Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Effects of early rehabilitation in sepsis patients by a specialized physical therapist in an emergency center on the return to activities of daily living independence: A retrospective cohort study

  • Yasunari Sakai ,

    Contributed equally to this work with: Yasunari Sakai, Shuhei Yamamoto, Tatsunori Karasawa, Masaaki Sato

    Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft

    yasunari_sakai1028@yahoo.co.jp

    Affiliation Department of Rehabilitation, Shinshu University Hospital, Matsumoto, Japan

  • Shuhei Yamamoto ,

    Contributed equally to this work with: Yasunari Sakai, Shuhei Yamamoto, Tatsunori Karasawa, Masaaki Sato

    Roles Conceptualization, Data curation, Investigation, Methodology

    Affiliation Department of Rehabilitation, Shinshu University Hospital, Matsumoto, Japan

  • Tatsunori Karasawa ,

    Contributed equally to this work with: Yasunari Sakai, Shuhei Yamamoto, Tatsunori Karasawa, Masaaki Sato

    Roles Data curation, Methodology

    Affiliation Department of Rehabilitation, Shinshu University Hospital, Matsumoto, Japan

  • Masaaki Sato ,

    Contributed equally to this work with: Yasunari Sakai, Shuhei Yamamoto, Tatsunori Karasawa, Masaaki Sato

    Roles Data curation, Methodology

    Affiliation Department of Occupational Therapy, School of Health Sciences, Shinshu University, Matsumoto, Japan

  • Kenichi Nitta ,

    Roles Data curation, Methodology

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of advanced emergency critical care center, Shinshu University Hospital, Matsumoto, Japan

  • Mayumi Okada ,

    Roles Data curation

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of advanced emergency critical care center, Shinshu University Hospital, Matsumoto, Japan

  • Kanako Takeshige ,

    Roles Data curation

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of advanced emergency critical care center, Shinshu University Hospital, Matsumoto, Japan

  • Shota Ikegami ,

    Roles Supervision, Writing – review & editing

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of Rehabilitation, Shinshu University Hospital, Matsumoto, Japan

  • Hiroshi Imamura ,

    Roles Supervision, Writing – review & editing

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of advanced emergency critical care center, Shinshu University Hospital, Matsumoto, Japan

  • Hiroshi Horiuchi

    Roles Supervision, Writing – review & editing

    ‡ KN, MO, KT, SI, HI and HH also contributed equally to this work.

    Affiliation Department of Rehabilitation, Shinshu University Hospital, Matsumoto, Japan

Abstract

Background

Early rehabilitation allows patients to better perform the activities of daily living after hospital discharge. A specialized physical therapist has been assigned as part of the early rehabilitation, but the effectiveness of the program remains unclear. We investigated how early rehabilitation provided by a specialized physical therapist affects ADL in patients with sepsis.

Methods

This was a retrospective cohort study. This study’s subjects were sepsis patients who entered the advanced emergency critical care center of Shinshu University Hospital between April 2014 and March 2020. Electronic medical records were reviewed to obtain information on demographic characteristics, severity score, primary source of infection, therapeutic medication, the number of days after hospital admittance until rehabilitation begins, length of hospital stay, discharge to home, and an assessment of daily living activities for each patient. The patients were divided into two groups based on whether they were treated before or after a specialized physical therapist had been hired by the advanced emergency critical care center.

Results

Assigning a physical therapist to a patient significantly shortened the number of days until rehabilitation began. In a multivariable model, the strongest predictors of return to independent living after hospital discharge were (1) assigning a specialized physical therapist (odds ratio = 2.40; 95% confidence interval = 1.09–5.79; P = 0.050) and (2) the number of days until rehabilitation started (odds ratio = 0.24; 95% confidence interval = 0.08–0.76; P = 0.014).

Conclusions

Assigning a specialized physical therapist to sepsis patients at an advanced emergency critical care center significantly shortened the number of days until a patient can begin rehabilitation after hospital admittance and improved activities of daily living after hospital discharge.

