Research

Original Investigation

A Risk Prediction Score for Kidney Failure or Mortality

in Rhabdomyolysis
Gearoid M. McMahon, MB, BCh; Xiaoxi Zeng, MD; Sushrut S. Waikar, MD, MPH

Invited Commentary
IMPORTANCE Rhabdomyolysis ranges in severity from asymptomatic elevations in creatine page 1828
phosphokinase levels to a life-threatening disorder characterized by severe acute kidney CME Quiz at
injury requiring hemodialysis or continuous renal replacement therapy (RRT). jamanetworkcme.com and
CME Questions page 1852
OBJECTIVE To develop a risk prediction tool to identify patients at greatest risk of RRT or
in-hospital mortality.

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 2371 patients admitted
between January 1, 2000, and March 31, 2011, to 2 large teaching hospitals in Boston,
Massachusetts, with creatine phosphokinase levels in excess of 5000 U/L within 3 days of
admission. The derivation cohort consisted of 1397 patients from Massachusetts General
Hospital, and the validation cohort comprised 974 patients from Brigham and Women’s
Hospital.

MAIN OUTCOMES AND MEASURES The composite of RRT or in-hospital mortality.

RESULTS The causes and outcomes of rhabdomyolysis were similar between the derivation
and validation cohorts. In total, the composite outcome occurred in 19.0% of patients (8.0%
required RRT and 14.1% died during hospitalization). The highest rates of the composite
outcome were from compartment syndrome (41.2%), sepsis (39.3%), and following cardiac
arrest (58.5%). The lowest rates were from myositis (1.7%), exercise (3.2%), and seizures
(6.0%). The independent predictors of the composite outcome were age, female sex, cause
of rhabdomyolysis, and values of initial creatinine, creatine phosphokinase, phosphate,
calcium, and bicarbonate. We developed a risk-prediction score from these variables in the
derivation cohort and subsequently applied it in the validation cohort. The C statistic for the
prediction model was 0.82 (95% CI, 0.80-0.85) in the derivation cohort and 0.83
(0.80-0.86) in the validation cohort. The Hosmer-Lemeshow P values were .14 and .28,
respectively. In the validation cohort, among the patients with the lowest risk score (<5),
2.3% died or needed RRT. Among the patients with the highest risk score (>10), 61.2% died or
needed RRT.

CONCLUSIONS AND RELEVANCE Outcomes from rhabdomyolysis vary widely depending on

the clinical context. The risk of RRT or in-hospital mortality in patients with rhabdomyolysis
can be estimated using commonly available demographic, clinical, and laboratory variables on
admission.
Author Affiliations: Renal Division,
Department of Medicine, Brigham
and Women’s Hospital, Harvard
Medical School, Boston,
Massachusetts (McMahon, Zeng,
Waikar); Framingham Heart Study,
National Heart, Lung, and Blood
Institute, and Center for Population
Studies, Framingham, Massachusetts
(McMahon); Department of
Nephrology, West China Hospital of
Sichuan University, Chengdu, China
(Zeng).
Corresponding Author: Gearoid M.
McMahon, MB, BCh, Renal Division,
Brigham and Women’s Hospital, 75
JAMA Intern Med. 2013;173(19):1821-1828. doi:10.1001/jamainternmed.2013.9774 Francis St, Boston, MA 02115
Published online September 2, 2013. (gearoidmm@gmail.com).

