Managing the immediate demands of the current COVID-19 global pandemic has tested
many healthcare systems across the world, to their limits. As we move forward, new
challenges due the impact of this must be faced. In the months since the initial outbreak
of COVID-19 in December 2019, worldwide there have been more than 4.2 millions cases
of infection with the SARS-Cov-2 virus reported
1
. However, the rapidity of spread appears to be slowing, the curve is flattening in
many countries, and attention is now turning towards how the international healthcare
community will address the ongoing needs of those most significantly affected by the
pandemic. Recent UK data (covering February-April 2020) suggests 17% of cases admitted
to hospital require support in high dependency or critical care environments, and
of those just over 50% require mechanical ventilation
2
. About 20% of those requiring mechanical ventilation will be discharged with a further
27% receiving ongoing care. Critical care survival in other countries including Italy,
the US and China has been reported as 16-37%, although many cohorts include those
receiving ongoing care in ICU3, 4, 5. Given the number of global infections, this
suggests a cohort of critically ill survivors of unprecedented size.
The treatment needs of COVID-19 survivors are not yet fully appreciated. Although
initially assumed to be a respiratory disease, it is now clear that it affects a variety
of systems. Multi-organ failure can occur, with reports of cardiac, renal, haematological
and neurological effects in the acute stages. It is likely therefore, that these survivors
will have significant multi-domain impairment requiring ongoing support. There has
been a recent ‘call to action’ amongst the rehabilitation community to act quickly
to ensure adequate resources to provide early phase, multidisciplinary interventions
to promote physical and psychological recovery
6
.
We can perhaps learn from previous studies of critical care survivorship, which has
been relatively neglected until recently. This complex challenge has been termed post-intensive
care syndrome (PICS)
7
. It incorporates the cognitive, physical and psychological dysfunction reported following
ICU discharge that can have profound effects on quality of life. Chronic pain is often
part of this, but how this additional co-morbidity affects critical care survivors
is poorly understood. Estimates of chronic pain prevalence following ICU vary from
14-77% depending on timescale, method of measurement and population
8
. Pain also appears to be an important factor affecting ability to return to work
and quality of life up to 5 years following discharge
9
. It is likely that those surviving critical illness with COVID-19 will be at particular
risk of developing chronic pain. There are a number of reasons why this may be the
case (Figure 1
).
Figure 1
Potential risk factors for development of chronic pain following COVID-19. (PTSD=post-traumatic
stress disorder).
Figure 1
As a consistent risk factor for chronic pain development is the occurrence of acute
pain, it is worth considering how this is managed in ICU. Those recalling higher pain
and distress during ICU admission appear to be at higher risk of developing chronic
pain after discharge
10
. Unfortunately, even in quiet periods on ICU, pain is an often neglected symptom
receiving low priority and surprisingly poor assessment and management given the highly
staffed, well-skilled environment
11
. Guidelines to improve pain assessment and management in ICU have been developed
in the US and Europe, and initiatives such as the ICU Liberation ABCDEF bundles of
care have been adopted in some centres. These are aimed at improving long-term outcomes
through multidisciplinary management of symptoms, mobility and communication
12
,
13
.
However, these processes, which often involve non-pharmacological strategies, are
labour intensive and realistically may be unachievable in current pandemic conditions.
Furthermore, during this outbreak, the ICU workforce has been stretched beyond its
capacity with patients being treated, through necessity, by staff with rapidly scaled-up
training in units with reduced staffing ratios
14
. There is therefore the potential that non-lifesaving symptomatic control may have
been further neglected. The critically ill undergo a significant pain burden during
everyday procedures in ICU, such as tracheal tube suctioning, turning, positioning
and line insertion
15
. Due to the severity of COVID-19 critical illness it is likely that survivors will
have undergone multiple pain-associated interventions.
