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Systematic Review
Cryotherapy and inflammation: evidence
beyond the cardinal signs
Chris M. Bleakley
1
, Gareth W. Davison
2
1
Health and Rehabilitation Sciences Research Institute and
2
Sport and Exercise Sciences, Research Institute,
University of Ulster, Northern Ireland
Background: Cryotherapy is one of the most popular electro-physical agents used to ‘treat’ acute
inflammation after a soft tissue injury. Much of the clinical rationale for this is based on anecdotal reports,
with most clinicians accepting that cryotherapy has an ‘anti’ inflammatory effect after injury. There have
been a number of recent advances towards improving our understanding of the inflammatory process after
soft tissue injury.
Objectives: To review the rationale for cryotherapy intervention in the acute phases of soft tissue injury,
whilst considering physiological, cellular and molecular models of inflammation.
Methods: Qualitative review of recent evidence.
Results: Research is restricted to animal models, applying various forms of cryotherapy after induced soft
tissue injury. Outcomes focus on the effect that cooling has on key physiological, biochemical and
molecular inflammatory events including: secondary cell death, white blood cell behaviour, apoptosis,
blood flow and oedema formation.
Conclusion: Cryotherapy can have an influence on key inflammatory events at a cellular and physiological
level after an acute soft tissue injury. However, the relative benefits of these effects have yet to be fully
elucidated and it is difficult to contextualize within a human model. It is important to continue to update our
rationale for applying common electro-physical agents such as cryotherapy after acute soft tissue injury,
based on contemporary models of inflammation.
Keywords: Cryotherapy, Acute injury, Soft tissue, Inflammation
Introduction
Cryotherapy is one of the simplest and oldest
modalities for treating soft tissue injuries such as
sprains, contusions, and dislocations. The immediate
phase after soft tissue injury is characterized by an
acute inflammatory response. This often presents
clinically with cardinal signs such as heat, redness,
pain and swelling. Few clinicians may look beyond
these cardinal signs when providing justification for
intervention; and it is commonly accepted that
cryotherapy has an ‘anti’ inflammatory effect after
soft tissue injury. Applying a cold agent to a hot and
red tissue may seem pragmatic; however, there is not
always an obvious link between inflammation visible
under the microscope and that clinically apparent
and characterized by the original cardinal signs.
1
Paradoxically, recent trends in sports medicine
involve delivering growth factors into healing muscle
tissue (e.g. via platelet rich plasma or autologous
blood injections)
2
which seems to lean more towards
a pro-inflammatory treatment approach.
Our aim is to review the rationale for cryotherapy
intervention in the acute phases of soft tissue injury,
whilst considering physiological, cellular and mole-
cular models of inflammation. Where appropriate,
relevance to injured human subjects will be assessed,
and recommendations for future research provided.
Search Strategy
In January 2010, we undertook a computerized literature
search on Medline, EMBASE and Cochrane Central
Register of Controlled Trials (CCTR) (via OVID) using
nine key words and subject headings relating to
cryotherapy. This was supplemented with ‘related article’
searches on PubMed, and biblography tracking.
Relevant studies were extracted, with exclusions made
based on titles, abstracts or full text versions. No
restrictions were made on study design or type/mechan-
ism of acute soft tissue injury. Relevant outcomes were
any physiological, cellular or molecular measurement
associated with inflammation; recorded before injury,
and up to one week post-injury. No restrictions were
made on the type/dosage of cryotherapy intervention.
Correspondence to: Chris Bleakley, Health and Rehabilitation Sciences
Research Institute, School of Health Sciences, University of Ulster, Shore
Road, Newtownabbey, Co Antrim, BT37 OQB, Northern Ireland. Email:
chrisbleakley@hotmail.com
430
ßW. S. Maney & Son Ltd 2011
DOI 10.1179/1743288X10Y.0000000014 Physical Therapy Reviews 2010 VOL.15 NO.6
Table 1 provides details of the cryotherapy inter-
ventions and reported outcomes across studies.
Qualitative comparisons were made and results were
grouped and discussed by outcome.
Secondary Cell Injury
Perhaps the most commonly cited rationale for
applying ice after acute soft tissue injury relates to the
‘secondary injury model’.