1821

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 Research Original Investigation
R
habdomyolysis is characterized by muscle injury
leading to the release of intracellular muscle contents
into the systemic circulation. Because muscle injury
from any cause can lead to rhabdomyolysis, the causes are
numerous and include trauma or muscle compression as
well as nontraumatic causes.1 The outcomes following rhab-
domyolysis are similarly variable, ranging from asymptom-
atic elevations of creatine phosphokinase (CPK) concentra-
tion to life-threatening electrolyte abnormalities and acute
kidney injury (AKI) requiring hemodialysis or continuous
renal replacement therapy (RRT). Acute kidney injury is a
feared and common complication of rhabdomyolysis, occur-
ring in 13% to 50% of patients,2,3 with reported mortality
rates as high as 59% in critically ill patients.4 Currently, clini-
cians lack tools to predict adverse outcomes in patients with
rhabdomyolysis. The degree of CPK elevation is often used
clinically as a marker of disease severity but has been
reported to have a weak correlation with risk.1
The ability to identify patients early in the course of rhab-
domyolysis who are likely to have adverse clinical outcomes
would be useful for risk stratification in the emergency de-
partment, early institution of aggressive prophylactic mea-
sures, and communication with patients and families about
prognosis. In this study, we used clinical and laboratory data
from 2 large hospitals to derive and validate a risk prediction
equation to estimate the chance of RRT or death in patients
with rhabdomyolysis.
Methods
Data Collection
We obtained data from 2 teaching hospitals in the northeast-
ern United States (Brigham and Women’s Hospital [BWH] and
Massachusetts General Hospital [MGH]) on patients admit-
ted between January 1, 2000, and March 31, 2011, through the
Partners Healthcare System Research Patient Data Registry, a
centralized clinical data warehouse designed for research and
quality improvement purposes that has been accessed for clini-
cal studies.5,6 We obtained information on patient demograph-
ics (age, sex, and race), length of stay, vital status at hospital
discharge, billing codes (International Classification of Dis-
eases, Ninth Revision, Clinical Modification [ICD-9-CM]; Cur-
rent Procedural Terminology [CPT]; and diagnosis-related group
[DRG]), electronic discharge summaries, and inpatient labo-
ratory values, including CPK, creatinine, phosphate, cal-
cium, potassium, albumin, bicarbonate, white blood cell count,
hemoglobin, and platelet count. Approval for this study was
granted by the institutional review board at Partners, and the
need for informed consent was waived.
Study Population
The inclusion criteria were age older than 18 years and CPK lev-
els in excess of 5000 U/L within 72 hours of admission. We ex-
cluded patients with preexisting end-stage renal disease and
those transferred from an outside facility who were receiving
RRT for at least 24 hours. We also excluded 539 patients with
CPK elevation considered due to acute myocardial infarction
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Risk Prediction Score in Rhabdomyolysis
by reviewing ICD-9-CM codes (410.x), DRG codes, and medi-
cal record review of selected cases. For those patients with mul-
tiple admissions during the study period, we included the first
admission only.
Ascertainment of Clinical Characteristics and Outcomes
We determined the most likely cause of rhabdomyolysis by hav-
ing 1 of us (G.M.M.) review the DRG code assigned at dis-
charge, ICD-9-CM codes, CPT codes, and electronic discharge
summaries when administrative data were not informative; pa-
tients were then further classified as “medical” or “surgical.”
We confirmed in-hospital mortality and dates of death ob-
tained by administrative data by reviewing electronic death
notes and/or discharge summaries from the electronic medi-
cal record. Acute kidney injury was defined and staged ac-
cording to the definition by the Kidney Disease: Improving
Global Outcomes group using creatinine values but not urine
output because accurate urine output data were not available.7
For the baseline creatinine, we used the preadmission creati-
nine value or, if not available, the lowest creatinine mea-
sured during hospitalization. We confirmed every case of RRT
during hospitalization by reviewing the electronic medical rec-
ords of all patients with appropriate diagnostic and proce-
dure codes (ICD-9-CM codes 39.95 and 54.98 and CPT codes
90935, 90937, 90945, and 909475).
Statistical Analysis
Categorical covariates were described by frequency distribu-
tion, while continuous covariates were expressed in terms of
their mean (SD) or median and interquartile range as appro-
priate. Unadjusted associations between the covariates and the
primary outcome were evaluated using χ2 tests for categori-
cal data, while for continuous data, the t test was used for nor-
mally distributed variables and the Kruskal-Wallis test for non-
parametric data. Unadjusted restricted cubic spline analysis
was performed to explore the reported nonlinear relation-
ship between initial CPK and risk of the composite outcome.
Adjusted odds ratios were estimated by multivariable logistic
regression.
We used the MGH cohort to derive a risk prediction score
and then externally validated the score in the BWH cohort. We
chose MGH as the derivation cohort because complete data
were available in 98.9% of patients (16 were missing calcium
and/or phosphate values) compared with 69.3% of patients in
the BWH cohort, due primarily to missing phosphate values
in the latter (299 [30.7%] with missing phosphate values, of
whom 4 were also missing calcium values). Phosphate values
were more likely to be missing in the BWH cohort than in the
MGH cohort because of differences in ordering laboratory tests
between the 2 hospitals. At BWH, in contrast to MGH, a stan-
dard chemistry panel includes calcium but not phosphate,
whereas at MGH, calcium and phosphate are typically or-
dered together with the standard chemistry panel. We ex-
cluded those with missing values from the derivation cohort
and assumed normal values for missing laboratory values in
the validation cohort. We first selected clinically plausible vari-
ables that were potentially associated with the composite out-
come of RRT or in-hospital mortality. Those variables associ-
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 Risk Prediction Score in Rhabdomyolysis
ated with the composite outcome in bivariable analyses were
then subjected to a backward stepwise logistic regression pro-