COVID-19 survivors are likely to have sustained a prolonged period of immobilisation,
sedation and ventilation
5
, putting them at high risk of associated ICU-acquired weakness (ICUAW). Commonly
manifesting as any combination of critical illness myopathy (CIM), critical illness
polyneuropathy (CIN) and muscle atrophy, known risk factors include the use of neuromuscular
blockade and corticosteroids, the presence of sepsis and multiorgan dysfunction as
well as prolonged mechanical ventilation
16
. Neuromuscular blockade is now highlighted in several guideline publications as a
strategy to improve ventilation in those with ARDS associated with COVID-19
17
,
18
; although there is no consensus, some recommendations also include use of corticosteroids
in certain populations
19
. The prevalence of ICUAW in the general ARDS population is estimated at 25-96%,
20
and although reported following the Middle East Respiratory Syndrome (MERS) epidemic
21
is yet to be determined in those critically ill with COVID-19. Whilst the focus of
ICUAW is often the motor component, there is growing evidence for sensory disruption
and associated pain. Weakness can lead to rapid deconditioning, joint related pain
and contractures and, although mechanisms remain unclear, shoulder pain in particular
has been highlighted as a significant problem in the post ICU population
22
.
A mainstay of respiratory support through the COVID-19 pandemic has been use of repeated
patient proning to improve ventilation17, 18, 19. Complications associated with proning
sedated patients include brachial plexopathy, joint subluxation and soft tissue damage.
These have the potential to result in persistent neuropathic and musculoskeletal pain
23
.
Neuropathic symptoms including numbness, paraesthesia and pain are well documented
following critical illness with abnormalities in nerve conduction studies demonstrated
up to 5 years following ICU discharge
24
. Even in the absence of electrophysiological abnormalities, small nerve fibre impairment
associated with neuropathic symptoms can persist for several months
25
. Reports of neurological sequelae of COVID-19 infection are emerging, indicating
both central and peripheral nervous system involvement; symptoms such as confusion,
headache and dizziness, as well as anosmia, ageusia and nerve pain are now described
in retrospective cohorts and case reports
26
. This has led to speculation of potential neurotropism, with both muscle and neural
tissue expressing Angiotensin Converting Enzyme-2 (ACE2) receptor, the functional
receptor for SARS-CoV-227. The related SARS-CoV virus is also associated with neural
injury, including axonopathic polyneuropathy
28
, and has been detected in both the CSF and brain tissue
29
. There are ongoing efforts to determine which human cells are susceptible to SARS-CoV-2
infection, but direct neural invasion has not yet been demonstrated
30
.
Regardless of direct neural entry, SARS-CoV-2, like SARS and MERS, appears to have
the capacity to induce painful para-infectious neurological disease as shown by a
number of case reports of Guillan-Barre syndrome
31
and polyneuritis
32
. Thrombotic, hypotensive and hypoxaemic consequences of infection can also contribute
to longstanding, potentially painful neurological sequelae such as stroke. Renal dysfunction
is also common and may be associated with a peripheral neuropathy, particularly if
renal impairment persists after the acute injury. A further aspect to consider is
neuropathic pain as a side effect of putative therapeutic agents currently under investigation
for modifying disease severity, such as lopinavir/ritonavir and hydroxychloroquine.
It is now clear that COVID-19 itself is associated with painful symptoms, including
myalgia, arthralgia, abdominal pain, headache and chest pain, and even those not admitted
to critical care environments may have pain requiring opioids for symptom management
33
.
An important area to recognise is the psychological impact of COVID-19, with the unique
social restrictions likely to create an additional burden. Severe psychological sequelae
have been reported in ICU survivors with up to 30% of ARDS survivors developing post-traumatic
stress disorder (PTSD)
34
. In COVID-19 this may be augmented by separation from family, use of personal protective
equipment (PPE) adding to the already alien environment, breakdown of social networks
and fear of mortality; this increases the potential for development of PTSD, anxiety
and depression, as observed in the SARS outbreak
35
. Pain is thought to have a bidirectional relationship with such psychological factors:
in the acute phase it may be a risk factor contributing to the development of mental
health co-morbidities, with chronic pain being a well-recognised co-morbidity. Even
baseline patient characteristics, identified as factors associated with the development
of severe COVID-19, overlap with those associated with chronic pain after critical
illness, including multi-morbidity and increasing age
36
. It is also likely that those with pre-existing multi-morbidity were at higher risk
of chronic pain prior to infection, which may predispose them to exacerbation of current
or development of new pain conditions
37
.