3
This is based on the premise
that after an initial trauma (e.g. muscle strain or
contusion), the patho-physiological events associated
with acute inflammation can induce secondary damage
to cells around the injury site. Of particular concern is
that this can involve collateral damage to healthy cells
not injured in the initial trauma. This phenomenon is
known as secondary cell injury, and may be caused by
both enzymatic and ischaemic mechanisms.
4
One of the
most important cellular effects associated with
cryotherapy is its potential to reduce the metabolic
rate of tissue at, and surrounding the injury site. This
reduction in metabolic demand may allow the cells to
better tolerate the ischaemic environment in the
immediate phases after injury thus minimizing the
potential for secondary cell injury or death.
Table 1 Details of cryotherapy intervention and reported outcomes
Author
Details of cryotherapy
intervention Directness of cooling
Time after injury
of ice initiation
Outcomes
(blinded assessor Y/N)
Osterman et al.
5
CWI (ice and isotonic
saline); duration up to
13 hours (until ATP
depletion)
Amputated limb with
a single layer of
plastic wrap (mean
intramuscular
temperature: 1.2uC)
Immediately post
amputation
ATP/PCr
depletion (N)
Sapega et al.
6
CWI (isotonic saline at
1, 10, 15 and 22uC);
duration 45 minutes, up to
13 hours
Amputated limb
with a single layer of
plastic wrap
(intramuscular temperature as
low as 0.5–1uC)
Immediately post
amputation
ATP/PCr depletion;
pH (N)
Farry et al.
17
Crushed and compression,
20 minutes62
Intact skin Immediate (likely) IHA (Y)
Hurme et al.
18
Cold pack with
compression and elevation;
5 minutes every 1464
Intact skin (lowest
temperature recorded
in deep muscle: 20uC)
Immediate IHA (Y)
Smith et al.
22
Ice cylinders;
20 minutes
every 6 hours63
Intact unshaven skin Immediate (likely) Intravital microscopy
with MC (Y)
Laser Doppler
fluxmetry
Curl et al.
29
Ice cylinders;
20 minutes
every 6 hours for 2 days
Intact skin 5 minutes Intravital
microscopy
with MC
Laser fluxmetry (N)
Dolan et al.
30
CWI in 12.8–15.6uC;
30 minutes64
CWI to intact
shaved limbs
5 minutes Water
displacement (N)
Merrick et al.
7
Ice pack with elastic tape;
5 hours
Unshaven intact skin Immediate (likely) Biochemical
assay (N)
Westermann et al.
13
Ice cold saline solution;
1 hour duration
Through MC,
muscle surface
temperature
decreased to 10¡2uC
Immediate Intravital
microscopy
with MC (N)
Deal et al.
31
Cylinder of ice to skin side
of MC; 20 minutes
Unshaven intact skin 15 minutes Intravital
fluorescent
microscopy with
MC (N)
Dolan et al.
30
CWI at 12.8uC; 3 hours,
followed by 1 hour rest
CWI intact
shaven limbs
5 minutes Water
displacement (N)
Lee et al.
14
Saline at 3uC; 10 minutes Cooling directly
onto exposed
muscle surface
5 minutes Intravital
microscopy (N)
Real time laser
scanning
Schaser et al.
15
Saline at 8uC; 20 minutes Direct to surgically
exposed muscle
(muscle surface
temperature
cooled to 10uC)
Immediate (likely) Intravital
microscopy
IHA (Y)
Schaser et al.
16
Saline at 8uC; 6 hours Shaven intact skin
(muscle surface
temperature
cooled to 10uC)
Immediate (likely) Intravital microscopy
IHA (Y)
Note: CWI, cold water immersion; IHA, immunohistological analysis; MC, microvascular chamber; ATP, adenosine triphosphate; PCr,
phosphocreatine.
Immediate (likely): although not stated specifically, it was likely based on the experimental set-up.
