Acute outcomes and 1-year mortality of ICU-acquired weakness. A cohort study and propensity matched analysis

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1 Acute outcomes and 1-year mortality of ICU-acquired weakness A cohort study and propensity matched analysis Greet Hermans, Helena Van Mechelen, Beatrix Clerckx, Tine Vanhullebusch, Dieter Mesotten, Alexander Wilmer, Michael P. Casaer, Philippe Meersseman, Yves Debaveye, Sophie Van Cromphaut, Pieter J. Wouters, Rik Gosselink, Greet Van den Berghe Online data supplement

2 Methods Patients All patients were included in the EPaNIC trial. This randomized controlled trial compared early (within 48 h) with late (not before day 8 in the intensive care unit) parenteral supplementation of insufficient enteral nutrition in 4640 critically ill patients from 7 units in 2 centers (the University Hospitals Leuven and Jessa Hospitals Hasselt, Belgium) 1. Patients were excluded if <18 years of age, moribund or DNR-coded, were enrolled in another trial, had short-bowel syndrome, received home ventilation, were in diabetic coma, were referred to the ICU with nutritional regimen, were pregnant or lactating, had no central line, were taking oral nutrition, were readmitted to the ICU, had BMI below 17 or nutritional risk score below 3, had other reason, or lack of consent. Randomisation was performed in a 1:1 ratio, stratified according to 16 diagnostic categories. Initially, sequentially numbered, sealed, opaque envelopes were used in permuted blocks of 10 per stratum, after addition of the Jessa Hospitals this was switched to an identical digital system. Treating physicians and nurses were unaware of the block size. Both intervention arms received early parenteral trace elements, minerals and vitamins. Blood glucose was targeted between 80 and 110 mg/dl. Early initiation of enteral nutrition was attempted in both groups. In the early PN group, 20% of glucose was administered targeting a total energy intake of 400 kcal on D1 and 800 kcal on D2. On the third day, parenteral nutrition was started aiming to reach the caloric goal through combined enteral and parenteral intake. In the late PN group, 5% of glucose solution was administered in a volume equal to the amount of PN given in the early PN group. If enteral nutrition was still deficient after 7 days of ICU stay, PN was started at day 8 targeting the calculated caloric goal. Written informed consent was obtained from the patients or next-of-kin and the protocol was approved by the KU Leuven Institutional Review Board (ML4190). From December 2008, consecutive patients who were still in the ICU on day 8 (±1 day) were evaluated 3 times weekly for awakening and cooperation until ICU discharge or death. We focused on the long- E2

3 stay patients because they were considered at increased risk for developing ICUAW. The cut-off of 8 days was arbitrarily chosen as previously 2;3. Five standard commands were used for this purpose as previously reported 4. Providing correct response to all of these, muscle strength was then assessed using the MRC sum score. Patients were excluded if contra-indications for measurement were present (medical instability), in case of preexisting neuromuscular disease, if they never awakened at the planned evaluation points, spoke a language not understood by the assessor, could not be assessed because the assessor was unavailable or if they declined participation. Diagnosis of weakness The MRC sum score was determined as previously described 5;6. In summary, 6 muscle groups of upper and lower limbs bilaterally (abduction of the arm, flexion of the forearm, extension of the wrist, flexion of the hip, extension of the knee, dorsal flexion of the foot) were scored between 0 and 5 (0: no visible/palpable contraction; 1: visible/palpable contraction without limb movement; 2: limb movement only with gravity eliminated; 3: limb movement possible against gravity but not against resistance; 4: subnormal contraction against resistance; 5: normal muscle strength). When added, this results in a maximum score of 60. Clinically relevant weakness was diagnosed when the MRC sum score was lower than Measurements were performed by one of two physiotherapists (BC and TV) who were extensively trained before the start of the study. This resulted in good interobserver reliability as reported before 5. As more severe weakness was previously suggested to be related to worse prognosis 7, we examined the impact of persisting weakness as well as its severity at last evaluation in the ICU on 1y mortality. For this purpose, we used an additional cut-off of 36, which we previously chose arbitrarily 5. Measurement of maximal inspiratory pressure E3