Trial registration

Trial registration [University Hospital Medical Information Network Clinical Trials Registry, number UMIN000040570 (2020/5/28).]

Background

Sepsis is a powerful systemic response to severe infection, and its incidence is estimated to be between 50 and 100 cases per 100,000 people in developed countries [1]. Sepsis patients have significantly worse functional outcomes in the physical and cognitive domains than age-matched healthy individuals [2] and other hospitalized patients [3]. A previous study showed that long-term cognitive and motor functions were significantly reduced in patients with severe sepsis compared to patients with mild or moderate sepsis [3].

Sepsis patients in the intensive care unit (ICU) can develop post-intensive care syndrome (PICS) [4], which is classified by a decline in physical, cognitive, or mental functions, and ICU-acquired weakness (ICU-AW) [5, 6]. ICU-AW occurs in 46% of critically ill patients with sepsis, multiple organ failure (MOF), or long-term ventilation [7]. These patients are often discharged to long-term physical rehabilitation facilities [8], which consume resources [9] and are costly [10]. It would be beneficial to develop strategies for sepsis patients to improve outcomes following hospitalization, and early rehabilitation interventions are preventive measures for PICS and ICU-AW.

In a previous study of 104 critically ill ICU patients, an early rehabilitation group (sedation interruption, extremity mobilization, and early activities of daily living training) was compared to a control group that had received standard care, using the Barthel Index (BI), which measures the capability to carry out the activities of daily living (ADL) (BI score: 75 points vs. 55 points, respectively); functional status was also significantly improved (59% vs. 35%) [11]. In addition, a large improvement in physical function was seen in a study of hospitalized patients who received early rehabilitation and active exercise at the bedside [1214]. These previous studies, however, included patients with a wide range of conditions: postoperative, with acute lung injury, in the ICU, or on ventilators. Studying a wide variety of diseases diminishes specificity, and few studies have focused solely on the rehabilitation of sepsis patients.

In 2018, a randomized controlled trial studied long-term rehabilitation methods limited to sepsis patients [15], but it the only result was that a beneficial effect was obtained in severely ill patients. We have already treated patients based on the Awakening and Breathing Coordination, Delirium monitoring / management, and Early exercise / mobility bundle [16]. Following the example of other countries, early mobilization and rehabilitation in Japan has made considerable progress and is now being implemented in many facilities. Then More and more facilities are assigning full-time physical therapists for the purpose of increasing clinical effectiveness and clinical efficiency.

Our hospital is also a specialized physical therapist has been assigned since April 2017 at the advanced emergency critical care center (AECCC) as a part of the promotion early rehabilitation. However, there are no studies to date that have shown the effects of assigning a specialized physical therapist, and the dilution of the significance of assigning a specialized physical therapist has become a problem in society.

We hypothesized that having a specialized physical therapist would increase the facilitation of early rehabilitation and have a more beneficial effect on the ADLs of critically ill sepsis patients. Therefore, we investigated how early rehabilitation provided by a specialized physical therapist affects ADL in patients with sepsis.

Methods

This was a retrospective cohort study. The outcome assessors and researchers were blinded to prevent bias. The information detailed below was collected from electronic medical records for each patient. In 2017, a specialized physical therapist was hired by the AECCC to promote early rehabilitation, and we compared outcomes from groups of patients treated before or after the specialist joined the staff. Patients in the treatment after assigning specialized physical therapist were admitted between April 2017 and March 2020, and patients in the before assigning specialized physical therapist were admitted from April 2014 to March 2017.

Sample size

Sample size calculations used the G*power 3.1. A sample size of 64 per group (total 128) was calculated with an effect size of 0.5 and 80% power with a type 1 error rate of 0.05 with a Bonferroni adjustment.