cedure based on a Wald χ2 P value of more than .05. The final
variables included in the model were age; sex; quintiles of ini-
tial phosphate, calcium, creatinine, and bicarbonate; CPK lev-
els in excess of 40 000; and cause of rhabdomyolysis (sei-
zure, syncope, statins, myositis, or exercise vs other causes).
We selected the first available result for each laboratory vari-
able for analysis. For each variable, quintiles with β coeffi-
cients that were not significantly different were grouped for
the final logistic regression model. We then divided the β co-
efficients for each category by the smallest value of a β coef-
ficient in the model to allocate an integer or half integer score
for each variable. We generated a score for each individual
based on the sum of the scores for every variable; this score
was incorporated into a final model. We assessed the model’s
discrimination using the C statistic and calibration with the
Hosmer-Lemeshow (H-L) goodness-of-fit test using deciles.
Confidence intervals (95%) were calculated using a nonpara-
metric bootstrap method. We validated the final multivari-
able logistic regression model in the BWH cohort. Because of
the large number of missing phosphate values in the valida-
tion cohort, we performed a sensitivity analysis to determine
whether the model performed equally well in patients who did
and did not have complete data.
Results
Between January 1, 2000, and March 31, 2011, we identified 3501
hospitalizations of adults with a CPK level in excess of 5000
U/L. After excluding 58 patients with end-stage renal disease
or RRT on transfer from an outside institution, 74 multiple ad-
missions, 459 with CPK elevation more than 3 days after ad-
mission, and 539 admitted with an acute myocardial infrac-
tion, the final study population included 2371 patients (1397
from MGH and 974 from BWH). Mean (SD) age was 50.7 (19.2)
years, and 73.8% were male (Table 1). Review of administra-
tive codes and electronic discharge summaries identified medi-
cal conditions as the clinical setting for rhabdomyolysis in 47.1%
of patients compared with 52.9% for surgical settings. The clini-
cal conditions most frequently associated with rhabdomyoly-
sis were trauma (26.3%), immobilization (18.1%), sepsis (9.9%),
and vascular and cardiac operations (8.1% and 5.9%, respec-
tively). Other causes are shown in Table 1.
Outcomes Associated With Rhabdomyolysis
Among patients with rhabdomyolysis in the 2 cohorts, 47.7%
developed AKI as described by the Kidney Disease: Improv-
ing Global Outcomes consensus definition.7 The composite out-
come occurred in 19.0% of patients (8.0% required RRT and
14.1% died during hospitalization). In-hospital mortality was
higher in patients with AKI (22.5% vs 7.1%, P < .001) and sub-
stantially higher in patients requiring RRT (40.0% vs 11.9%,
P < .001). Outcomes were comparable between MGH and BWH
(Table 1). The clinical conditions with the highest rates of the
composite outcome of RRT or in-hospital mortality were com-
partment syndrome (41.2%), sepsis (39.3%), neuroleptic ma-
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Original Investigation Research
lignant syndrome (36.4%), abdominal or thoracic surgery
(27.4%), and following cardiac arrest (58.5%). The lowest rates
of the primary outcome were from myositis (1.7%), exercise
(3.2%), and seizures (6.0%) (Figure 1). When stratified by cause
of rhabdomyolysis, the rates of the primary outcome were simi-
lar in the MGH and BWH cohorts (Table 1).
Degree of CPK Elevation
In the 2 cohorts, we found no evidence of a linear association
between CPK and risk of the composite outcome. In unad-
justed logistic regression models with restricted cubic splines,
we found increased risk of the composite outcome only with
CPK levels in excess of 40 000 U/L. The C statistics for logistic
regression models containing initial and peak CPK were only
0.52 and 0.61, respectively.
Derivation and Validation of Prediction Rule
Using MGH as the derivation cohort, we constructed a multi-
variable logistic regression model with RRT or in-hospital mor-
tality as the outcome. Significant predictors of the primary out-
come included age, female sex, cause of rhabdomyolysis, initial
creatinine, CPK, phosphate, calcium, and bicarbonate (Table 2).
The C statistic for the model was 0.82 (95% CI, 0.79-0.85). The
model was well calibrated according to the H-L test (P = .07).
A risk score was generated for each individual using the β co-
efficients from the logistic regression model. The parameters
for the risk score are shown in Table 3. The mean (SD) risk score
was 6.4 (3.2) (range, 0-17.5). A low risk score predicted a fa-
vorable outcome: a score of less than 5 identified patients with
a 3% risk of the primary outcome, while a score of more than
10 was associated with a risk of 59.2%. Using 5 as the cutoff,
the negative predictive value for the primary outcome was
97.0%, while the positive predictive value was 29.6%. In a lo-
gistic regression model using the score as a predictor, the C sta-
tistic was 0.82 (95% CI, 0.80-0.85) and the H-L P value was .14.
Each 1-point increase in the risk score was associated with an
adjusted odds ratio of 1.49 (95% CI, 1.42-1.57) for the primary
outcome.
We performed external validation of the model in the BWH
cohort. The C statistic for the model including the risk score
was 0.83 (95% CI, 0.80-0.86), and the H-L P value was .28.
Figure 2 shows the observed probabilities in the derivation and
validation cohorts. A score of less than 5 was associated with
a risk of the primary outcome of 2.3%, while a score of more
than 10 was associated with a risk of 61.2%. The negative pre-
dictive value for a score of less than 5 in the validation cohort
was 97.7%, while the positive predictive value was 27.2%. In
the validation cohort, 30.1% of patients were missing phos-
phate values. The risk of the primary outcome was lower in
patients with missing values (8.7% vs 20.5%, P < .001), sup-
porting the imputation of normal values in those with miss-
ing phosphate values. In addition, in sensitivity analyses, we
found similar calibration and discrimination when restrict-
ing the validation cohort to those with nonmissing phos-
phate values (area under the curve [AUC] = 0.81 [0.77-0.85] and
H-L P = .73). In the validation cohort, the C statistics for the
prediction of AKI (stage I and higher), AKI stage II and higher,
AKI stage III, in-hospital mortality, and RRT were 0.68 (95%
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 Research Original Investigation Risk Prediction Score in Rhabdomyolysis