4 At the same 3-weekly evaluation points, in patients who were awake and cooperative and had no artificial airway, we measured maximal static inspiratory pressure (MIP) according to the ATS guidelines 8. Measurements were performed by the same experienced physiotherapists (TV and BC), specifically trained for this by pulmonary lung function technicians. We used a mouth piece that incorporated a small leak to prevent glottic closure during the inspiratory manoever. Pressures were measure with the Micro Medical respiratory pressure meter, CareFusion using Puma PC software. The patient was asked to perform a maximal inspiratory maneuver starting from FRC. Maximal static inspiratory pressure was determined as the mouth pressure measure at the side port of a mouth piece, maintained for 1 second. The best of 3 consecutive measurements was recorded. Contra-indications consisted of flail chest, pneumothorax, hemodynamic instability, intracranial hypertension, respiratory distress or high flow oxygen therapy. In a number of patients, measurement was initiated, but failed to produce a value. These were categorized according to predefined categories: anxiety, occurrence of desaturation or hemodynamic instability during the manoever, inability to avoid leak at the mouth piece or other. Physiotherapy All patients received progressive and systematic passive and active mobilization adapted to the medical situation, muscle strength and the level of cooperation. This was started on the second day of ICU admission and included passive/active range of motion, resistance training of arms/legs, passive/active bedcycling, sitting at the edge of the bed or chair, standing and eventually walking. This was provided to the best of the physiotherapists abilities. We did not record the number of sessions or duration of sessions provided. Rehabilitation after ICU discharge was left at the discretion of the treating medical team. Baseline characteristics and risk factors E4

5 BMI categorization We chose to group patients with BMI<25 and >40 as this was a pre-specified subgroup in the EPaNIC protocol 1;9 considered at increased risk for death. This choice was made, based on literature suggesting that patients with normal to high BMI have better outcome than patients with extremely high or low BMI We therefore categorized and matched patients according to the presence or absence of this BMI-related risk factor, as one among other risk factors for poor prognosis. As matching patients with BMI <25 and those with BMI >40 could possibly be problematic, we further performed sensitivity analysis by repeating the matching procedure in which BMI was further subdivided for BMI <25 and BMI >40 and recalculated the primary outcome measures. Conclusions remained unchanged (data not shown). New infections New infections were defined as infections not present on admission and included respiratory tract infections, urinary tract infections, wound infections, blood stream infection or other infections, all requiring antibiotic treatment 1. Neuromuscular blocking agents and corticosteroids NMBA exposure included the single use for intubation. NMBA use was dichotomized, similar as in Fan et al. 14 because administration was limited in time (median duration: 0 days, IQR: 0-1days). The substantial amount of patients receiving multiple days of corticosteroids (median duration: 1 day, IQR 0-8days) urged us to take this into consideration by including this as a continuous variable. Post-hoc analysis of discharge destination We performed a retrospective chart review to determine discharge destination of the survivors. This was categorized as discharged home, discharged to other hospital and discharged to a rehabilitation E5

6 unit. This data extraction was performed by investigators blinded for MRC results. We need to stress that in Belgium there is no culture of transferring ICU patients to rehabilitation units, as the capacity of rehabilitation beds is very limited. Patients generally will receive home based rehabilitation according to their needs. Patients are only transferred to rehabilitation units in case of extremely limited physical function. Post-hoc exploratory analysis of circumstances of ICU and hospital deaths We performed a post-hoc exploratory and therefore inevitably retrospective review of the files of the patients who died during their ICU or hospital stay. This included review of the physicians and nurses notes and the patient data management system. We report readmissions, recurrent respiratory failure as defined by resumption of mechanical ventilation after 48 hours of discontinuation and whether tracheostomy was performed. We also sought for any indication of aspiration in the files and also noted whether any formal swallowing evaluation was performed. We extracted the main cause of death and noted presence or absences of do-not-resuscitate order prior to death. This data extraction was performed by investigators blinded for MRC results. Results Respiratory muscle strength Maximal inspiratory pressure (MIP) was measured in fewer weak than not-weak patients (41.8% versus 62.3%, p=0.001). Reasons for not receiving MIP measurement were similar among weak and not-weak patients, and significance for time to MIP (p=0.088) and MIP values (0.079) was lost in the matched population (see table E3). Circumstances of ICU and in-hospital deaths E6

