.

Participants

Eligible participants were adults requiring invasive mechanical ventilation with Richmond Agitation-Sedation Scale (RASS) scores between − 2 and − 4 to ensure that patients remained passive but not fully unresponsive. This range allowed prevention of voluntary muscle activation while preserving minimal arousal and autonomic reactivity, which is necessary to observe measurable cardiometabolic responses to PROM [13]. Inclusion criteria included hemodynamic stability and a minimum of 48 h in the ICU. Hemodynamic stability accepted as mean arterial pressure (MAP): ≥ 65 mmHg without recent fluctuations, Heart rate (HR): 50–120 bpm, vasopressor support: low-dose norepinephrine ≤ 0.1 µg/kg/min with no recent dose escalation, Cardiac rhythm: absence of new-onset arrhythmias (e.g., AF with RVR, VT, frequent PVCs), temperature: 36–38 °C, with no shivering or active cooling, and respiratory stability: SpO₂ ≥ 90% with unchanged ventilator settings in the preceding 30 min.

Exclusion criteria comprised acute neurological trauma, and cerebrovascular events, chest drain with air leakage, extracorporeal membrane oxygenation (ECMO), and renal replacement therapy to ensure both patient safety and validity of indirect calorimetry measurements. Additionally, FiO₂ values greater than 0.6 were excluded because levels above 0.6 indicate moderate-to-severe hypoxic respiratory failure. In such cases, even minor physiological stressors, such as limb manipulation or transient increases in oxygen demand, may cause desaturation or hemodynamic instability. PROM is routinely performed in our ICU only after adequate oxygenation is achieved; therefore, including patients requiring FiO₂ > 0.6 would have conflicted with standard clinical practice. Patients were enrolled after being clinically stable as determined by the attending intensivist. Additionally, to ensure intervention safety, we also applied prespecified pause/stop criteria during PROM. The intervention was immediately stopped if any of the following occurred: MAP < 60 mmHg or a drop > 20% from baseline, HR > 130 bpm, < 45 bpm, or new arrhythmia, SpO₂ < 88% or a fall > 5% from baseline, respiratory distress, ventilator asynchrony, or increased work of breathing, new agitation, posturing, shivering, or increase in sedation requirement, and any clinical concern raised by the attending nurse/physician.

Intervention

PROM was initiated within 24–48 h of ICU admission by the ABCDEF bundle recommendations. All procedures were performed by a physical therapist who had completed a four-year degree in physical therapy. Each procedure lasted 10 min and followed a standardized sequence:

• PROM_{1 − 2 mins}: Right shoulder flexion/abduction.

• PROM_{3 min}: Right elbow/wrist flexion-extension.

• PROM_4–5 mins: Right hip/knee flexion and abduction.

• PROM_{5 min}: Right ankle flexion-extension.

• PROM_6–7 mins: Left hip/knee flexion and abduction.

• PROM_{7 min}: Left ankle flexion-extension.

• PROM_8–9 mins: Left shoulder abduction and flexion.

• PROM_{10 min}: Left elbow/wrist flexion-extension.

PROM was conducted in the supine position on the first day the patient was deemed eligible. No sedation changes, repositioning, nutrition, or nursing interventions were allowed 30 min before and after PROM. All interventions were applied in the morning (10:00–12:00) to ensure standardization of metabolic conditions and minimize potential confounders that could influence indirect calorimetry measurements.

Data collection and measurements

Data was extracted from the hospital’s electronic health records and bedside logs by researchers blinded to the study hypothesis. Collected variables included demographics, diagnosis, sedation medications, and severity scores: Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores.

Indirect calorimetry (VO₂ and VCO₂) and cardiorespiratory measurements were obtained using the CARESCAPE™ Respiratory Module (E-sCAiOVX, GE HealthCare) integrated into both the CARESCAPE™ B650 and CARESCAPE™ B850 bedside monitoring systems. The module provides continuous breath-by-breath gas exchange analysis and is calibrated daily in our ICU in accordance with the manufacturer’s specifications. Measurements were administered 16 time points, including three minutes before intervention (T0, T1, T2), 10 min during intervention (T3 to T13, PROM_{1− 10 min}), and three minutes after intervention (T14, T15, T16).

Sample size calculation

Based on Medrinal et al.’s findings (15% change in cardiac output; effect size: 0.625), G*Power version 3.1.9.7 was used to determine that a sample of 18 participants would provide 80% power at α = 0.05 [14].

