Introduction
The world is in the grips of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
pandemic. What started as an innocuous viral infection in China in December 2019,
has quickly traveled around the world and infected almost all countries on the planet.
At the time of writing, there are almost 5 million cases and over 300,000 death attributed
to coronavirus disease 2019 (COVID-19).[1]
A large majority of COVID-19 infections are mild and do not require hospitalization.
The spectrum of presentations ranges from mild acute respiratory infection to severe
acute respiratory tract infections with sepsis and multiple organ system failure.
About 5% of infections require intensive care management.[2] The case fatality ratio ranges between 4 and 16%.[3] Most common presenting features are fever, cough, malaise, and breathlessness. The
COVID-19 patients may sometimes present with neurological manifestations such as headache,
hypogeusia/anosmia, acute cerebrovascular events, seizure, and ataxia.[4] Older patients have been observed to have hypoxemia without displaying clinical
signs of respiratory distress, a condition described as “happy hypoxemia.”[5] Hypertension, diabetes, and preexisting kidney disease are overrepresented in the
disease cohort, and obesity has been observed to be an independent risk factor of
disease severity ([Table 1]).[6]
[7]
[8]
[9]
Table 1
All India Institute Of Medical Sciences New Delhi coronavirus disease data (unpublished)
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Total number of patients
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173
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Hypertension
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48 (27%)
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Chronic Kidney disease
On maintenance hemodialysis
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37 (21%)
12 (6.9%)
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Diabetes mellitus
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23 (13.2%)
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Patients requiring intensive care management have respiratory failure secondary to
COVID-19 viral pneumonia. Viral pneumonia often progresses to acute respiratory distress
syndrome, and the disease course may be complicated by myocarditis, acute kidney injury,
secondary infections, and sepsis/septic shock.[10]
[11]
[12]
[13]
The absence of any proven treatment complicates the issue. The literature abounds
with novel experimental therapies and old drugs being repurposed to treat COVID-19.
The purpose of this review is to summarize the existent therapies which might be useful
in management of COVID-19 patients in the intensive care unit (ICU).
Management of Respiratory Failure
COVID-19 typically presents with respiratory tract illness of varying degrees which
may or may not be associated with fever. The clinical progression is observed to be
biphasic. The first phase is characterized by fever, cough, and other constitutional
symptoms and is accompanied by radiological worsening during the first week. This
is associated with rapid viral replication. By second week, symptoms begin to resolve
in most patients. A small subset of patients continues to worsen with radiological
and clinical deterioration, with the onset of respiratory failure.
The management of respiratory failure in COVID-19 patients are governed by well-established
clinical practices with a few important caveats.
Oxygen Therapy and Mechanical Ventilation
Increasing the oxygen concentration of inhaled air is one of the basic pillars of
respiratory failure management. This can be done in several ways. Hypoxic patients
are started on oxygen therapy with face masks to target an oxygen saturation (SpO2) of greater than 90%. For patients requiring low-flow supplementation, nasal cannula
is appropriate. Higher flows may be administered using a simple face mask, venturi
device, or nonrebreather mask. One must be vary of the aerosol generating capacity
of various therapeutic or diagnostic techniques used commonly in the intensive care
unit. Risk of aerosolization increases with the use of higher flows.
Awake Prone Positioning
When oxygenation does not improve with increasing FiO2, patients are made to lie prone. Proning during invasive mechanical ventilation is
advocated for acute respiratory distress syndrome (ARDS) and is almost the standard
of care. Prone positioning during severe ARDS improved oxygenation and demonstrated
a mortality benefit.[14] Awake proning works on the same principles and a small, single center study has
demonstrated improved oxygenation in COVID-19 patients.[15] Patient selection is important. Patients—who can communicate and cooperate, change
position independently, and have no anticipated difficult airway issues—can be given
a trial of awake proning. Patients who require an FiO2 of more than 30% should be given a trial of this technique. Patients with a P:F ratio
of less than 100 do not seem to benefit from awake prone positioning.[16]
Thus, any patient with an FiO2 requirement greater than 30% and a P:F ratio greater than 100 who can cooperate is
a good candidate for awake proning. The procedure should be explained to the patient
beforehand. Pillows may be required for comfortable positioning, especially below
the chest. Adequate length of circuit tubing should be ensured.
After proning, the patient’s saturation should be closely observed to ensure that
there is no decrease. If there is no decrease, prone positioning should be maximized
as much as possible, preferably for at least 2 hours. If the patient is cooperative,
cyclic position change as described in [Fig. 1] can be done. Oxygen saturation should be monitored after every position change and
oxygen therapy titrated down as tolerated. If the patient desaturates, looks tired
or in distress, or is unable to tolerate position; he or she should be made supine
and care escalated as required.
