Acquired Weakness, Handgrip Strength, and Mortality

in Critically Ill Patients

Naeem A. Ali1, James M. O’Brien, Jr.1, Stephen P. Hoffmann1, Gary Phillips2, Allan Garland3, James C. W. Finley4,
Khalid Almoosa5, Rana Hejal6, Karen M. Wolf7, Stanley Lemeshow8, Alfred F. Connors, Jr.9, and Clay B. Marsh1,
for The Midwest Critical Care Consortium
1
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 2Department of Internal Medicine, Center for Biostatistics, Ohio State
University, Columbus, Ohio; 3Division of Critical Care, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
4
Division of Pulmonary and Critical Care Medicine, MetroHealth Medical Center, Cleveland, OH; 5Division of Pulmonary, Critical Care and
Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio; 6Division of Pulmonary and Critical Care Medicine,
Department of Internal Medicine, University Hospitals Case Medical Center, Case-Western Reserve University, Cleveland, Ohio; 7Division of
Pulmonary and Critical Care Medicine, Department of Internal Medicine, Indiana University Medical Center, Indianapolis, Indiana; 8College of
Public Health, Ohio State University, Columbus, Ohio; and 9Department of Internal Medicine, MetroHealth Medical Center, Columbus, Ohio

Rationale: ICU-acquired paresis (ICUAP) is common in survivors of

critical illness. There is significant associated morbidity, including
prolonged time on the ventilator and longer hospital stay. However,
it is unclear whether ICUAP is independently associated with mor-
tality, as sicker patients are more prone and existing studies have not
adjusted for this.
Objectives: To test the hypothesis that ICUAP is independently
associated with increased mortality. Secondarily, to determine if
handgrip dynamometry is a concise measure of global strength and
is independently associated with mortality.
Methods: A prospective multicenter cohort study was conducted in
intensive care units (ICU) of five academic medical centers. Adults
requiring at least 5 days of mechanical ventilation without evidence
of preexisting neuromuscular disease were followed until awakening
and were then examined for strength.
Measurements and Main Results: We measured global strength and
handgrip dynamometry. The primary outcome was in-hospital
mortality and secondary outcomes were hospital and ICU-free days,
ICU readmission, and recurrent respiratory failure. Subjects with
ICUAP (average MRC score of , 4) had longer hospital stays and
required mechanical ventilation longer. Handgrip strength was
lower in subjects with ICUAP and had good test performance for
diagnosing ICUAP. After adjustment for severity of illness, ICUAP was
independently associated with hospital mortality (odds ratio [OR],
7.8; 95% confidence interval [CI], 2.4–25.3; P 5 0.001). Separately,
handgrip strength was independently associated with hospital
mortality (OR, 4.5; 95% CI, 1.5–13.6; P 5 0.007).
Conclusions: ICUAP is independently associated with increased hospi-
tal mortality. Handgrip strength is also independently associated with
poor hospital outcome and may serve as a simple test to identify ICUAP.
Clinical trial registered with www.clinicaltrials.gov (NCT00106665).
Keywords: polyneuropathy, critical illness; muscle weakness; hand
strength
The development of generalized weakness related to critical
illness is a common and important complication for many
patients in intensive care units (ICU) (1, 2). While most
critically ill patients likely experience some weakness, it is only
termed ICU-acquired paresis (ICUAP) (1, 3) when severe.
Patients with ICUAP have a constellation of pathologic findings
in peripheral nerve and skeletal muscle that has been described
as critical illness polyneuromyopathy (CIPNM) (4–6). Recovery
(Received in original form December 14, 2007; accepted in final form May 27, 2008)
Correspondence and requests for reprints should be addressed to Naeem A. Ali,
M.D., 201G DHLRI, 473 W. 12th Avenue, Columbus, OH 43221. E-mail:
Naeem.ali@osumc.edu
Am J Respir Crit Care Med Vol 178. pp 261–268, 2008
Originally Published in Press as DOI: 10.1164/rccm.200712-1829OC on May 29, 2008
Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Intensive care unit (ICU)-acquired weakness is a known
complication of critical illness that has significant associ-
ated morbidity.
What This Study Adds to the Field
ICU-acquired weakness is independently associated with
increased hospital mortality. Handgrip strength may serve
also as a simple test to identify ICU-acquired paresis.
from this disorder may take months or years (7). Subclinical
weakness may also contribute to the physical limitations com-
monly found in survivors of critical illness (8–11).
Increased mortality is inconsistently observed in studies of
subjects with either ICUAP or its physiologic surrogates critical
illness polyneuropathy (CIP), myopathy (CIM), or neuromyop-
athy (CIPNM) (1, 12, 13). Several investigators suggest that the
varied diagnostic approaches used in ICU-acquired weakness
syndromes contributes to this inconsistency (3, 14). In pro-
spective studies of subjects who survive to awakening, patients
with ICUAP have increased observed mortality in unadjusted
analyses. However, these same patients were also older and
experienced more hyperglycemia and multiple organ failure.
Any or all of these could have influenced outcome (1, 13, 15).
To prevent (16, 17) or treat (18) ICUAP, the syndrome must
first be recognized. Diagnostic strategies include specialized neu-
rophysiologic testing and the bedside Medical Research Council
physical strength exam. Neurophysiologic testing, such as electro-
myography, can be performed easily on most ICU patients; how-
ever, interpretation requires special expertise and is not universally
available in all ICUs. In contrast, the bedside strength exam can be
performed by most clinicians. However, to be performed properly
the strength exam requires an awake and attentive patient with the
mobility and stamina to participate in the evaluation of all twelve
major limb muscle groups. A simpler assessment may result in
improved recognition of ICUAP. One such measure is handgrip
dynamometry, which has been used as a surrogate for global
strength in other neuromuscular diseases (19, 20).
We performed a multicenter study in critically ill, mechan-
ically ventilated patients to test the hypothesis that ICUAP is
associated with increased mortality independent of severity of
illness or organ failure. Our secondary hypothesis was that
handgrip strength as measured by dynamometry would provide
a concise measure of global strength and would be indepen-
262 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008