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA). Data distribution was assessed with the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation or median (interquartile range), as appropriate. We used a Repeated Measures Multivariate General Linear Model (GLM) to analyze changes in six physiological parameters (VO₂, VCO₂, HR, systolic and diastolic blood pressure, and tidal volume over time. Time was defined as an intra-subject factor at three levels: Time 1 (pre-exercise average, encompassing T0, T1, and T2), Time 2 (the peak metabolic point, PROM_6min), and Time 3 (post-exercise average, encompassing T14, T14, and T16). Within the statistical assumptions, Mauchly’s Test of Sphericity was performed; however, due to violation of this assumption for HR (p = 0.030) and TV (p = 0.033), Greenhouse–Geisser (GG) adjusted degrees of freedom were reported in the respective univariate analyses. Bonferroni-corrected pairwise comparisons were used to examine specific differences between the three-time levels and control for Type I error. Trend analysis, using polynomial contrasts on repeated measurement levels, was performed to identify systematic patterns of physiological change in response to the exercise load.

Results

Participant flow and characteristics

Between May and September 2023, 167 patients were screened in the ICU. Out of these, 30 patients receiving invasive mechanical ventilation and appropriate sedation levels (RASS scores between − 2 and − 4) were identified. Seven patients were excluded due to hemodynamic instability, presence of chest drain with air leaks, acute neurological events, or ECMO therapy (Fig. 1). Consequently, 23 patients were included, presenting with a variety of diagnoses, some of which were comorbid conditions. The most common clinical diagnoses were acute cardiac and cerebral vascular events (n = 13), such as cerebral hemorrhage, myocardial infarction and coronary artery disease. Additionally, respiratory problems (n = 10) included pneumonia, pulmonary edema, asthma, and COPD. Furthermore, there were eight cases of neuromuscular and chronic systemic insufficiencies, such as heart failure, neuromuscular diseases, and chronic kidney diseases. Lastly, surgical procedures and oncological diseases (n = 6) were observed, such as gastric perfusion, postoperative care, colectomy, leukemia and thymoma.

Fig. 1.

Flow chart for patient enrolment

Demographic and clinical characteristics

Participants’ mean age was 63 (Min-Max: 30–90) years, and 34.8% were male. The median APACHE II and SOFA scores were 21 (IQR: 15–23) and 7 (IQR: 5–10), respectively (Table 1). Primary diagnoses and baseline clinical parameters are summarized in Table 1.

Table 1.

Demographics, clinical Parameters, and baseline laboratory values

Demographic and Clinical Parameters	Values (n = 23)	Baseline Laboratory	Values (n = 23)
Age (years)/mean (min-max)	63 (30–90)	Midazolam, mg/h	0.032 (0–0.1.1)
Gender, male/female	15/8 (65.2%,34.8%)	Fentanyl, mcg/h	1.7 (0–5)
Height (cm)/mean (min-max)	169 (160–180)	Ketamin, mg/h	0.17 (0–1)
Weight (kg)/mean (min-max)	77 (55–100)	Vasopressor Use, no. (%)	18 (78%)
SOFA score/median (IQR)	7 (5–10)	Noradrenalin, mcg/kg/h	0.09 (0–0.5.5)
APACHE score/median (IQR)	21 (15–23)	ICU Stay, day/median (IQR)	6 (3–14)
RASS/median (IQR)	−4 (−4- −4)	IMV Duration, day	4 (2–11)
GCS/median (IQR)	4 (4–6)	Plt Count, x1000/uL/median (IQR)	196 (92–269)
Hgb, g/Dl/median (IQR)	9.2 (8.1–10)	WBC, x1000/mcL/median (IQR)	11 (8–15)
Neurologic	13 (56%)	CRP, mg/L/median (IQR)	152 (110–208)
Respiratory	10 (43%)
Methabolic	8 (35%)
Malignancy	6 (26%)

Abbreviations: SOFA Sequential Organ Failure Assessment, APACHE Acute Physiology and Chronic Health Evaluation, RASS Richmond Agitation-Sedation Scale, GCS Glasgow Coma Score, ICU Intensive care unit, IMV invasive mechanical ventilation, Hgb hemoglobin, Plt platelet, WBC White blood cell, CRP c-reactive protein

Metabolic response (VCO₂ and VO₂)

The analysis revealed a boundary significant main effect of time for VCO₂ (F (2,44) = 3.220, p = 0.050, η² = 0.128). Mauchly’s test indicated that the assumption of sphericity was met for VCO₂ (p = 0.315). Post-hoc Bonferroni-corrected pairwise comparisons showed that the difference between PROM_{6th min} (Mean = 203.000) and baseline (Mean = 188.362) approached significance (p = 0.155), while the difference between PROM_{6th min} and early resting (Mean = 189.812) also approached significance (p = 0.064). Furthermore, trend analysis confirmed a significant quadratic effect for VCO₂ (F (1,22) = 6.686, p = 0.017, η² = 0.233), indicating the expected rise, peak, and subsequent decline. The main effect of time for VO₂ was not statistically significant (F (2,44) = 1.821, p = 0.174, η² = 0.076), although a quadratic trend was observed at the boundary of significance (F (1,22) = 4.320, p = 0.050, η² = 0.164) (Tables 2 and 3, and Fig. 2) .