7 Though statistically more weak patients were DNR coded at the time of death (p=0.044), the vast majority of patients died because care was withdrawn. No significant difference was detected in the incidence of readmissions, recurrence of respiratory failure, possible aspiration, tracheostomy or cause of death (see table E4). These data are limited by their retrospective nature and by the low statistical power as only 12 deaths occurred in not-weak patients. We note that in both cases of cardiac arrest in weak patient, files indicated that the arrest was due to aspiration and hypoxia. Both patients had severe hypoxemic brain damage following CPR and were DNR coded prior to death. No such connection was made in the 2 patients with cardiac arrest in the notweak group. 4 weak versus no not-weak patients received a DNR code and subsequently died because of what is described as in the files as general deterioration and weak condition. Also, 7 weak versus no not-weak patients died due to documented respiratory failure, including the inability to clear secretions and hypoxic/hypercapnic respiratory failure. All of these patients had a no reintubation code. E7

8 Reference List E1. Casaer, M. P., D. Mesotten, G. Hermans, P. J. Wouters, M. Schetz, G. Meyfroidt, C. S. Van, C. Ingels, P. Meersseman, J. Muller, D. Vlasselaers, Y. Debaveye, L. Desmet, J. Dubois, A. A. Van, S. Vanderheyden, A. Wilmer, and G. Van den Berghe Early versus late parenteral nutrition in critically ill adults. N.Engl.J Med. 365: E 2. Hermans, G., A. Wilmer, W. Meersseman, I. Milants, P. J. Wouters, H. Bobbaers, F. Bruyninckx, and G. Van den Berghe Impact of Intensive Insulin Therapy on Neuromuscular Complications and Ventilator-dependency in MICU. Am J Respir Crit Care Med. 175: E 3. Van den Berghe, G., K. Schoonheydt, P. Becx, F. Bruyninckx, and P. J. Wouters Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64: E 4. De Jonghe, B., T. Sharshar, J. P. Lefaucheur, F. J. Authier, I. Durand-Zaleski, M. Boussarsar, C. Cerf, E. Renaud, F. Mesrati, J. Carlet, J. C. Raphael, H. Outin, and S. Bastuji-Garin Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 288: E 5. Hermans, G., Clerckx, B., Vanhullebusch, T., Segers, J., Vanpee, G., Robbeets, C., Casaer, M. P., Wouters, P., Gosselink, R., and Van den Berghe G. Inter-observer agreement of MRC-sum score and handgrip strength in the intensive care unit. 31st International Symposium on Intensive Care and Emergency Medicine Brussels Ref Type: Abstract E8

9 E 6. Hermans G, M. P. Casaer, B. Clerckx, Guiza F, T. Vanhullebusch, S. Derde, P. Meersseman, Derese I, D. Mesotten, Wouters P, S. Van Cromphaut, Y. Debaveye, R. Gosselink, J. Gunst, A. Wilmer, Van den Berghe G, and I. Vanhorebeek Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. The Lancet Respiratory Medicine 1: E 7. De Jonghe, B., S. Bastuji-Garin, M. C. Durand, I. Malissin, P. Rodrigues, C. Cerf, H. Outin, and T. Sharshar Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med. 35: E ATS/ERS Statement on respiratory muscle testing. Am.J.Respir.Crit Care Med. 166: E 9. Casaer, M. P., G. Hermans, A. Wilmer, and Van den Berghe G Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial. Trials 12:21. E 10. Alberda, C., L. Gramlich, N. Jones, K. Jeejeebhoy, A. G. Day, R. Dhaliwal, and D. K. Heyland The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study. Intensive Care Med. 35: E 11. Langouche, L., S. V. Perre, S. Thiessen, J. Gunst, G. Hermans, A. D'Hoore, B. Kola, M. Korbonits, and B. G. Van den Alterations in adipose tissue during critical illness: An adaptive and protective response? Am J Respir Crit Care Med. 182: E 12. Nasraway, S. A., Jr., M. Albert, A. M. Donnelly, R. Ruthazer, S. A. Shikora, and E. Saltzman Morbid obesity is an independent determinant of death among surgical critically ill patients. Crit Care Med. 34: E9