Table 1. Baseline Clinical Characteristics, Cause of Rhabdomyolysis, Laboratory Values, and Outcomes
Associated With Rhabdomyolysis

No. (%)
Brigham and
Massachusetts Women’s Hospital
General Hospital (Validation
Characteristic Total (Derivation Cohort) Cohort) P Value
No. 2371 1397 974
Male sex 1749 (73.8) 1029 (73.7) 720 (73.9) .89
Age, mean (SD), y 50.7 (19.2) 52.4 (19.7) 51.3 (18.6) .12
White race 1731 (73.0) 1058 (75.7) 673 (69.1) <.001
Diabetes mellitus 443 (18.7) 224 (16.0) 219 (22.5) <.001
Creatinine, mean (SD), mg/dL 1.7 (1.6) 1.8 (1.7) 1.6 (1.3) .004
Initial CPK, median (IQR), U/L 5114 5519 3759 <.001
(1101-9660) (1437-10 571) (798-8981)
Phosphate, mean (SD), mg/dL 4.2 (2.5) 4.2 (2.6) 4.1 (2.3) .16
Calcium, mean (SD), mg/dL 8.4 (1.2) 8.4 (1.2) 8.3 (1.2) .02
Potassium, mean (SD), mEq/L 4.2 (1.0) 4.2 (1.1) 4.2 (0.9) .62
Bicarbonate, mean (SD), mEq/L 22.5 (5.1) 22.8 (5.2) 22.1 (4.9) .004
Surgical 1255 (52.9) 704 (50.4) 551 (56.6) .003
Trauma 624 (26.3) 398 (28.5) 226 (23.2) .004
Vascular surgery 192 (8.1) 114 (8.2) 78 (8.0) .89
Cardiac surgery 139 (5.9) 32 (2.3) 107 (11.0) <.001
Abdominal/thoracic surgery 164 (6.9) 83 (5.9) 81 (8.3) .03
Burns 69 (2.9) 46 (3.3) 23 (2.4) .18
Orthopedic surgery 50 (2.1) 19 (1.4) 31 (3.2) .002
Compartment syndrome 17 (0.7) 12 (0.9) 5 (0.5) .33
Medical 1116 (47.1) 693 (49.6) 423 (43.4) .003
Immobilization 429 (18.1) 298 (21.3) 131 (13.5) <.001
Sepsis 234 (9.9) 139 (10.0) 95 (9.8) .88
Seizures or syncope 133 (5.6) 85 (6.1) 48 (4.9) .23
Cardiac arrest 82 (3.5) 49 (3.5) 33 (3.4) .88
Statin myopathy 65 (2.7) 35 (2.5) 30 (3.1) .40
Exercise 62 (2.6) 40 (2.9) 22 (2.3) .36
Myopathy or myositis 59 (2.5) 18 (1.3) 41 (4.2) <.001
Diabetic ketoacidosis 20 (0.8) 13 (0.9) 7 (0.7) .58
Neuroleptic malignant 11 (0.5) 7 (0.5) 4 (0.4)
.75
syndrome
Cocaine 9 (0.4) 6 (0.4) 3 (0.3) .64
Unknown 12 (0.5) 3 (0.2) 9 (0.9) .02
Outcomes
Acute kidney injury
Stage I 453 (19.1) 264 (18.9) 189 (19.4) Abbreviations: CPK, creatine
Stage II 191 (8.1) 114 (8.2) 77 (7.9) .95 phosphokinase; IQR, interquartile
range.
Stage III 437 (18.4) 262 (18.8) 175 (18.0)
SI conversion factors: To convert
Renal replacement therapy 190 (8.0) 122 (8.7) 68 (7.0) .12
creatinine to micromoles per liter,
In-hospital mortality 335 (14.1) 205 (14.7) 130 (13.3) .36 multiply by 88.4; calcium to
Composite outcome 450 (19.0) 281 (20.1) 169 (17.4) .09 millimoles per liter, multiply by 0.25;
and potassium and bicarbonate to
Length of stay, median (IQR), d 9 (4-18) 9 (5-19) 8 (4-16) .01
millimoles per liter, multiply by 1.0.