Table 2.

Estimated marginal means of physiological parameters across time points

Parameter	T1 (PrePROM)	T2 (Highest Point PROM6min)	T3 (PostPROM)
VCO₂ (ml/min)	275.32 ± 118.44	275.32 ± 118.44	275.32 ± 118.44
VO₂ (ml/min)	188.36 ± 77.28	188.36 ± 77.28	188.36 ± 77.28
HR (beats/min)	95.49 ± 4.33	92.30 ± 3.86	92.13 ± 3.96
Systolic BP (mmHg)	120.23 ± 18.22	120.23 ± 18.22	120.23 ± 18.22
Diastolic BP (mmHg)	63.78 ± 14.33	63.78 ± 14.33	63.78 ± 14.33
Tidal Volume (TV) (ml)	525.94 ± 95.93	525.94 ± 95.93	525.94 ± 95.93

Table 3.

Repeated measures ANOVA (Within-subjects effects and key contrasts)

Parameter	General Time Effect	p value	Partial η2	Trend	p value
VCO₂	F(2,44) = 3.220	0,050	0,128	Quadratic	0,017
Heart Rate	FGG​(1.56, 34.26) = 3.072	0,071	0,123	T1-T2 Pairwise	0,043
VO₂	F(2,44) = 1.821	0,174	0,076	Quadratic	0,050
Systolic BP	F(2,44) = 0.662	0,521	0,029	No	p > 0.05
Diastolic BP	F(2,44) = 0.228	0,797	0,010	No	p > 0.05
Tidal Volume (TV)	FGG​(1.57, 34.46) = 0.167	0,794	0,008	No	p > 0.05

Fig. 2.

Trajectory of Oxygen Consumption (VO2) and Carbon Dioxide Production (VCO2) showing the boundary significant quadratic trend across the three phases of the PROM intervention

Hemodynamic and ventilatory responses (HR, BP, TV)

The overall main effect of time was not significant for heart rate (p_GG​ = 0.071), systolic tension (p = 0.521), diastolic tension (p = 0.797), or tidal volume (p = 0.794). However, post-hoc Bonferroni-corrected pairwise comparisons revealed a significant difference in HR between baseline (Mean = 95.493) and PROM_6thmin (Mean = 92.304) (p = 0.043). This suggests a significant reduction in heart rate during the peak exercise time point compared to baseline. No significant differences were observed in systolic tension, diastolic tension, or tidal volume across any pairwise comparisons (p > 0.05), (Fig 3).

Fig. 3.

Changes in systolic and diastolic blood pressure, and tidal volume across measurement phases, highlighting the lack of a significant time effect during the intervention

Safety and adverse events

No significant adverse events such as extubation, tube displacement, hemodynamic instability, or desaturation were observed during or after PROM interventions.

Discussion

The primary aim of this study was to investigate the cardiorespiratory responses to early passive range of motion (PROM) exercises in adults with critical illness requiring invasive mechanical ventilation. A borderline significant time effect was observed on only VCO2, and no other parameters demonstrated a time effect in the repeated measure ANOVA. VCO₂ and VO₂ exhibited a markedly quadratic trend, with parameters peaking at the sixth minute of the intervention. Thereafter, a return to baseline levels during periods of rest was observed, indicative of a transient response. Conversely, heart rate exhibited a substantial decline at the same peak point as compared to its baseline levels in pairwise comparison. No clinically significant change was observed in systolic and diastolic blood pressure levels and tidal volume.