Patients

This study’s subjects were sepsis patients who entered the AECCC of Shinshu University Hospital between April 2014 and March 2020. Patients were included if they were 18 years or older, had received intensive treatment, and were diagnosed with sepsis (two or more criteria of a systemic inflammatory response plus proven or strongly suspected infection) [17], sepsis plus organ failure, or septic shock (sepsis with hypotension not responding to fluid management). To be enrolled, patients also needed to meet the criteria for baseline functional independence, defined a priori as a BI score ≥70, obtained from a proxy describing patient function before admission [18, 19]. Patients were excluded if they had head injuries, burns, spinal injuries, lower limbs with multiple fractures, septic shock unresponsive to treatment, or expected mortality within 48 hours. We recorded each patient’s age, gender, body mass index, sequential organ failure assessment score [20], systemic inflammatory response syndrome score [21], disseminated intravascular coagulation (DIC) score, laboratory data (procalcitonin), primary source of infection, use of therapeutic medication, use of mechanical ventilation, BI baseline and discharge, length of hospital stay, patients discharge outcome, and the number of days until rehabilitation after hospital admittance.

Physical rehabilitation content of the AECCC

We recorded data from the physical therapy sessions of both groups. Participants in both groups received standard AECCC care, which included physical therapy rehabilitation. Participants in the intervention arm worked with the specialized physical therapist hired by the hospital in 2017 and each was given an individualized therapy plan for physical rehabilitation that started on average 2.7 days after admission to the hospital. The therapy ran once or twice daily, for 20–40 min per session, until discharge from the AECCC. The therapy included pulmonary rehabilitation (deep breathing, periodic noninvasive ventilation, and supported cough), active and passive ranges of motion in both upper and lower extremities, getting out of bed, transfer, electrical muscle stimulation (EMS) (General Therapeutic Electrical Stimulator; Homer Ion Co., Tokyo, Japan), ambulation, and other mobilization techniques. Therapeutic interventions were continued regularly throughout the patient’s hospital stay, until he or she returned to a previous function, and/or was discharged. A safety audit was completed on patients in the intervention group during treatment. Recently published literature recorded patients who suffered falls, endotracheal tube removal, systolic blood pressure over 200 mmHg, systolic blood pressure less than 90 mmHg, and oxygen desaturation less than 80% [22]. In this study, we focused on these adverse events and developed a rehabilitation program.

Primary outcomes

Using the BI, participants were assessed objectively by the physical therapist for ADL recovery at discharge from the hospital [18, 19]. Using the parameters of previous studies, a BI of 70 points or more is defined as ADL independence [18].

Secondary outcomes

Secondary measures included length of hospital stay and discharge outcome.

Statistical analysis

Single variables were compared using a Student’s t test and a Mann-Whitney U test. Dichotomous outcomes were analyzed using a chi-square test. Moreover, we used logistic regression analysis to examine the relationship between therapy and return to independent ADL at hospital discharge. We performed multivariable analysis (logistic regression analysis) that included therapy by a specialized physical therapist and the number of days until rehabilitation began after hospital admittance. We used previous research as a reference to stratify the number of days until rehabilitation began (≤ five days vs. ≥ six days) [23, 24]. To avoid overfitting, we reduced all potential confounding factors, including treatment by the specialized physical therapist and the number of days until rehabilitation, to a single composite characteristic by applying a propensity score. The analyses were performed using the EZR statistical program (open-source software) [25]. Descriptive statistics (mean ± standard deviation or median [25%, 75%]) were calculated. All tests at P ≤ 0.05 were considered statistically significant.

Ethics

This study met the requirements for appropriateness to achieve the intended aims and complied with all ethical principles pertinent to this type of study design. All data were fully anonymized before the analyses. No informed consent was required due to the characteristics of the design and we obtained an opt-out format was adopted for all participants. The study was approved by the Ethics Committee of Shinshu University (No, 4161) and registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000040570 (2020/5/28). This study was conducted in accordance with the standards set forth by the latest revision of the Declaration of Helsinki.

Results

In total, 257 patients were diagnosed with sepsis and were entered the AECCC of Shinshu University hospital between April 2014 and March 2020. Of 145 (56.4%) sepsis patients that met inclusion criteria during the study period. 86 patients between April 2014 and March 2017 and 59 patients were recruited between April 2017 and March 2020 (Fig 1). There were no adverse events related to rehabilitation observed in this study.

thumbnail
Fig 1. Flow chart of study participation.