CI, 0.65-0.72), 0.75 (0.72-0.79), 0.80 (0.76-0.83), 0.80 (0.77-
0.84), and 0.83 (0.78-0.88), respectively.
Discussion
In this study involving more than 2000 patients admitted with
rhabdomyolysis during a 10-year period to 2 teaching hospi-
tals, we have derived and externally validated a simple risk pre-
diction score to estimate the risk of RRT or in-hospital mortal-
ity. The risk score has several important attributes for clinical
utility. It is easily calculated with readily available clinical, demo-
graphic, and laboratory values; has good discrimination (ie, ac-
curacy) and calibration (ie, accuracy across a range of pre-
dicted probabilities); and provides estimates of “hard” clinical
end points of importance to clinicians caring for patients with

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 Risk Prediction Score in Rhabdomyolysis Original Investigation Research

Figure 1. Rates of In-hospital Mortality or Acute Kidney Injury Requiring Renal Replacement Therapy,
Stratified by Cause of Rhabdomyolysis

60
RRT + in-hospital mortality
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AKI indicates acute kidney injury;
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RRT, renal replacement therapy.

Table 2. Outcomes by Category of Risk Score

No. (%)
Mortality or Renal Renal
Replacement Replacement
Variable No. Therapy Therapy Mortality
Total 2371 450 (19.0) 190 (8.0) 335 (14.1)
Age, y
≤50 1162 165 (14.2) 93 (8.0) 99 (8.5)
>50 to ≤70 759 168 (22.1) 65 (8.6) 127 (16.7)
>70 to ≤80 274 68 (24.8) 26 (9.5) 61 (22.3)
>80 176 49 (27.8) 6 (3.4) 48 (27.3)
Male sex 1749 304 (17.4) 142 (8.1) 212 (12.1)
Female sex 622 146 (23.5) 48 (7.7) 123 (19.8)
Initial creatinine, mg/dL
≤1.4 1493 149 (10.0) 44 (3.0) 125 (8.4)
>1.4 to ≤2.2 442 111 (25.1) 36 (8.1) 92 (20.8)
>2.2 436 190 (43.6) 110 (25.2) 118 (27.1)
Initial calcium, mg/dLa
≥7.5 1855 287 (15.5) 103 (5.6) 227 (12.2)
<7.5 499 163 (32.7) 87 (17.4) 108 (21.6)
Initial CPK, U/L
≤40 000 2235 402 (18.0) 148 (6.6) 324 (14.5)
>40 000 136 48 (35.3) 42 (31.0) 11 (8.1)
Cause
Seizures, syncope, exercise, statins, 313 16 (5.1) 13 (4.2) 6 (1.9)
or myositis
Not seizures, syncope, exercise, stat- 2058 434 (21.1) 177 (8.6) 329 (16.0)
ins, or myositis Abbreviation: CPK, creatine
Initial phosphate, mg/dLa phosphokinase.
≤3.9 1250 129 (10.3) 41 (3.3) 105 (8.4) SI conversion factors: To convert
creatinine to micromoles per liter,
>3.9 to ≤5.4 399 93 (23.3) 16 (11.5) 67 (19.8)
multiply by 88.4; calcium to
>5.4 410 201 (49.0) 102 (24.9) 136 (33.2) millimoles per liter, multiply by 0.25;
Initial bicarbonate, mEq/L and bicarbonate to millimoles per
liter, multiply by 1.0.
≥19 1902 257 (13.5) 109 (5.7) 195 (10.3)
a
Data may not sum to total due to a
<19 469 193 (41.2) 81 (17.3) 140 (29.9)
small number of missing values.