dently associated with mortality. Some of the results of this Human Subjects Protection
study have been previously reported in abstract form (21). Local institutional review boards at each site approved both the study and
the use of The Ohio State University as the Data Coordinating Center.
METHODS We screened patients in these ICUs daily for eligible subjects. Subjects or
We conducted a prospective multicenter cohort study from May 2005 their surrogates provided written informed consent in all cases.
through April 2007 at five medical ICUs in academic medical centers Sample Size Estimates
affiliated with the Midwest Critical Care Consortium (see APPENDIX A).
Adult patients (age > 18 yr) were eligible for enrollment if they required Based on preliminary data, in subjects awakening after requiring more
mechanical ventilation for at least 5 days. Exclusion criteria included than 5 days of mechanical ventilation, we expected a mortality rate of
patients with known diagnoses causing generalized weakness, mechan- 30% for patients with ICUAP and 10% for subjects without this di-
ical ventilation for more than 24 hours before transfer from a referring agnosis. We estimated that 153 examined subjects would provide 80%
hospital, surrogate or physician not committed to full support, inability to power to detect this difference with a two-sided a level of 0.05. We
communicate with an examiner, and those without at least two limbs to planned to enroll 170 subjects to account for a 10% expected mortality
examine. The complete list of exclusion criteria are listed in APPENDIX B. before a patient being eligible for examination.
We collected baseline data including demographics (age, race, sex,
and ethnicity), co-morbidities associated with weakness (diabetes Statistical Analysis
mellitus, alcoholism, HIV, and a history of stroke), severity of illness Demographic information was expressed for the total cohort or by
(Acute Physiology and Chronic Health Evaluation [APACHE] III) (22) strength group (ICUAP or No ICUAP) and compared using appro-
and organ failures (Sequential Organ Failure Assessment [SOFA]) (23) priate statistical tests. The primary explanatory variable was ICUAP
on the day of enrollment (Ventilator Day 5). We assessed reasons for and the a priori secondary explanatory variable was hand grip strength.
admission through review of the physician notes in the medical record. The primary outcome was death during hospitalization. Secondary
outcome analyses were performed using the number of HFD60 or
Screen for Awakening and Strength Exams ICUFD30. We used exact logistic regression for the primary analysis of
After enrollment, subjects were assessed daily for awakening and for hospital mortality and negative binomial regression (over dispersed
their ability to focus attention to verbal commands. In calm and awake
subjects (Richmond Agitation Sedation Scale [RASS] 21 to 11) (24),
attentiveness was assessed using the random letter A test of the
Attention Screening Exam (ASE), a validated method for ICU
patients (25). When subjects were found to be both awake and
attentive (ASE score > 8) they were examined for muscle strength
by physician investigators using the standard muscle strength exam
(Medical Research Council Scale [MRC]; APPENDIX C) (1, 26). Before
the study, investigators at each site received standardized instructions
about the performance of the MRC exam. Twelve muscle groups in
upper (wrist extension, elbow flexion, and shoulder abduction) and
lower extremities (dorsiflexion of the foot, knee extension, hip flexion)
were tested, unless determined to be unavailable by clinical staff due to
pain or extensive dressings. Immediately after the MRC exam, the
same examiner would ask subjects to perform dominant hand dyna-
mometry (Jamar handgrip dynamometer; Sammons Preston Rolyan,
Bolingbrook, IL) three times (27, 28). Subjects were positioned as close
to sitting upright with their elbows at 908 as possible. All assessments
were repeated on the following day. The maximum total MRC score
and handgrip from either day was defined as each subject’s strength for
all analyses. The clinical team was unaware of the results of study