Two hundred fifty-seven subjects were in the initial patient pool. After exclusion criteria were applied, 145 subjects were included in the analysis.

https://doi.org/10.1371/journal.pone.0266348.g001

Adherence

There were no withdrawals during the study. All participants adhered to the protocol and remained in the study for an average of 33 days.

Demographics, AECCC, and hospital measures

The patients who underwent treatment with the specialized physical therapist had a significantly shortened period of days to begin the rehabilitation regimen compared to the control group (2.7 ± 1.6 days vs. 6.1 ± 5.8 days respectively, P<0.001, Fig 2). Table 1 compares the demographics of the treatment and control groups and shows significant differences in the DIC scores, medication use, BI at discharge, independent ADL rates, and length of hospital stay. Seventy-eight patients in the study returned to independent ADL at hospital discharge (independent ADL rate = 53.8%). Fig 3 shows the BI score distribution among the study patients at the time of hospital discharge.

thumbnail
Fig 2. The number of days until rehabilitation in patients with sepsis.

https://doi.org/10.1371/journal.pone.0266348.g002

thumbnail
Fig 3. Distribution of patients with sepsis by BI score at hospital discharge.

https://doi.org/10.1371/journal.pone.0266348.g003

thumbnail
Table 1. Demographic clinical characteristics in AECCC and hospital measures.

https://doi.org/10.1371/journal.pone.0266348.t001

Multivariate Logistic regression analysis

Table 2 shows the logistic regression analysis. According to the multivariable analyses, (1) assigning a specialized physical therapist (odds ratio = 2.40; 95% confidence interval = 1.09–5.79; P = 0.050) and (2) the number of days until rehabilitation (odds ratio = 0.24; 95% confidence interval = 0.08–0.76; P = 0.014) were significantly associated with the prevalence of return to independent ADL at hospital discharge.

thumbnail
Table 2. Logistic regression analysis of return to independent ADL at hospital discharge.

https://doi.org/10.1371/journal.pone.0266348.t002

Discussion

This study found that sepsis patients who received early rehabilitation with a specialized physical therapist had a significantly better return to independent ADL, BI at discharge, and shortened length of hospital stay. This suggests that treating sepsis patients by a specialized physical therapist improved rehabilitation awareness in the AECCC, increased rehabilitation requests, and enrichment team medical care. Logistic regression analysis showed that treatment by the specialized physical therapist and the number of days until rehabilitation after hospital admittance also predicted the return to independent ADL in sepsis patients. To our knowledge, this is the first study to examine sepsis patients and discuss the relationship between early rehabilitation by a specialized physical therapist and the return to independent ADL. As opposed to previous studies that examined the relationship between long-term rehabilitation and ADL recovery for septic patients [15], this study looked at short-term rehabilitation and ADL recovery. The physical therapy treatment at our center focused primarily on physical rehabilitation, which is the function measured by the BI.

In Europe and the United States, early mobilization is defined as physical activity that occurs within two to five days after admittance to a hospital in Europe and America [23, 24]; this is the period in which muscle mass degenerates due to immobility onset of disease, surgery, or acute exacerbation [26]. In this study, the duration time between admission and rehabilitation intervention by the specialized physical therapist was 2.7 ± 1.6 days, which can be considered to indicate that early rehabilitation was successful. In scientific studies, physical exercise for patients with sepsis has been found to improve physical function. In animal models of sepsis, physical exercise increased bacterial clearance from blood and organs, decreased the release of pro- and anti-inflammatory cytokines, and improved survival [27].

Assigning a specialized physical therapist is one method for reducing the number of days until rehabilitation begins, and it is easy to adopt in many hospitals. Furthermore, changes in vital signs during the rehabilitation therapy and laboratory data suggest that early rehabilitation therapy could be safely performed in sepsis patients who required intensive care or had worsening complications. However, in AECCC facilities without adequate numbers of well-trained staff, this level of rehabilitative support might be difficult.