10 E 13. O'Brien, J. M., Jr., G. S. Phillips, N. A. Ali, M. Lucarelli, C. B. Marsh, and S. Lemeshow Body mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury. Crit Care Med. 34: E 14. Fan, E., D. W. Dowdy, E. Colantuoni, P. A. Mendez-Tellez, J. E. Sevransky, C. Shanholtz, C. R. Himmelfarb, S. V. Desai, N. Ciesla, M. S. Herridge, P. J. Pronovost, and D. M. Needham Physical Complications in Acute Lung Injury Survivors: A 2-Year Longitudinal Prospective Study. Crit Care Med. 42(4): E10

11 Table E1: Main admission categories Cardiac surgery (elective or urgent) 116/415 (28.0%) Medical ICU 89/415 (21.4%) Elective admission after other surgery 14/415 (3.4%) Emergency admission after other surgery, burns, trauma 196/415 (47.2%) Table E2: Outcome data for long-stay patients that received MRC sum evaluation as compared to those who never awakened Received MRC sum score Never awakened P-value N=415 N=257 Time to alive ICU discharge, days median (IQR)* 17 (11-30) 19 (11-283) ICU mortality, % 23 (5.5) 81 (31.5) <0.001 Time to alive hospital discharge, days, median (IQR)* 45 (27-93) 94 (31-380) <0.001 Hospital mortality, % 58 (14.0) 115 (44.7) <0.001 *Time to events were calculated from ICU admission Table E3: Respiratory muscle strength using volitional measurement of maximal inspiratory pressure in patients without artificial airway Total population Matched population Unmatched population weak (n=227) not-weak (n=188) p-value Weak (n=122) not-weak (n=122) p-value Weak (n=105) *p-value First MIP available 97 (42.7) 126 (67) < (41.8) 76 (62.3) (43.8) First MIP, reasons not available tracheostomy/ett refusal medical contra-indication failure of measurement 59 (45.4) 3 (2.3) 11 (8.5) 57 (43.8) 22 (35.5) 1 (1.6) 6 (9.7) 33 (53.2) (38.0) 2 (2.8) 6 (8.5) 36 (50.7) 18 (39.1) 1 (2.2) 4 (8.7) 23 (50.0) (54.2) 1 (1.7) 5 (8.5) 21 (35.6) First MIP (cmh2o) -22 (-32 to -16) -31 (-43 to -21) < (-34 to -16) -30 (-39 to -19) (-31 to -16) Time to first MIP (days) 15 (11-22) 10 (8-13) < (10-21) 11 (9-16) (12-27) Abbreviations: MIP: maximal inspiratory pressure. *p value for not-matched versus matched weak patients 0.293

12 Table E4: Circumstances of death for ICU and hospital non-survivors Place of death Readmission to ICU Recurrent respiratory failure 1 Presumed aspiration Swallowing evaluation (FEES) Main cause of death DNR order DNR specification Patient Tracheostomy Not weak 1 ICU no yes no no NA brain death/irreversible neurological damage yes care withheld 2 ward no no no no NA cardiac arrest no 3 ward no no no yes NA cardiac arrest no 4 ICU no no no no NA cardiac failure yes care withdrawn 5 ward yes yes no yes abnormal cardiac failure yes care withdrawn 6 ICU no yes yes no NA fatal surgical complication yes care withdrawn 7 ICU no yes yes no NA MOF/irreversible shock yes care withdrawn 8 ICU no yes yes no NA MOF/irreversible shock yes care withdrawn 9 ward yes yes no yes NA MOF/irreversible shock yes care withdrawn 10 ward yes yes no no NA MOF/irreversible shock yes care withdrawn 11 ward yes yes no yes abnormal progression underlying disease (ILD/malignancy) yes care withheld 12 ward no no no yes NA progression underlying disease (ILD/malignancy) yes care withheld Weak 13 ward yes yes no no NA brain death/irriversible neurological damage yes care withheld 14 ward no yes no yes NA brain death/irriversible neurological damage yes care withheld 15 ward yes yes no yes NA brain death/irriversible neurological damage yes care withdrawn 16 ICU yes yes no yes NA cardiac arrest 2 yes 2 care withdrawn 17 ward no yes no yes abnormal cardiac arrest 2 yes 2 care withheld 18 ICU no yes no no normal cardiac failure yes care withdrawn 19 ICU no no no yes NA cardiac failure yes care withdrawn 20 ward yes yes yes yes NA cardiac failure yes care withdrawn 21 ward no no yes no NA cardiac failure yes care withheld 22 ICU no yes no yes NA fatal surgical complication yes care withdrawn 23 ward yes yes no no NA general deterioration and weak condition yes care withheld 24 ward yes yes no yes NA general deterioration and weak condition yes care withheld 25 ward no no yes yes NA general deterioration and weak condition yes care withdrawn 26 ward no yes no yes abnormal general deterioration and weak condition yes care withdrawn 27 ICU no yes yes no NA MOF/irreversible shock yes care withdrawn 28 ICU no yes yes no NA MOF/irreversible shock yes care withdrawn 29 ICU no no no yes abnormal MOF/irreversible shock yes care withdrawn