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 Research Original Investigation Risk Prediction Score in Rhabdomyolysis

rhabdomyolysis. Compared with other risk prediction scores in of rhabdomyolysis, and a score that predicted just RRT would
nephrology and critical care—for example, prediction of the risk be limited since death may be a competing outcome. In post hoc
of RRT after cardiac surgery (C statistic, 0.78-0.81),8 prediction analyses, the risk score had reasonable discrimination for the 2
of contrast nephropathy following cardiac catheterization (C sta- individual components of the composite outcome (AUC = 0.83
tistic, 0.67),9 and prediction of mortality using the admission and H-L P = .36 for RRT; AUC = 0.80 and H-L P < .001 for in-
Sequential Organ Failure Assessment score in the intensive care hospital mortality).
unit (C statistic, 0.67-0.90)10-12—the rhabdomyolysis risk score A key finding from our analyses relates to the nature of the
has comparable or better discrimination. We chose to develop relationship between CPK levels and risk. Previous smaller
a tool to predict the composite outcome of RRT or in-hospital studies of rhabdomyolysis have shown that CPK has a weak
mortality because of considerations of clinical relevance: a score relationship with the risk of RRT.2,13,14 However, other groups
that predicted just mortality would not provide information on have documented large rises in CPK after vigorous exercise with
RRT, an important, common, costly, and morbid complication no deleterious consequences,15,16 and there is evidence of a ge-
netic component to the variability in CPK levels following
injury.17-19 We found an association between elevated initial
Table 3. Risk Score
CPK levels in excess of 40 000 U/L and the risk of RRT or in-
Variable β Score hospital mortality, but admission CPK levels alone were not
Age (continuous) 0.022 …a sufficiently predictive to enable clinical decision making. The
Age, y incorporation of cause of rhabdomyolysis provides impor-
>50 to ≤70 …b 1.5 tant additional prognostic information, as suggested by pre-
>70 to ≤80 …b 2.5 vious smaller studies.2,20 The risk of the composite outcome
>80 …b 3 in the overall cohort with low-risk causes (seizures, syncope,
Female sex 0.404 1 exercise, statins, or myositis) was only 5.1% compared with
Initial creatinine, mg/dL 21.1% in those with other causes. The components of the risk
1.4 to 2.2 0.589 1.5 score also include age, sex, and clinical laboratory values. All
>2.2 1.083 3 laboratory variables are plausible as risk factors: high creati-
Initial calcium <7.5 mg/dL 0.933 2 nine reflects AKI or CKD, which are both strong and indepen-
Initial CPK >40 000 U/L 0.805 2 dent risk factors for poor outcomes; high phosphate values may
Origin not seizures, syncope, exercise, 1.301 3
signify greater severity of muscle injury and impaired renal
statins, or myositis function; and low calcium results from deposition within dam-
Initial phosphate, mg/dL aged skeletal muscle and may be a marker of increased muscle
4.0 to 5.4 0.565 1.5 injury.21
>5.4 1.221 3 The risk score may be particularly useful in the emer-
Initial bicarbonate <19 mEq/L 0.811 2 gency department to evaluate and triage patients with exer-
tional rhabdomyolysis. For example, a 30-year-old female pa-
Abbreviation: CPK, creatine phosphokinase.
tient with myalgia following exercise with a CPK level of 20 000
SI conversion factors: See Table 2.
a U/L but normal laboratory values for calcium, phosphate, cre-
Age is categorical, therefore there is no value.
b atinine, and bicarbonate has a risk score of 1, corresponding
Age is continuous, therefore there is no value.
to less than a 1% risk of RRT or in-hospital mortality. Knowl-

Figure 2. Probability of In-hospital Mortality or Acute Kidney Injury Requiring Renal Replacement Therapy

1.0
Probability of In-hospital Mortality or RRT

MGH—Derivation
0.9
BWH—Validation
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
<3 3 4 5 6 7 8 9 10 11 12 13 14 15 >15
Risk Score
Event rate 0 4 3 27 48 40 43 52 45 47 47 38 19 19 18
Patient count 130 358 105 387 307 269 203 164 134 101 75 57 34 24 23

Dark blue bars and light blue bars show the observed risk at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH), respectively.
RRT indicates renal replacement therapy.