This study’s results show that introducing early rehabilitation provided by a specialized physical therapist not only improved the BI score at discharge but also significantly increased return to independent ADL and shortened the length of hospital stay. In previous studies, one third of patients with sepsis had not returned to independent living after six months [28]. While the number of critically ill patients who survive after admittance to AECCC and ICU has increased, the number of patients who do not regain ADL at the time of discharge has also increased. If these patients need to go to a long-term rehabilitation center after hospital discharge, they face increased medical expenses and a strain on medical resources. They can also experience physical deterioration, which may lead to further complications and the necessity for hospital readmission [810, 28, 29]. Therefore, this study suggests that overall medical costs can be reduced by increasing the speed of return to ADL and shortening the length of hospital stay. However, there was no significant difference in the discharge to home. Most likely, this is because the family environment and social background of the patients influenced their discharge decisions.

Rehabilitation using EMS was performed for patients with difficulty in sitting up in bed and transfer before early rehabilitation was provided by a specialized physical therapist. The physiological effect of EMS on ICU patients, including those with sepsis, has been shown in previous studies; concentrated EMS in the ICU also induced systemic benefits on the microcirculation, which is closely related to endothelial function [30]. In our study, patients in both groups received EMS, so its individual effect is unknown, especially for subjects with difficulty leaving their beds. Introducing EMS in early rehabilitation can minimize ICU-AW.

The demand for early and intensive rehabilitation is increasing, especially in the fields of emergency and intensive care medicine. For effective and safe rehabilitation in the emergency room or ICU, there must be information sharing and discussion among the hospital’s medical staff members. Hospitals must commit to adding a specialized physical therapist for their critically ill patients in the emergency units and ICUs. Further research can demonstrate the importance of having this specialized therapy available to allow sepsis patients to return to independent ADL.

This study had limitations. First, we only included patients from a single center, which limits the validity of the study. Second, we did not assess cognitive or emotional status to evaluate the effects of this specialized physical therapy and the importance of returning to independent ADL after sepsis. Finally, details about the rehabilitation program and the effect of the amount of time spent with each patient are not discussed. Future clinical studies should include patients from multiple centers, and more details about the patient’s pre-hospitalization.

Conclusion

Assigning specialized physical therapists for sepsis patients at our AECCC significantly shortened the number of days until rehabilitation began after the patient was admitted to the hospital and improved the ADL at hospital discharge. Multivariate logistic regression analysis showed that the two factors predicting an independent ADL in sepsis patients were (1) assigning a specialized physical therapist and (2) the number of days between hospitalization and the beginning of rehabilitation. We that recommend this method will be easy to adapt for other centers and will be effective for their patients with sepsis. This study revealed that assigning a physical therapist as part of early rehabilitation may be more effective in achieving ADL independence in sepsis patients.

Acknowledgments

The authors are grateful to the paramedics, nurses, and staff of the Department of Rehabilitation at Shinshu University Hospital. The authors would like to thank Enago for the English language review.