13 30 ICU no no no no NA MOF/irreversible shock yes care withheld 31 ICU no yes yes no NA MOF/irreversible shock yes care withdrawn 32 ICU no yes no yes NA MOF/irreversible shock yes care withheld 33 ICU no no no no NA MOF/irreversible shock yes care withheld 34 ICU no yes yes no NA MOF/irreversible shock yes care withheld 35 ICU yes no yes no NA MOF/irreversible shock yes care withdrawn 36 ICU no no yes no NA MOF/irreversible shock yes care withdrawn 37 ICU no no yes yes NA MOF/irreversible shock yes care withheld 38 ward yes yes no yes abnormal MOF/irreversible shock yes care withdrawn 39 ward yes yes no yes NA MOF/irreversible shock yes care withdrawn 40 ward no yes yes yes abnormal MOF/irreversible shock yes care withheld 41 ICU no yes no yes NA Other 3 yes care withdrawn 42 ward yes no no no NA Other 3 yes care withheld 43 ward no no no no NA Other 3 yes care withdrawn 44 ICU no yes no no NA progression underlying disease (ILD/malignancy) yes care withdrawn 45 ICU no yes no no NA progression underlying disease (ILD/malignancy) yes care withdrawn 46 ward no yes no no NA progression underlying disease (ILD/malignancy) yes care withheld 47 ward no no no no NA progression underlying disease (ILD/malignancy) yes care withheld 48 ward yes yes no no NA progression underlying disease (ILD/malignancy) yes care withheld 49 ward no no no no NA progression underlying disease (ILD/malignancy) yes care withheld 50 ward yes yes no yes abnormal respiratory failure yes care withheld 51 ward yes yes no no NA respiratory failure yes care withheld 52 ward no no no yes NA respiratory failure yes care withheld 53 ward no no no no abnormal respiratory failure yes care withheld 54 ward yes no no yes abnormal respiratory failure yes care withheld 55 ward yes yes yes yes NA respiratory failure yes care withheld 56 ward no yes no yes NA respiratory failure yes care withdrawn 57 ward yes yes yes yes abnormal unwitnessed death no 58 ward no no yes yes NA unwitnessed death yes care withheld 1 Recurrent respiratory failure is defined by resumption of invasive mechanical ventilation following at least 48h of spontaneous breathing 2 DNR code because of irreversible hypoxemic brain damage following CPR 3 Other involves: dissiminated mucor mycosis/treatment refusal/nonresolving ARDS DNR: do not resuscitate, FEES: fiberoptic endoscopic evaluation of swallowing, ILD: interstitial lung disease, MOF: multiple organ failure, NA: not assessed