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 Risk Prediction Score in Rhabdomyolysis Original Investigation Research

edge of the predicted risk of adverse outcomes may lead cli-
nicians to choose intravenous fluid administration in the emer-
gency department followed by discharge with plans for
repeated outpatient laboratories rather than inpatient hospi-
talization for observation. The safety of this approach and clini-
cal implementation of the risk score in this manner would re-
quire additional study. The risk score has particular utility in
identifying low-risk patients. Although the documentation of
a high risk score may not directly influence treatment deci-
sions, it may be useful in conveying prognosis and expecta-
tions to the care team, patient, and family members.
Clinical trials of therapeutic agents for rhabdomyolysis
may also be aided by the use of a risk score as inclusion and
exclusion criteria. Low-risk patients, in whom the event rate
may be too low to warrant inclusion, and high-risk patients,
for whom interventions may not carry clinical benefit due
to severity of illness, may be excluded to optimize study
design.
This study has a number of important strengths. To our
knowledge, it is the largest study to date of rhabdomyolysis
and, more important, has identified patients on the basis of
CPK levels rather than administrative codes. Only patients
with moderate to severe biochemical evidence of rhabdo-
myolysis were included, thus removing some of the ambi-
guity in previous studies in which a lower CPK cutoff for
inclusion was used. The study drew data from 2 large uni-
versity teaching hospitals, allowing external validation of
the risk prediction model. However, we recognize some
limitations. The study was retrospective in nature; the
cause of rhabdomyolysis was ascertained by medical record
review and administrative codes and may not have been
accurate in all cases. The timing of the insult was not certain
in many cases, and patients came to the hospitals at varying
intervals following injury. There was no information on
urine output or the treatments that were used or their rela-
tive effectiveness in preventing the primary outcome. Cre-
atine phosphokinase was not routinely checked in all
patients seeking treatment at the hospital, and therefore a
number of patients may have developed rhabdomyolysis
without being diagnosed. Finally, because this study
includes patients from 2 large tertiary teaching hospitals in a
single city in the northeastern United States, it may not be
generalizable to other non–tertiary care hospitals in differ-
ent geographical locations. Further validation studies may
be informative.
In summary, we have described the incidence, causes, and
outcomes of rhabdomyolysis in a large cohort of patients seek-
ing treatment at 2 large university hospitals during a 10-year
period. From these data, we derived and validated an easy-
to-use risk score based on readily available parameters that can
aid in estimating the probability of RRT or in-hospital mortal-
ity in patients with rhabdomyolysis.

ARTICLE INFORMATION REFERENCES 9. Mehran R, Aymong ED, Nikolsky E, et al. A

Accepted for Publication: June 9, 2013.
Published Online: September 2, 2013.
doi:10.1001/jamainternmed.2013.9774.
Author Contributions: Dr McMahon had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: McMahon, Waikar.
Acquisition of data: All authors.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: McMahon.
Critical revision of the manuscript for important
intellectual content: Zeng,Waikar.
Statistical analysis: McMahon, Zeng.
Study supervision: Waikar.
Conflict of Interest Disclosures: Dr Waikar
reported serving as a consultant to CVS Caremark,
BioTrends Research Group, Harvard Clinical
Research Institute, and Takeda; providing expert
testimony for GE Healthcare, Northstar Rx, and
Salix; and receiving grants from the National
Institute of Diabetes and Digestive Kidney Diseases,
Otsuka, Merck, Genzyme, and Satellite Healthcare.
Funding/Support: Dr Zeng was supported by the
China Scholarship Council. Dr Waikar is supported
by grants DK093574 and DK085660.
Previous Presentation: The results of this study
were presented in part as a poster at the American
Society of Nephrology Annual Meeting; November
3, 2012; San Diego, CA.
Additional Contributions: Shawn Murphy, MD,
PhD, Henry Chueh, MD, MS, and the Partners
Healthcare System Research Patient Data Registry
group facilitated the use of their database.
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Invited Commentary

Predicting the Outcomes of Rhabdomyolysis

A Good Starting Point
Emilee R. Wilhelm-Leen, MD; Wolfgang C. Winkelmayer, MD, MPH, ScD