exams. Inter-rater reliability was determined for the MRC exam by the
performance of a repeat examination by a second physician investiga-
tor within 4 hours of the first exam in a sample of subjects.
ICUAP was defined as an average muscle strength score of less than
4 (anti-gravity strength) across all muscles tested, as described previously
(1). Since grip strength is influenced by sex (29), we used sensitivity
analysis to determine the optimal handgrip strength cutoff to identify
ICUAP for males and females. A force value of less than 11 kg-force for
males and less than 7 kg-force for females resulted in the maximum
combination of sensitivity and specificity for the diagnosis of ICUAP.
Follow-up and Outcomes
On each follow-up day from enrollment through the day the strength
exam was performed, ventilator use, organ failure, hyperglycemia, and
clinical treatments (including any use of neuromuscular blocking
agents, aminoglycosides, corticosteroids, or intravenous insulin) were
recorded. Organ failures after enrollment were quantified as the
proportion of days of observation with more than one organ failure
as defined by the SOFA organ-specific subscore. After the strength
exam, subjects were followed until hospital discharge for ventilator use,
hospital survival, and other secondary outcomes. Specific predefined
secondary outcomes measured were ICU-free days (ICUFD30), Hos-
pital-free days (HFD60), ICU readmission, respiratory failure at the
time of ICU readmission and discharge location for all survivors.
ICUFD30 were calculated as the number of days alive and outside of
the ICU up to Day 30 after ICU admission. HFD60 was similarly
calculated to Day 60 after ICU admission. Figure 1. CONSORT enrollment diagram.
Ali, O’Brien, Jr., Hoffmann, et al.: Handgrip Strength and Mortality
Poisson regression) for analyses of HFD60 or ICUFD30. We used a risk
factor modeling approach for these analyses with covariates included if
they changed the risk factor coefficient by more than 15% in either
direction or were otherwise felt to be clinically important (APACHE
III and multiple organ failure days). We separately assessed for
interactions between severity adjusted mortality and study site and
found no significant differences. An additional analysis suggested by
peer review was performed using a propensity score of factors
associated with ICUAP in a logistic regression analysis as an alternate
approach to adjustment. Analyses were run using Stata 9.2 or 10.0
(Stata Corporation, College Station, TX), and we considered a P value
less than 0.05 to be statistically significant.
RESULTS
Cohort Development
One-hundred seventy-four subjects were enrolled in the study
and 136 (78%) survived to awakening, allowing strength
263
measurement. All 38 subjects not examined for strength were
deemed continuously ineligible from enrollment to death or
hospital discharge. Subjects not examined had higher mortality
(68.4% versus 12.6%, P , 0.001), were more often nonwhite
(36.8% versus 19.8%, P 5 0.03), less likely to have diabetes
mellitus (13.2% versus 30.4%, P 5 0.03), and had higher
average APACHE III score at enrollment (102 versus 66, P ,
0.001). The subjects undergoing strength examinations formed
the final study cohort (Figure 1).
Strength Exams
Figure 2 shows the average muscle strength for each muscle
group assessed. The majority of patients (68.8%) were able to
have all 12 muscle groups examined; 28.5% of the cohort had at
least 9 muscle groups examined (11 groups, 13.2%; 10 groups,
10.2%; and 9 groups, 5.1%). One subject only had eight and two
had only six groups examined. Consistent with previous reports
Figure 2. Strength assessment by muscle group. (A)
Upper extremity and (B) lower extremity muscle groups,
as well as (C) handgrip strength, are presented. The
relationship between handgrip strength and Medical Re-
search Council Scale (MRC) score is presented in D.
Handgrip strength was compared using ANOVA. * P value
for the comparison of mean hand-grip strength in study
subjects based on intensive care unit–acquired paresis
(ICUAP) and sex is , 0.001.
264 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008