14 Table E5: Healthcare cost split by major cost categories Total population Matched population Unmatched population weak (n= 227) not-weak (n= 188) p-value weak (n=122) not-weak (n=122) p-value ICUAW (n=105) *p-value Total hospital stay Fees 9,110 (5,372-14,187) 6,780 (3,459-9,426) < ,289 (4,666-11,458) 7,232 (3,607-10,392) ,938 (6,475-18,643) Pharmacy 6,316 (3,148-13,398) 4,220 (1,895-8,059) < ,593 (2,494-9,866) 4,326 (2,326-8,251) ,905 (3,674-18,011) Hospitalization 3,451 (2,086-5,285) 2,309 (1,628-3,710) < ,834 (1,955-4,570) 2,324 (1,613-3,442) ,683 (2,212-6,045) costs (PD) Blood Products 1,774 (646-3,977) 961 (215-2,396) < ,522 (577-3,376) 1,098 (400-2,930) ,184 (804-4,415) Clinical Chemistry 2,194 (1,374-3,282) 1,326 (871-2,271) < ,840 (1,146-2,972) 1,554 (947-2,388) ,730 (1,683-4,297) <0.001 Radiology 1,125 (663-1,845) 663 (443-1,028) < (607-1,595) 699 (473-1,115) ,243 (811-2,013) Miscellaneous 22 (0-106) 9 (0-100) (0-104) 9 (0-99) (0-112) Graft products 0 (0-0) 0 (0-0) (0-0) 0 (0-0) (0-0) Total 26,348 (16,637-44,519) 17,356 (11,507-30,205) < ,277 (15,369-36,147) 17,834 (12,227-31,306) ,334 (19,866-60,331) <0.001 Period 1 (ICU) Fees 7,588 (4,297-12,159) 5,077 (2,703-7,683) < ,814 (3,128-9,590) 5,997 (2,937-7,827) ,242 (5,002-16,001) Pharmacy 4,742 (2,597-10,897) 3,004 (1,337-6,300) < ,838 (1,774-8,071) 3,105 (1,724-6,672) ,597 (3,124-14,927) Hospitalization 1,584 (1,056-2,761) 1,261 (801-1,803) < ,450 (941-2,298) 1,303 (870-1,924) ,860 (1,272-2,975) costs (PD) Blood Products 1,625 (538-3,338) 739 (213-2,086) < ,316 (429-2,889) 879 (215-2,414) ,935 (703-4,015) Clinical Chemistry 1,738 (1,112-2,749) 1,084 (746-1,652) < ,440 (871-2,170) 1,159 (813-1,863) ,229 (1,406-3,412) <0.001 Radiology 759 (496-1,295) 430 ( ) < (397-1,055) 473 ( ) (588-1,620) <0.001 Miscellaneous 0 (0-0) 0 (0-0) (0-0) 0 (0-0) (0-5) Graft products 0 (0-0) 0 (0-0) (0-0) 0 (0-0) (0-0) Total 19,678 (12,186-33,901) 12,517 (7,692-20,523) < ,416 (10,083-28,470) 13,622 (8,539-20,847) ,539 (15,048-50,623) <0.001 Period 2 (post ICU) Fees 799 (262-1,938) 574 (217-1,700) (224-1,902) 581 (207-1,719) (301-2,295) Pharmacy 296 (41-1,488) 222 (33-1,296) (34-1,245) 258 (33-1,311) (49-1,743) Hospitalization 1,241 (528-2,686) 989 (435-1,758) ,054 (455-2,651) 943 (433-1,752) ,320 (642-2,761) costs (PD) Blood Products 0 (0-320) 0 (0-213) (0-235) 0 (0-213) (0-323) Clinical Chemistry 223 (53-626) 125 (48-497) (49-621) 135 (55-527) (64-634) Radiology 195 (52-477) 153 (44-371) (48-476) 153 (49-383) (55-480) Miscellaneous 4 (0-61) 1 (0-16) (0-58) 1 (0-16) (0-91) Graft products 0 (0-0) 0 (0-0) (0-0) 0 (0-0) (0-0) Total 3,633 (1,143-8,597) 2,712 (1,127-6,886) ,289 (1,054-8,267) 2,904 (1,095-6,911) ,293 (1,313-9,258) 0.290

15 Abbreviations: PD: Per diem Data are provided as median (IQR) Cost were divided into period 1, covering from ICU admission to ICU discharge, and period 2, extending from ICU discharge until hospital discharge.