Bleakley and Davison Cryotherapy and inflammation
Physical Therapy Reviews 2010 VOL.15 NO.6 431
Evidence to support secondary injury theory is
based largely on studies of limb preservation. Sapega
and colleagues
5,6
used phosphorous-31 nuclear mag-
netic resonance imaging to monitor cellular metabo-
lism in ischaemic (amputated) cat limbs, stored for up
to 10 hours, at a range of temperatures between 22
and 1uC. Limbs were removed at hourly intervals for
rescanning; overall, results showed that muscle cells
survived better at lower muscle temperatures. This
was exemplified by lower levels of adenosine tripho-
sphate (ATP) and phosphocreatine depletion, and
lower levels of acidosis, during the period of
ischaemia. Of note, these effects appeared to be
reversed at more extreme muscle temperatures
reductions below 5uC. This was attributed to extre-
me temperature reductions causing inhibition of
the calcium pump of the muscle’s sarcoplasmic
reticulum.
6
In a more recent and related study, Merrick and
colleagues
7
tried to quantify the effect of cryotherapy
on mitochondrial function after injury. Specifically
they measured the activity of the mitochondrial
enzyme, cytochrome c oxidase, after experimental
crush injury; comparing outcomes in cold treated and
untreated muscle tissue. Fitting with the ‘secondary
injury model’, 5 hours of continuous cooling with a
crushed ice pack inhibited the loss of mitochondrial
oxidative function after injury when compared to the
untreated controls. Although the model used by
Merrick et al.
7
is not directly determining the effects
of cryotherapy on the inflammatory process or
muscle injury per se, it is the first study to have
taken a novel approach to indirectly assess the effects
of secondary generated free radicals, and their
possible interference with enzymes controlling oxida-
tive phosphorylation (cytochrome c oxidase) and thus
ATP production after injury.
White Blood Cells (WBCs)
When muscle or joint injury occurs, phagocytic white
cells, such as neutrophils, monocytes, eosinophils ad
macrophages become activated and dominate the
inflammatory response in the early stages. Although
these cells have a critical role in healing through their
removal of necrotic debris and release of cytokines;
8
they can also have a negative effect on soft tissue
healing after injury.
8,9
For example, white cell
activation results in a series of reactions termed the
‘respiratory burst’.
10
These reactions are a source of
reactive oxygen species (ROS) such as superoxide
(O{
2), hydrogen peroxide (H
2
O
2
) and hydroxyl (OH
.
);
and hypochlorous acid (HOC1) which is a powerful
antibacterial agent. In certain circumstances the
production of ROS and antibacterial agents are
important immune defense mechanisms; however,
they can also be a potentially dangerous mechanism if
inappropriately activated. For example, overproduc-
tion of ROS may cause unwanted collateral damage
to adjacent tissues and surrounding molecules.
11
This
may be particularly likely in the event of a closed soft
tissue injury such as an ankle sprain, which is not
associated with bacteria or infection. Indeed, there is
evidence that blocking the respiratory burst, using
anti-CD11b antibody (M1/70), produces a three-fold
reduction in myofibre damage in an animal model at
24 hours post-injury.
12
Interestingly, a number of animal models have
studied the effect that crotherapy has on WBC
behaviour after soft tissue injury. A popular
approach has been to use fluorescent intravital
microscopy
13–16
to observe the effect that ice has on
leukocyte activity within the microvasculature. These
studies found a clear trend that icing significantly
lowered the percentage of both adherent and rolling
neutrophils after injury, in comparison to injured
untreated tissue. This finding was consistent over the
first 24 hours after injury.
13–16
Other animal models
7,15–18
have undertaken histo-
logical analysis on excised tissue after soft tissue
injury. In each case, various staining techniques were
used to identify leukocyte sub-types at the injury site.
Again each study made comparisons between ice
treated, and untreated injured tissue samples. Using
an injured ligament model and assessor blinding,
Farry et al.
17
found that ice treated groups had lower
levels of WBCs (polymorphs, lymphocytes and
plasma cells) at 48 hours, in comparison to injured
contra-lateral untreated limbs. Hurme et al.,
18
who
also used blinded outcome analysis, found that at
various time points post-injury, the ice treated animal
tissue had lower levels of erythrocytes (1 hour),
neutrophils (6 hours) and macrophages (at 24 hours)
in comparison to the untreated control limbs.
Although Schaser et al.
15
also found cooling
decreased neutrophilic granulocyte muscle infiltra-
tion, in comparison to control muscle, there were
higher levels of macrophages. In a follow-up study
16
using longer periods of cooling (5 hours), tissue
analysis at 24 hours post trauma also found lower
levels of neutrophilic granulocytes in the cold treated
muscle.