Emerging reports from Wuhan, which is now operating several rehabilitation institutions
for COVID-19 survivors, and Italy indicate a significant symptom burden in COVID-19
survivors including anxiety, sleep disorders, fatigue, limited exercise tolerance
as well as memory and executive function impairment
38
. Such symptoms are likely to be exacerbated or even attributed to pain although this
is yet to be explored. What remains unclear is the level of rehabilitation that will
be possible for different countries in the early phase of recovery. Early intervention
including adequate pain management, psychological and physical therapy has the potential
to reduce the risk of long-term pain as well as other features of PICS
39
. However, currently resources are focused on frontline services which may leave limited
support for such an unprecedented cohort of patients.
There is conflicting evidence on the beneficial effects of post-ICU rehabilitation
strategies in general on exercise tolerance and health-related quality of life in
the pre-COVID era.
40
,
41
Qualitative evaluation suggests increased patient satisfaction and reduced anxiety
42
. Although pain forms a component of health-related quality of life measures, specific
research into the effect of post-ICU rehabilitation on pain has never been formally
evaluated. The majority of studies on efficacy of pain management and post-critical
illness rehabilitation have focused on face-to-face delivery, often in a group-based
setting. Such traditional models of care may not be possible for some time, with ongoing
social distancing and diversion of healthcare resources. We therefore must develop
and assess innovative ways to deliver therapy that is accessible to those who need
it. Telemedicine and promotion of self-management programmes are being explored for
this cohort, and may become part of the ‘new normal’ for delivery of this type of
service. Yet for some vulnerable patient groups (e.g. elderly, cognitively impaired,
high deprivation) access may be problematic.
Stratifying patients to high intensity or speciality specific rehabilitation through
a stepped care model may be required but is difficult given the lack of specific COVID-19
research and experience. Extrapolation of best practice evidence from other cohorts
will be required. Historically, rehabilitation for survivors of critical illness has
been disease specific. For example, cardiac patients may get streamed to a cardiac
rehabilitation pathway; those with chronic respiratory disease to pulmonary rehabilitation;
those with a stroke to post-stroke resources. However this was problematic for two
reasons: firstly, these classes and pathways were not designed to address the additional
burden of PICS in addition to the patients underlying condition, and secondly, there
was a large proportion of patients that did not fall into these categories, ‘slipped
through the net’ and received suboptimal care.
Several models of more contemporary general ICU follow-up clinics currently exist,
43
but they are by no means universal. It is likely that these have not been subject
to the number of patients that will need their services in the foreseeable future.
The make-up of such services may also need to be adjusted to address COVID-19-specific
sequelae, and this may represent an opportunity to develop better links between pain
and ICU survivorship programmes, as well as improving dialogue with other specialties
such as renal, respiratory and mental health to build existing collaborations and
manage multi-morbidity. Pain services are traditionally multidisciplinary, incorporating
physical and psychological expertise with the goal of improving function and quality
of life, and could therefore have a great deal to offer overwhelmed critical care
services. Such integrated follow up pathways also provide an opportunity to develop
embedded research and registries to learn more about the features, aetiology, risk
factors and therapeutic interventions for chronic pain following critical illness,
an as yet neglected area of critical care survivorship.
In the rapidly changing clinical environment, flexibility and changes to health and
social care delivery are required. Whilst the trajectory of this pandemic has not
given us the luxury of developing a high-quality evidence base on which to base our
management decisions, it is beholden on us to critically assess what we are doing.
Perhaps now more than ever we need to work collaboratively to assess interventions
used in rehabilitation of post-COVID-19 patients. There is the opportunity to use
a similar approach to that of some clinical trials of acute interventions (such as
RECOVERY (https://www.recoverytrial.net/)), where adaptive trial design allows rapid
evaluation of a range of potential COVID-19 treatments. Although the acute challenges
of managing COVID-19 have been significant, it may be the long-term effects, including
pain, that will have the greatest impact on survivors and society, As an academic
community, understanding post-COVID-19 effects and ensuring a strong evidence base
for how to manage these is vital for patients, health and social care systems, and
for policy makers.
Authors’ contributions
LC and HK devised the topic of the manuscript; HK, LC, EC drafted sections for and
finalised the manuscript.
Declaration of interests
LC is an editor for the British Journal of Anaesthesia. HK is a fellow with the British
Journal of Anaesthesia Peer Review Fellowship Programme.
Funding
National Institute for Health Research (HK).
Uncited References
27.