Fig. 1 Awake prone positioning protocol.
Noninvasive Ventilation and High-Flow Nasal Cannula
If awake proning does not result in improvement in oxygenation and the patient deteriorates,
the patient may be put on either high-flow nasal cannula (HFNC) or noninvasive ventilation
(NIV). It is important to understand that both modalities lead to increased aerosolization,
consequently increased risk to health care workers, and lead to delay in intubation,
which may increase mortality. A school of thought advocates not using these modalities
at all in COVID-19 patients. But this viewpoint must be balanced by the availability
of resources, both material and human. Intubating all deteriorating patients might
be feasible in a setting with adequate resources, but this is not possible in a resource
poor scenario. Following, it will result in an undue strain on ventilator demand in
case of a surge.
At our institution, HFNC and NIV are important steps on the management ladder, though
we prefer NIV over HFNC. The ERS/ATS guidelines recommend the use of NIV as a preventive
strategy for avoiding intubation in hypoxemic acute respiratory failure.[17]
[18] NIV and HFNC may be an option for mild to moderate ARDS (PaO2/FiO2 > 100).
Helmet NIV has better acceptance than NIV by facemask. Using a helmet with double
limb circuit and a good seal at the neck-helmet interface is a safe option in the
COVID setting.[18]
[19] The use of a “helmet continuous positive airway pressure (CPAP) bundle” has been
suggested to improve patient comfort and compliance with the helmet.[20] We start CPAP with the lowest effective pressures (5 to 10 cm of H2O). For HFNC, we start with low-flow rates (20 L/min) and titrate according to the
patient’s requirement. This strategy allows us to mitigate the risk of aerosolization.
HFNC or NIV can also be combined with awake proning resulting in improved oxygenation.
Early application of HFNC or NIV in a patient of moderate ARDS in prone position resulted
in avoidance of intubation and improvement in oxygenation.[16] Presumably, these findings can be extrapolated to COVID-19 respiratory failure as
well. One of the drawbacks of using noninvasive modes of ventilation in pursuit of
avoidance of intubation is the higher level of vigilance required on part of the health
care personnel. Thus, patients on such modalities must be monitored closely with frequent
blood gas analysis (every 2–3 hours) to ensure safety. A low threshold for intubation
should be maintained.
Invasive Ventilation
Most COVID-19 patients with severe ARDS will ultimately need invasive mechanical ventilation.
Timing of intubation is important. If the patient is on NIV/HFNC, it is imperative
that he/she is monitored closely for clinical and/or biochemical deterioration and
intubation is not delayed as it is known to increase mortality. Intubation is known
to have the highest risk of transmission due to aerosol generation.[21] It is important that certain pertinent points are kept in mind before performing
intubation ([Table 2]).[22]
Table 2
Important issues to remember during intubation
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Things to keep in mind
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-
Personnel involved in intubation should be properly donned with personnel protective
equipment which includes a fit tested N-95 mask, eye protection, cap, gown shoe covers,
and gloves
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“Aerosol boxes” have been devised to prevent aerosol dissemination during endotracheal
intubation.[23] In our experience, such boxes hinder arm movement and may actually delay intubation.
We prefer to use a supranormal dose of succinylcholine or rocuronium, and propofol
as part of a Rapid sequence intubation technique and intubate using the precautions
mentioned previously.
The primary aim of ventilation strategy in a COVID-19 patient is avoidance of ventilator
induced lung injury. That means using a low tidal volume ventilation (LTVV) strategy
as described by the ARDS network.[24] We use tidal volumes 6 mL/kg predicted body weight which targets a Pplat <30 cm of H2O with the prescribed positive end-expiratory pressure (PEEP). As is the practice
in ARDS, ventilation is adjusted to keep driving pressure (DP = Pplat − PEEP) less than 15 cm of H2O.
The mode of ventilation used varies, but a volume limited assist control mode is the
most used mode. This mode provides a consistent tidal volume and is less prone to
breath-to-breath changes in the respiratory system compliance, which might lead to
unstable volumes being delivered. In the case of pressure limited modes, changes in
compliance can lead to breath to breath variability in delivered tidal volume. Delivery
of LTVV requires deep sedation, and the higher than normal rates can lead to generation
of auto-PEEP. Ventilator dyssynchrony is common and may occur in up to 25% of ventilated
patients[25]
[26] and includes double triggering, ineffective triggering and flow dyssynchrony. Various
maneuvers and changes to the ventilatory settings can be performed to address these
problems.
If these maneuvers fail to rectify dyssynchrony, the ventilatory modes can be changed.
There are various options such as pressure-regulated volume control (PRVC), pressure
support, airway pressure release ventilation (APRV), volume-targeted pressure-controlled
ventilation (e.g., VC plus), and neurally adjusted ventilatory assist (NAVA) mode.