Figure 2. Continued

(1), weakness was seen across all muscle groups tested. Inter- examiners MRC designation of ICUAP and the average MRC
rater exams were performed in 8.8% (n 5 12) of subjects by scores were highly correlated (Pearson’s correlation coefficient 5
blinded examiners. There was complete agreement between 0.96, P , 0.001). One-hundred twenty-three subjects (90.4%)

Figure 3. Handgrip dynamometry test performance anal-

ysis. Using the available handgrip data, we generated
receiver operating characteristic curves to determine the
discrimination of ICUAP by handgrip strength testing.
Because there was a significant association between ex
and handgrip, males (A) and females (B) were analyzed
separately. From these graphs the point that appeared to
have the maximal combination of sensitivity and specificity
was determined to be the ‘‘best’’ cutoff value. These
cutoffs corresponded to a handgrip threshold of 11 and
7 kg-force for males and females, respectively (sensitivity
80.6%, specificity 83.2%, negative predictive value
92.3%, positive predictive value, 63.0%, for the diagnosis
of ICUAP).
Ali, O’Brien, Jr., Hoffmann, et al.: Handgrip Strength and Mortality 265

received serial exams and again there was excellent agreement in Weakness and Outcomes
ICUAP assignment (Kendall’s tau-b 5 0.96, P , 0.001) and Outcomes were significantly different between the strength
average MRC scores were highly correlated (Spearman’s corre- groups. In unadjusted analyses, mortality increased as average
lation coefficient 5 0.90, P , 0.001). In subjects with ICUAP, the muscle strength or maximum handgrip strength declined (Fig-
maximum handgrip strength was significantly lower. Using sex- ure 4). Hospital mortality was higher in patients with ICUAP
specific thresholds (males, , 11 kg-force; females, , 7 kg-force; than those without weakness (Table 2). After adjustment for
Figure 3), handgrip strength had good test performance (overall severity of illness and organ failures, the odds of hospital mor-
sensitivity 80.6%, specificity 83.2%, negative predictive value tality were significantly higher in subjects with ICUAP (odds
92.3%, positive predictive value, 63.0%) when compared with an ratio [OR], 7.8; 95% confidence interval [CI], 2.4–25.3; P 5
ICUAP diagnosis by MRC exam. Performance did not differ 0.001, Table 3) by MRC exam. We observed similar results
significantly by sex (males: sensitivity 78.6%, specificity 82.4%, when we used handgrip force as the risk factor (Table 3). An
negative predictive value 93.3%, positive predictive value, additional analysis using a propensity score to account for
55.0%; females: sensitivity 81.8%, specificity 84.0%, negative factors associated with ICUAP (including age, sex, ventilator
predictive value 91.3%, positive predictive value, 69.2%). days, and organ failures before MRC exam and severity of
Cohort Characteristics illness) yielded similar increases in mortality risk for subjects
with ICUAP (OR, 5.2; 95% CI, 1.5–18.3; P 5 0.01). After risk
Thirty-five subjects (25.7%) in the examined cohort had ICUAP. adjustment, the numbers of ICU- and hospital-free days were
Demographics and severity of illness at enrollment (Day 5 of also significantly reduced in ICUAP subjects by MRC exam.