References

  1. 1. Danai P, Martin GS. Epidemiology of sepsis: recent advances. Curr Infect Dis Rep. 2005 Sep;7(5):329–34. pmid:16107228
  2. 2. Hofhuis JG, Spronk PE, van Stel HF, Schrijvers AJ, Rommes JH, Bakker J. The impact of severe sepsis on health-related quality of life: a long-term follow-up study. Anesth Analg. 2008 Dec;107(6):1957–64. pmid:19020144
  3. 3. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27;304(16):1787–94. pmid:20978258
  4. 4. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med. 2012 Feb;40(2):502–9. pmid:21946660
  5. 5. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 Oct;10(10):931–41. pmid:21939902
  6. 6. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med. 2014 Apr 24;370(17):1626–35. pmid:24758618
  7. 7. Stevens RD, Dowdy DW, Michaels RK, Mendez-Tellez PA, Pronovost PJ, Needham DM. Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med. 2007 Nov;33(11):1876–91. pmid:17639340
  8. 8. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012 Mar;40(3):754–61. pmid:21963582
  9. 9. Dick A, Liu H, Zwanziger J, Perencevich E, Furuya EY, Larson E, et al. Long-term survival and healthcare utilization outcomes attributable to sepsis and pneumonia. BMC Health Serv Res. 2012 Nov 26;12:432. pmid:23181764
  10. 10. Weycker D, Akhras KS, Edelsberg J, Angus DC, Oster G. Long-term mortality and medical care charges in patients with severe sepsis. Crit Care Med. 2003 Sep;31(9):2316–23. pmid:14501962
  11. 11. Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009 May 30;373(9678):1874–82. Epub 2009 May 14 pmid:19446324
  12. 12. Burtin C, Clerckx B, Robbeets C, Ferdinande P, Langer D, Troosters T, et al. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009 Sep;37(9):2499–505. pmid:19623052
  13. 13. Adler J, Malone D. Early mobilization in the intensive care unit: a systematic review. Cardiopulm Phys Ther J. 2012 Mar;23(1):5–13. pmid:22807649
  14. 14. Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: a systematic review and meta-analysis. Crit Care Med. 2013 Jun;41(6):1543–54. pmid:23528802
  15. 15. Ahn JY, Song JE, Ann HW, Jeon Y, Ahn MY, Jung IY, et al. Effects of Early Exercise Rehabilitation on Functional Recovery in Patients with Severe Sepsis. Yonsei Med J. 2018 Sep;59(7):843–851. pmid:30091317
  16. 16. Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: the ’ABCDE’ approach. Curr Opin Crit Care. 2011 Feb;17(1):43–9. pmid:21169829
  17. 17. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296–327. pmid:18158437
  18. 18. MAHONEY FI, BARTHEL DW. FUNCTIONAL EVALUATION: THE BARTHEL INDEX. Md State Med J. 1965 Feb;14:61–5. pmid:14258950
  19. 19. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study. Int Disabil Stud. 1988;10(2):61–3. pmid:3403500
  20. 20. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707–10. pmid:8844239
  21. 21. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992 Jun;20(6):864–74. PMID: 1597042
  22. 22. Bailey P, Thomsen GE, Spuhler VJ, Blair R, Jewkes J, Bezdjian L, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med. 2007 Jan;35(1):139–45. pmid:17133183
  23. 23. Hodgson CL, Berney S, Harrold M, Saxena M, Bellomo R. Clinical review: early patient mobilization in the ICU. Crit Care. 2013 Feb 28;17(1):207. pmid:23672747
  24. 24. Cameron S, Ball I, Cepinskas G, Choong K, Doherty TJ, Ellis CG, et al. Early mobilization in the critical care unit: A review of adult and pediatric literature. J Crit Care. 2015 Aug;30(4):664–72. pmid:25987293
  25. 25. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transplant. 2013 Mar;48(3):452–8. pmid:23208313
  26. 26. Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Clinical review: Critical illness polyneuropathy and myopathy. Crit Care. 2008;12(6):238. pmid:19040777
  27. 27. Sossdorf M, Fischer J, Meyer S, Dahlke K, Wissuwa B, Seidel C, et al. Physical exercise induces specific adaptations resulting in reduced organ injury and mortality during severe polymicrobial sepsis. Crit Care Med. 2013 Oct;41(10):e246–55. pmid:23887230
  28. 28. Yende S, Austin S, Rhodes A, Finfer S, Opal S, Thompson T, et al. Long-Term Quality of Life Among Survivors of Severe Sepsis: Analyses of Two International Trials. Crit Care Med. 2016 Aug;44(8):1461–7. pmid:26992066
  29. 29. Goodwin AJ, Rice DA, Simpson KN, Ford DW. Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med. 2015 Apr;43(4):738–46. pmid:25746745
  30. 30. Prescott HC, Langa KM, Liu V, Escobar GJ, Iwashyna TJ. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014 Jul 1;190(1):62–9. pmid:24872085