Rhabdomyolysis is commonly encountered in the hospital;
however, national estimates on the incidence of rhabdomyoly-
sis are not available. While patients with highly elevated cre-
atine phosphokinase (CPK) concentrations are generally closely
monitored, it is often less clear how to best handle patients with
moderate CPK elevations. Clinicians are usually fixated on these
patients’ (repeated) CPK measurements, yet it is likely that other
relevant information can help stratify these patients by their like-
lihoods of experiencing unfavorable outcomes.
In this issue of JAMA Internal Medicine, McMahon and
colleagues1 present perhaps the largest study to date of pa-
tients hospitalized with clinically significant rhabdomyoly-
sis. From the detailed data repository of 2 Harvard-affiliated
teaching hospitals in Boston, Massachusetts, they identified
from all primary admissions
between January 1, 2000, and
Related article page 1821 March 31, 2011, nearly 2400
patients who had at least 1
CPK level in excess of 5000 U/L; patients with myocardial in-
farction were excluded. This means that each hospital had ap-
proximately 10 patients per month with significant rhabdo-
myolysis, clearly not a rare event. The mean age of the study
cohort was 50.4 years, 73.8% were men, and 27% were of non-
white race. The patients were almost evenly split between pri-
mary surgical and medical services. The most common causes
of rhabdomyolysis included trauma, immobilization, sepsis,
and vascular and cardiac operations.
The primary outcome of interest was a composite of acute
kidney injury requiring hemodialysis or hemofiltration, at least
temporarily, and in-hospital mortality, which occurred in 19.0%
of patients (8.0% required hemodialysis or hemofiltration, and
14.1% died). The primary analysis confirmed a counterintui-
tive but previously reported observation: no strong relation-
ship exists between CPK and outcome—initial CPK levels pre-
dicted poor outcomes for patients with rhabdomyolysis no
better than a coin flip (C statistic, 0.52). Prediction using peak
CPK level was not much better (C statistic, 0.61).
Using data from 1 hospital, the researchers then devel-
oped a prediction tool for poor outcomes using commonly col-
lected clinical data, including age, sex, origin of rhabdomy-
olysis, and laboratory parameters (initial creatinine, CPK,
phosphate, calcium, and serum bicarbonate levels). The par-
simonious regression model performed quite well, as did the
simplified integer-based prediction tool derived from it (C sta-
tistic, 0.82 for both). The researchers then validated their pre-
diction tool in the cohort of patients from the second hospi-
tal, where it performed just as well (C statistic, 0.83), which is
remarkable.
This tool for the prediction of poor outcomes in patients
with rhabdomyolysis has other attractive properties; it uses a
limited set of variables that are routinely and inexpensively
measured and readily available. Thus, it can be easily applied
to patients in the emergency department, allowing physi-
cians to prognosticate which patients are at high risk for poor
outcomes early in their clinical course. For example, a man aged
71 years, admitted following a traumatic injury, with an initial
creatinine concentration of 1.8 mg/dL (to convert to micro-
moles per liter, multiply by 88.4), CPK level of 10 000 U/L, phos-
phate concentration of 4.5 mg/dL, calcium concentration of
10.0 mg/dL (to convert to millimoles per liter, multiply by 0.25),
and serum bicarbonate concentration of 18 mEq/L (to con-
vert to millimoles per liter, multiply by 1.0), would carry a risk
score of 10.5, which corresponds to a risk of dialysis or in-
hospital mortality of 61.2%. This degree of risk may surprise
some physicians, since the laboratory values are abnormal but
not spectacularly so. Early risk estimation, especially if unin-
tuitive, may improve outcomes for patients, particularly if sup-
portive care such as aggressive fluid resuscitation can be started
early. The early prediction of high risk will also allow physi-
cians to seek timely subspecialty (nephrology) consultation,
triage patients more quickly and appropriately to the highest
level of care (such as the intensive care unit), and provide pa-
tients and their families with more accurate prognostic infor-
mation. By contrast, on the lower end of the scale, the scoring
system performed particularly well in that among the 488 pa-
tients with a score of 3 or less, only 4 (<1%) experienced in-
hospital mortality or the need for hemodialysis, thus indicat-
ing that such patients may be discharged from the emergency
department (dependent on other circumstances) and moni-
tored closely as outpatients.
Prior literature on the incidence and outcomes of rhabdo-
myolysis is surprisingly sparse. Early literature focused on case
reports and case series, primarily of crush victims in man-
made and natural disasters.2,3 Generally, these reports fea-

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