mechanical ventilation) are presented in Table 1. There were no There also was a strong association between handgrip strength
major differences in the demographics of subjects with or without and the number of ICU- and hospital-free days (Table 3). Fi-
a diagnosis of ICUAP. Severity of illness was significantly higher in nally, there was significantly greater morbidity in those subjects
the group with ICUAP. Average glucose levels and intravenous with ICUAP as measured by the secondary outcomes (Table 2).
insulin use were equivalent during follow-up between the groups.
TABLE 1. COHORT CHARACTERISTICS DISCUSSION
Characteristic ICUAP No ICUAP Total P Value We have prospectively shown that, among patients requiring at
Subjects (%) 35 (25.7) 101 (74.3) 136 least 5 days of mechanical ventilation, ICUAP, assessed by MRC
Age, mean 6 SD 59.5 6 13.0 57.1 6 16.2 57.7 6 15.5 0.36 exam or handgrip dynamometry, is independently associated
Sex, % male 40.0 50.5 47.8 0.28 with hospital mortality, ICU, and hospital-free days. Handgrip
Race, % white 82.9 79.2 80.1 0.64
Co-morbidity (%)
Diabetes mellitus 40.0 27.0 30.4 0.15
Cirrhosis 5.7 5.0 5.2 0.86
Alcohol abuse 17.1 14.0 14.8 0.65
Admitting conditions, % 0.24
Severe sepsis 57.1 55.5 55.9
Pneumonia (%) (86.4) (86.6) (86.5)
Intrabdominal (9.1) (9.0) (9.0)
Urinary (4.6) (1.5) (2.3) (0.82)
Skin (0) (3.0) (2.3)
COPD/asthma 20.0 18.8 19.1
exacerbation
Drug overdose/acute 2.9 13.9 11.0
mental status change
Acute hemorrhage 11.4 4.0 5.9
6 shock
Other* 8.6 7.9 8.1
ARDS 14.3 20.8 19.1 0.46
Septic shock 31.4 20.8 23.5 0.25
Any corticosteroid use, % 45.7 41.6 42.6 0.67
Any neuromuscular 21.8 20.0 21.3 0.82
blocker use
Morning blood glucose, 133 6 28 135 6 34 135 6 33 0.88
mean 6 SD
Intravenous insulin use, 0 (0–7) 0 (0–2) 0 (0–3) 0.15
d [median (IQR)]
APACHE III, mean 6 SD 78.3 6 25.2 61.5 6 26.4 65.8 6 27.0 0.001
Total SOFA, mean 6 SD 8.0 6 3.6 5.8 6 2.6 6.4 6 3.0 ,0.001
Multiple organ-failure days, 88.0 77.0 80.0 0.08
% of follow-up days

Definition of abbreviations: APACHE 5 Acute Physiology and Chronic Health

Evaluation; ARDS 5 acute respiratory distress syndrome; COPD 5 chronic
obstructive pulmonary disease; ICUAP 5 intensive care unit–acquired paresis;
IQR 5 interquartile range; SOFA 5 Sequential Organ Failure Assessment.
Descriptive characteristics are displayed for the entire cohort and by the
Figure 4. Observed mortality and muscle strength. The cohort was
presence or absence of global weakness as defined by the Medical Research
Council exam (ICUAP). All comparisons were performed by use of the chi-square
divided according to measured strength. To normalize the MRC score,
or Student’s t test as appropriate. P values reflect the significance of observed strength was determined as the average of all assessed muscle groups.
differences in values from ICUAP and No ICUAP patient groups. The maximum MRC score and handgrip strength was used to de-
* Other includes cardiogenic shock (3), pancreatitis (2), diabetic ketoacidosis termine each subject’s strength. (A) MRC strength score or (B) handgrip
(2), upper airway obstruction (2), ILD (1), and radiation pneumonitis (1). strength value are presented.
266 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008