The observed increase in CO₂ production without a parallel rise in O₂ consumption suggests that active muscle contractions were unlikely to be responsible for this metabolic response. Typically, increased O₂ consumption accompanies active muscle contractions due to metabolic demand [15]. Instead, our findings suggest the increased CO₂ production might result from mobilizing venous blood reservoirs through passive limb movements against gravity. Wollersheim et al. reported similar findings, noting no change in O₂ consumption with increased CO₂ elimination during PROM exercises [16]. A recent meta-analysis supports this concept, suggesting PROM may prevent muscle wasting not through active muscle engagement but possibly via reduction in nitrosative stress and immune modulation [17]. One potential explanation for these results is that performing PROM exercises may increase the metabolic clearance of by-products, thereby reducing muscle loss in immobile patients [18, 19]. Unlike Wilkinson et al., who reported no change in VCO₂ with upper-limb PROM ergometry, our inclusion of lower-limb movements may explain the observed metabolic differences [20]. Indeed, the significant quadratic trend identified in the VCO2 analysis in our study provides statistical confirmation that the metabolic response is definable and reversible (transient), rapidly returning to the baseline after reaching its peak. The observation that the metabolic waste removed from the body increases during the initial six minutes and subsequently exhibits a downward trend prompts the question of whether the beneficial effects of PROM will also be apparent in short applications.

The study also demonstrated minimal hemodynamic responses during PROM, characterized by an initial rise followed by stabilization. Specifically, systolic blood pressure exhibited an initial increase, peaking at the sixth minute, corresponding with the completion of right-sided extremities and left hip PROM. Furthermore, our detailed analyses revealed a significant decrease in heart rate at the intervention’s peak compared to its baseline levels. This finding is critical in confirming that PROM does not trigger hemodynamic stress and reinforces its low-intensity nature. These transient changes align with previous findings by Medrinal et al., who observed similar cardiometabolic response patterns during initial phases of PROM [14]. Such transient increases may reflect acute physiological stress responses, highlighting the importance of initiating PROM exercises gradually and focusing initially on small (distal) joint mobilization to mitigate acute stress reactions [21, 22]. There is growing evidence that passive joint exercises do not significantly affect the haemodynamic stability of critically ill patients [23] even in patients receiving vasopressor support [24]. Muscle loss in critical illness has been linked to survival rates [25]. PROM exercises in sedated and ventilated critically ill patients could be used as an option to improve metabolic clearance and circulation and slow muscle breakdown.

Notably, no adverse events such as extubation, catheter removal, or hemodynamic instability occurred during the interventions, supporting previous evidence indicating that PROM is safe and feasible, even in patients receiving low-dose vasopressor support [26, 27]. Our protocol demonstrated minimal clinically relevant hemodynamic changes, suggesting PROM can be safely applied in the ICU if appropriate precautions and patient-specific adjustments are observed.

However, several limitations must be noted. Although statistical power analysis indicated adequate sample size, the generalizability of findings may be limited due to the relatively small and homogenous sample. Additionally, muscle blood flow or muscle activity measurements (e.g., electromyography) were not performed, which could have provided more profound insights into the observed metabolic changes.

Future studies should address these limitations by incorporating electromyographic measurements during PROM to investigate the underlying mechanisms more thoroughly. Further research is needed to determine the optimal duration and intensity of PROM exercises for maximizing metabolic benefits and minimizing muscle atrophy in patients with limited mobility, using more comprehensive assessment tools.

Conclusion

The results of this study suggest that PROM exercises have significant quadratic trend on VCO2 and VO2, and significant decrease effect on heart rate in critically ill adults requiring sedation and mechanical ventilation. The temporary metabolic shifts observed highlight PROM’s potential role in enhancing metabolic clearance in immobilized patients. All observed cardiorespiratory responses remained within clinically acceptable ranges, underscoring the safety of PROM interventions in ICU practice. Further studies should investigate muscle activity and varying exercise sequences to optimize early mobilization protocols.

Abbreviations

APACHE

Acute Physiology and Chronic Health Evaluation

ECMO

Extracorporeal Membrane Oxygenation

COPD

Chronic obstructive pulmonary disease

ICU

Intensive care unit

ICU-AW

ICU-acquired weakness

PICS

Post-intensive care syndrome

PROM

Passive range of motion

(RASS)

Richmond Agitation-Sedation Scale

SOFA

Sequential Organ Failure Assessment

Authors’ contributions

TA, AOK, and MPK conceptualized the study. Data collection was supervised by AOK, ÖFŞ, and MPK, and analysis was conducted by UA. The manuscript was conceptualized by TA, UA, and ÖFŞ and drafted by AOK and MPK. All authors contributed to revising the manuscript and approval of the final version. All authors read and approved the final manuscript.

Funding

None.

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the Ethics Committee of The Faculty of Medicine, Karadeniz Technical University, on 14 April 2023 (2023/27). This study was conducted following the tenets of the Declaration of Helsinki. Informed consent was obtained from a legally authorized representative of each unconscious patient before enrolment. The legally authorized representatives were informed about the purpose of the study, the methods, the potential risks and benefits, and their rights regarding participation. The confidentiality of the data collected and the patient's privacy were protected. The legally authorized also had the option to withdraw from the study at any time.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.