Although the examination of adherent and rolling
neutrophils following injury and cryotherapy may, in
some instances, be beneficial, these models must be
developed if we are to further our understanding in
this area. It may be more relevant for future research
to quantify the amount of direct neutrophil activation
that occurs following injury. This approach may allow
for estimation as to how much secondary cell and
surrounding tissue damage and inflammation will
likely occur. A popular marker that is commonly used
to determine neutrophil activation is myeloperoxidase.
Bleakley and Davison Cryotherapy and inflammation
432 Physical Therapy Reviews 2010 VOL.15 NO.6
This is produced by an increase in ROS activity and it
has been successfully used in studies looking at free
radical production and immune response after stretch
injury in animal skeletal muscle.
19
Apoptosis
Apoptosis is a programmed cell death. It is char-
acterized by a cascade of biochemical events cumu-
lating in altered cell morphology and eventual cell
death. Although apoptosis is the normal means by
which cells die at the end of their life span, its
incidence may be affected by soft tissue injury.
Higher numbers of apoptotic cells have been
recorded around the edges of rotator cuff tears when
compared to un-injured control muscles.
20
The
reasons for this increase have not yet been fully
elucidated; however, the accumulation of reactive
oxygen species in injured tissue (oxidative stress)
could again play a significant role.
21
Cell survival
requires multiple factors, including appropriate pro-
portions of molecular oxygen and various antiox-
idants. Although most oxidative insults can be
overcome by the cell’s natural defenses, sustained
perturbation of this balance may result in apoptotic
cell death.
There is limited evidence from animal models that
cryotherapy can reduce the incidence of apoptosis
after injury. Westermann et al.
13
found that after
chemically induced inflammation, the number of
apoptotic muscle cells (quantified by the number
with nuclear condensation and fragmentation) was
significantly higher in untreated controls, when
compared to the cryotherapy group (muscle surface
cooled to 10uC). This is an interesting finding as
reduced levels of apoptosis may again represent a
protective effect of cryotherapy after soft tissue
injury. We can only postulate as to the reasons for
this finding; however, this may be further evidence
that cryotherapy can reduce inflammation and
decrease secondary free radical production (from
the respiratory burst), thereby causing less interfer-
ence with important proteins and other cell metabo-
lites that control apoptosis.
Blood Flow and Oedema
Acute soft tissue injury incurs a multitude of changes
to the microvasculature. These include: increased
vessel diameter;
16,22
increased cell permeability and
macromolecular leakage into the injured tissue;
16
and
decreased tissue perfusion.
13,15,16
Paradoxically, there
is clear evidence that ice has a vasocontrictive response
in human tissue based on impedance plethysmography
outcomes.
23,24
Recent studies
25–28
also confirm that
topical cooling has a similar effect on deep tissue
haemodynamics, causing significant reductions in
capillary blood flow, with facilitated venous capillary
outflow in healthy humans. It is important to consider
if cryotherapy can reverse the effects that soft tissue
injury has on tissue haemodynamics using injured
models. Again much of the evidence in this area is
based on animal models.
Using intravital microscopy, some studies found
that ice application did not significantly change
capillary diameter,
15,16
arteriole diameter,
15,22,29
or
capillary velocity after injury.
15,16
In contrast, others
found that ice either significantly increased
15
or
decreased
13
arteriole diameter after injury.
There may be clearer patterns associated with
venular diameters. Three studies
14–16
reported smaller
venular diameters in ice treated groups in comparison
to injured (untreated) controls when measured at
both the initial stages
14,15
and at 24 hours
16
post-
injury. In two of these studies,
14,16
the differences
were significant, and in one case, venular diameter in
the cold group had returned to pre-injury levels.
16
Although this trend is supported with evidence that
iced tissue also had higher levels of venular blood
flow velocity in comparison to controls in the
immediate stages post-injury,
13–15
this trend was
reversed at 24 hours post-injury.
There is also conflicting evidence on the effect that
cryotherapy has on tissue perfusion post-injury.
Using fluorescent microscopic assessment of the
functional capillary density (length of erythrocyte-
perfused capillaries per observation area), three
studies
13,15,16
found that ice application significantly
increases tissue perfusion after injury, in comparison
to untreated injured controls. Again, in two
cases,
15,16
perfusion was restored to pre-injury levels.