TABLE 2. OBSERVED OUTCOMES electrophysiologic equipment or the expertise to interpret the

results can limit the utility of this test. Since limb positioning is
Characteristic ICUAP No ICUAP P Value
important for achieving valid results, the ICU environment can
Subjects (%) 35 (25.7) 101 (74.3) contain significant impediments to performing bedside strength
Ventilator use, d 12 6 ,0.001 assessments. As a result, some clinicians may perceive that the
Median (IQR) (6–19) (5–9)
strength exam is difficult and time consuming to perform. While
ICU stay, d, mean 6 SD 21 6 11 12 6 6 ,0.001
Median (IQR) 19 (14–26) 10 (8–14) we did not find the MRC exam in our study to be burdensome,
ICU-free to Day 30, d 6 20 ,0.001 it was done by researchers who dedicated specific time for this
Median (IQR) (0–15) (15–22) exam, rather than busy clinicians. It is possible that the
Hospital stay, d, mean 6 SD 34 6 21 20 6 12 ,0.001 perceived barriers to performing the full exam may lead to
Median (IQR) 28 (22–32) 16 (13–24) delays in formally assessing muscle strength. In addition, the
Hospital-free to Day 60, d 31 43 ,0.001
MRC scale has a subjective component (for example, MRC 5 5
Median (IQR) (0–38) (32–47)
ICU readmission, % 22.9 7.0 0.01 active movement against ‘‘full’’ resistance; APPENDIX C) (26),
Recurrent respiratory failure, % 21.2 10.1 0.09 which may introduce some variability in the measure. However,
Discharged to a location 83.3 52.1 0.01 our data indicate that when trained properly, physicians can
other than home, % generate highly reproducible results.
Hospital mortality, % 31.4 6.0 ,0.001 Because handgrip strength identifies patients at increased risk
Definition of abbreviations: ICU 5 intensive care unit; ICUAP 5 ICU-acquired
of death, it might provide a reasonable alternative for diagnosing
paresis; IQR 5 interquartile range. ICUAP and identifying patients at risk of poor outcomes and
Subjects were followed until hospital discharge for ventilator use, length of candidates for interventions to mitigate such risk. While we did
stay, and vital outcome. ICU readmission refers to any admission for a subject not collect data about the effort required for each exam, all
that occurs after strength exam and ICU discharge but before hospital discharge. subjects able to participate with the MRC exam were also able to
Respiratory failure at readmit indicates any need for mechanical ventilation
perform handgrip dynamometry. The time and precautions to
during an ICU readmission. All values are expressed as means 6 SD unless
otherwise stated. All comparisons were analyzed for significance using the
perform handgrip dynamometry would likely be less than the
Student’s t test for comparisons of means and Wilcoxon rank sum test for strength exam as there is no need to reposition the patient for
comparison of median values. P values refer to the significance of the differences testing of multiple muscle groups. Because handgrip dynamome-
between values for subjects with or without ICUAP. try does not require extensive repositioning and results in a more
objective numeric value (28), it may be able to be performed more
easily as a screening tool for global paresis in a busy ICU practice.
dynamometry may provide a rapid, simple alternative to the Additional research is needed to understand the appropriate
comprehensive MRC examination for the diagnosis of ICUAP. threshold of handgrip strength at which critically ill patients are
Previous studies have reported that ICUAP is a morbid at increased risk of death. Given that we attempted to determine
disease, but have not definitively demonstrated an independent the threshold of handgrip that optimized the diagnosis ICUAP,
association with mortality (1, 30–32). One study showed that these values may not accurately describe the wide range of
mortality was independently associated with CIPNM (13) as strength that may be ‘‘normal.’’ Studies in healthy adults suggest
diagnosed by electrophysiologic testing. It is unclear if these that age and gender both affect normal handgrip strength (29).
patients ever manifest weakness, as many may have died before Our analysis suggests that using a force value cutoff for each sex
awakening. It is possible that electrophysiologic abnormalities (males, , 11 kg-force; females, , 7 kg-force) is adequate.
are more common than clinical weakness (ICUAP) and may However, our cutoff values are well below age- and sex-matched
have different implications. For example, one study found hospitalized patient’s ‘‘normal’’ values (33), making it possible
electromyographic abnormalities in 58% of patients who re- that different factors influence handgrip strength in critically ill
quired 7 or more days of mechanical ventilation (12). But in patients than normal volunteers. Factors involved with testing
a separate study of a similar population, ICUAP only occurred hand strength, like handedness, bed position, and upper extrem-
in 25.3% (30). While not a definitive comparison of the preva- ity entrapment syndromes, should be more formally examined as
lence rates, the possibility exists that these techniques identify well. We also suggest that while most studies emphasize proximal
different patient groups. Such variation has been suggested as muscle weakness in ICUAP (1, 34), the involvement of distal
a possible limitation in interpreting studies of this syndrome (14). muscle groups may also be important. The observed association
While it may be important to identify ICUAP or CIPNM, between handgrip weakness and ICUAP should lead to further
there are barriers to accomplishing this goal. The availability of exploration of the pathogenesis and treatment of the syndrome.

TABLE 3. ADJUSTED OUTCOME ANALYSIS

OR for Mortality* Relative Reduction in ICU-free Days* Relative Reduction in Hospital-free Days*
Risk Factor (95% CI) P (95% CI) P (95% CI) P

ICUAP by MRC exam 7.8 0.001 54% 0.001 41% 0.007

(2.4 to 25.3) (67 to 36) (12 to 60)
†
Handgrip strength below threshold 4.5 0.007 41% 0.001 27% 0.073
(1.5 to 13.6) (56 to 19) (49 to -3)

Definition of abbreviations: 95% CI 5 95% confidence interval; ICU 5 intensive care unit; ICUAP 5 ICU-acquired paresis; MRC 5 Medical Research Council; OR 5 odds
ratio.
Exact logistic regression was used to determine the association of ICUAP or handgrip strength with mortality, whereas negative binomial regression was used for ICU-
or hospital-free days analysis. Free days analysis are reported as the percent reduction in the number of hospital- or ICU-free days experienced if the risk factor of ICUAP or
low handgrip strength was present compared to those in whom it was absent.
* Odds of hospital mortality, relative reduction in ICU, or hospital-free days if the risk factor was present were adjusted for enrollment, APACHE III, and multiple organ
failure days during the observation period.
†
Handgrip strength thresholds were determined for women to be 7 kg-force and for men 11 kg-force.
Ali, O’Brien, Jr., Hoffmann, et al.: Handgrip Strength and Mortality
There are limitations to our study. First, we did not employ
neurologists in the performance of the strength exams. We
chose this approach to improve the external validity of our
observations for bedside intensivists. Our sample of inter-rater
assessments suggested this still produced reliable exams. In
addition, given that our cohort is very similar in age, sex, and
co-morbidities to those in previously published studies (1, 34),
we feel that our exams identified patients with true ICUAP. All
ICUs participating in this study used ventilator liberation and
sedation protocols that included daily wake-ups and self-
breathing trials, but these practices were not standardized and
could have influenced outcome. We were unable to standardize
these practices for practical reasons, but analyses of mortality
by site found no significant differences. Because we observed
fewer deaths than anticipated in the examined cohort, our
ability to adjust for some clinically important factors was
limited. However, we remain confident in our results since
adjustment for severity of illness and the use of a propensity
score to ‘‘match’’ patients for factors associated with ICUAP
did not eliminate this association. In addition, the results of our
secondary outcome analyses support our mortality observation.
Finally, we do not have information as to the causes of
respiratory failure or death in our study participants, preventing
us from drawing conclusions as to the mechanisms by which
ICUAP could lead to mortality.
Despite these limitations, we feel that this study has impor-
tant implications. We believe handgrip dynamometry could be
used to screen patients for ICUAP by anyone in the ICU, leading
to earlier patient identification. Several strategies have been
developed to prevent ICUAP (17, 35), but few studies have ex-
plored the treatment of clinically evident disease. Given that some
of the known risk factors associated with ICUAP are non-
modifiable, it is likely that prevention alone will not eliminate
the burden of ICUAP. Therefore, treatments should be studied
to affect outcomes for those with established ICUAP while trying
to reduce its incidence. Handgrip dynamometry could represent
a useful tool to longitudinally assess strength recovery, allowing
a way to monitor the effectiveness of these interventions.
Our observations advance those made by other investigators
(1, 13) and, for the first time, show that ICUAP is independently
associated with increased odds of death after controlling for
severity of illness and organ failures. In addition, we show that
a simple measure of grip strength can serve as a useful surrogate
for the MRC examination and is itself independently associated
with hospital mortality. Further studies are needed to determine
if handgrip strength can be used in a clinical prediction rule to
help identify ICUAP patients as early as is feasible. Early
identification of critically ill patients with possible ICUAP who