In contrast, based on laser Doppler imaging after
injury, Curl et al.
29
found that cooling had little effect
on microvascular perfusion.
Using a related outcome measurement, Schaser and
colleagues
15,16
monitored intramuscular pressures in
rat limbs after soft tissue injury, randomizing limbs to
receive either cold saline, or no intervention. Lower
intramuscular pressures [17.7 mm Hg (SD: 4.7)] were
recorded at 1.5 hours post-injury in the cooling group
(treated with 20 minutes of saline cooling), when
compared to untreated controls [19.2 mm Hg (SD:
3.1)]. Their follow-up study also found that longer
periods of muscle cooling (5 hours) was associated
with lower intramuscular pressures
18
(95% CI: 5.5 mm
Hg) in comparison to untreated controls [26 (95% CI:
1.9 mm Hg)], at 24 hours post-injury.
Limitation and Future Study
There are a number of shortcomings associated with
the current evidence base, particularly when we try to
relate these findings to the injured human subject.
Primarily, much of the research relies on animal
models, applying various forms of cryotherapy after
an induced ‘crush type’ soft tissue injury. Furthermore,
Bleakley and Davison Cryotherapy and inflammation
Physical Therapy Reviews 2010 VOL.15 NO.6 433
in the majority of cases, the severity of the injury
was controlled to avoid excessive haemorrhage or
damage to major blood vessels,
14,22,30,31
and is
therefore not applicable to more serious soft tissue
injuries presenting clinically. Similarly, the majority
of studies have used a muscle contusion model,
which on a mechanical, anatomical and pathological
level, is different to a stretch type muscle injury or a
ligament sprain.
The use of amputated or excised tissues samples
has obvious drawbacks, when compared to models
using perfused tissue. We must also consider that
many of the in vivo models in this area used heavy
anaesthesia on the animals throughout the experi-
ment. Anaesthesia can alter tissue perfusion by as
much as 38%,
22
which could clearly confound
findings in an inflammatory study. Furthermore, an
induced injury on an anaesthetized animal means that
the muscle will be in a relaxed state. If the muscle is
contracted at the time of contusion injury, which is
usually the case in the sporting environment, we
might expect a significantly different impact response
and force displacement.
32,33
It is clear that cryotherapy can have an effect on
key inflammatory events at a cellular and physiolo-
gical level. However, the relative benefits of these
effects have yet to be fully elucidated and it is
currently difficult to contextualize within a clinical
model. Most of the work completed to date has
focused on the animal model, perhaps due to its
relative ease with regard to obtaining tissue. We must
consider that the temperature reductions reported in
animal tissues are extremely low (intra-muscular
temperatures of 1–10uC), and usually obtained within
15 minutes of injury. These tissue temperatures are
not only difficult to replicate in a human model, but
practically, cooling is usually initiated hours or days
after injury, particularly within randomized con-
trolled studies. Notwithstanding this, there needs be
more emphasis placed on the effects of cryotherapy
on inflammation and muscle injury using a human
approach and model. Much work needs to be done
using an array of peripheral and muscle specific
markers to determine and quantify the inflammatory
process per se. Considerable new information and
knowledge within cryotherapy may be obtained by
directly examining inflammatory related markers
such as high sensitive C-reactive protein, tumour
necrosis factor alpha, nuclear factor kappa B and
interleukin molecules such as interleukin-6. In-
vestigators should also be encouraged to examine
markers of cellular oxidative stress in order to
determine the relationship between primary and
secondary free radical production (caused by soft
tissue injury) and inflammation with and without
cryotherapy application.
Considerations must also be given to the type of
soft tissue affected. Muscle, ligaments and tendon
tissue may also have different levels of tolerance when
faced with post-injury ischaemia, and some may be
more at risk of secondary cell injury and collateral
damage. We must also clarify whether the potential
benefits of cryotherapy are restricted to reducing or
preventing secondary injury in cells not initially
damaged by primary trauma, or if they could also
target retardation of primary injury progression, i.e.
rescuing cells that were involved in primary injury but
not initially destroyed.
4
This could also have con-
siderable implications for clinical management of soft
tissue injury.
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