are at increased risk of death might allow for more expeditious
treatments that could reduce the morbidity and mortality of this
disease.
Conflict of Interest Statement: N.A.A. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. J.M.O.
has served as Principal Investigator of a clinical trial by Aerogen (8/05–6/06) but
received no direct funds, served as a paid consultant to Medical Stimulation
Corporation ($4,000, 2005–2006), co-authored a manuscript with Eli Lilly
employees (2006), and currently serves as a unpaid consultant to Keimar, Inc.
S.P.H. does not have a financial relationship with a commercial entity that has an
interest in the subject of this manuscript. G.P. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript. A.G. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. J.C.W.F. has been a co-
principal investigator on two multicenter research grants from Boehringer
Ingelheim, Inc. that included investigation of Tiotropium and Mirapex; K.A. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript. R.H. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. K.M.W.
does not have a financial relationship with a commercial entity that has an
interest in the subject of this manuscript. S.L. does not have a financial relation-
267
ship with a commercial entity that has an interest in the subject of this
manuscript. A.F.C. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. C.B.M. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript.
Acknowledgment: The Midwest Critical Care Consortium study of ICU-acquired
weakness was performed at The Ohio State University Medical Center in
Columbus, Ohio; MetroHealth Medical Center and University Hospitals Case
Medical Center, both in Cleveland, Ohio; Indiana University Hospital in Indian-
apolis, Indiana; and the University of Cincinnati in Cincinnati, Ohio. The authors
thank Wendy King, P.T., and Miriam Freimer, M.D., for their help in developing
the exam training tools used for this study.
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APPENDIX A
Members of the Midwest Critical Care Consortium: Case West-
ern Reserve University, University Hospital Case Medical
Center, Cleveland, Ohio—Rana Hejal, Jeffrey Kern; Case
Western Reserve University, MetroHealth Medical Center—
Alfred F. Connors, Jr., James C.W. Finley, Allan Garland, Ted
Warren; Indiana University—Karen M. Wolf; The Ohio State
University Medical Center—Naeem A. Ali, Nitin Bhatt, Elliott
Crouser, Stephen P. Hoffmann, Clay B. Marsh, John Mastro-
narde, James M. O’Brien, Jr.; University of Cincinnati—Khalid
Almoosa, Frank McCormack, Mitch Rashkin. Data Coordinat-
ing Center (The Ohio State University)—Stanley Lemeshow
and Gary Phillips.
APPENDIX B: EXCLUSION CRITERIA
1. Patient’s family, physician, or both not in favor of
aggressive treatment of patient or presence of an ad-
vanced directive to withhold life-sustaining treatment.
2. Pregnancy.
3. Admitted to ICU from outside hospital where mechanical
ventilation was used for more than 24 hours.
4. New or pre-existing diagnosis causing current neuromus-
cular weakness.
5. Profound and uncorrectable hypokalemia or hypophospha-
temia (K , 2.5 or P , 1.0 throughout enrollment window).
6. Inability to assess muscle strength in more than six muscle
groups in at least two extremities (bilateral amputation
[BKA or AKA], severe burns, skin lesions, or dressings
limiting ability of examiner to access and forcibly resist
movement of the patients extremities).
7. Inability to communicate or follow commands of the ex-
aminer (persistent coma, severe MRDD [mental retardation
and developmental disabilities] or non-English speaker).
8. Concurrent enrollment in another clinical trial involving
steroids greater than 20 mg/day prednisone equivalent for
over 3 days, neuromuscular blockade for over 24 hours, or
any aminoglycosides.
9. Prisoner or other subject where legal surrogate decision
maker is in question.
APPENDIX C
Medical Research Council scale for evaluating peripheral
muscle strength (26). 0: No muscular contraction detected; 1:
barely detectable flicker or trace of contraction; 2: active
movement with gravity eliminated; 3: active movement against
gravity; 4: active movement against gravity and some resistance;
5: active movement against gravity and full resistance.