We will briefly describe PRVC and APRV modes.
Pressure-Regulated Volume Control
In PRVC, the tidal volume is set and the inspiratory pressure changes to attain the
target tidal volume. The inspiratory pressure supplied depends on the pressure required
to attain the tidal volume during the previous breath. This is a time cycled mode
of ventilation. Thus, the duration of inspiration depends on the respiratory rate
and the I:E ratio.
Airway Pressure Release Ventilation
During APRV, a high continuous positive airway pressure (P high) is delivered for
a long duration (T high) and then falls to a lower pressure (P low) for a shorter
duration (T low). The transition from P high to P low deflates the lung and inflates
the lung when P low transitions to P high. The long duration at P high increases alveolar
recruitment.[27]
[28] Driving pressure is the difference between P high and P low, and tidal volume is
related to the driving pressure and the compliance. APRV has been shown to decrease
days on ventilator, days in the ICU, sedation, and muscle relaxant requirement, but
it had no effect on the mortality.[29]
Prone positioning has a proven benefit in ARDS and maybe especially beneficial in
COVID-19 ARDS given the greater propensity of peripheral and dorsal areas of the lungs
to be affected.[30] It is the logical next step when LTVV fails to improve the oxygenation. In our practice,
we prone patients for a minimum of 14 hours a day. Contraindications and complications
remain the same as for any other ARDS case. Care should be taken to avoid venting
of circuit to air which can be prevented by clamping it during disconnections. The
PROSEVA trial demonstrated that the benefit from proning was accrued when it was done
early rather than late.[14]
The decision to stop proning a patient must be individualized. PaO2/FiO2 >150 on a FiO2 <0.6 and PEEP <10 cm of H2O for at least 4 hours after the last prone session makes for a good candidate for
ceasing prone positioning.
Neuromuscular blockade is not used routinely because of concerns for critical illness
polyneuromyopathy. It should be used when there is refractory hypoxemia or patient
ventilator dyssynchrony.
Extracorporeal Membrane Oxygenation
Veno-venous-ECMO (VV-ECMO) is reserved for the most severe form of ARDS, and maybe
suitable for patients who have failed standard low-volume tidal ventilation strategies
and/or who have failed or cannot undergo prone ventilation and high PEEP strategies.
Few centers perform ECMO on a regular basis, especially so in medium- to low-income
countries and it is a resource intensive procedure. A cohort study of ECMO database
of patients with H1N1-related ARDS showed that hospital mortality rate was 23.7% for
ECMO-referred patients versus 52.5% for non-ECMO referred patients.[31] Retrospective data from ECMO usage in patients with middle eastern respiratory syndrome
(MERS) also demonstrated benefit.[32] On the flipside, experience from China has so far not demonstrated conclusive benefit
from the use of ECMO in COVID-19 patients.[33] In low-resource settings, thought should be given to the dilemma of providing an
advanced and expensive, yet unproven therapy to a few patients versus routine care
to many patients. We do not provide ECMO as a routine therapy for COVID-19 ARDS patients
at our institution.
Fluid Management
We prefer to use a conservative fluid management strategy as is advised for any ARDS
patient unless the patient has sepsis or volume depletion secondary to gastrointestinal
losses, fever, etc.[34] Management of COVID positive patients who have septic shock is similar to patients
having septic shock due to other causes. In the recovering COVID-19 patient on the
ventilator, we prefer to keep them “dry” on the day before planned extubation. In
our experience, this facilitates the weaning process. Colloids like starches and gelatin
or hypotonic crystalloids are no longer recommended for use in the intensive care
unit. If a colloid has to be used when patients require substantial amounts of crystalloid,
albumin can be used.
Antibiotics
All our patients receive empirical broad-spectrum antibiotic coverage as it is common
to have superimposed bacterial infection, especially in the presence of comorbidities.
The specific antibiotic coverage can be tailored according to the local infectious
disease epidemiology.[35] In the presence of local seasonal influenza, a neuraminidase inhibitor (e.g., Oseltamivir)
may be added.
Thromboprophylaxis
Routine thromboprophylaxis is warranted in all patients receiving mechanical ventilation
in the absence of any contraindications.[36] This recommendation is valid for COVID-19 patients as well. Anecdotal evidence and
local guidelines at various hospitals across the world suggests that physicians consider
COVID-19 patients to be at a higher risk of venous thromboembolism.[37] This is reflected in the adoption of an intermediate intensity (i.e., administering
the usual daily low molecular weight heparin (LMWH) dose twice daily) or even a therapeutic
intensity dosing strategy.
We prefer to administer the standard prophylactic once daily dosing of LMWH and instituting
therapeutic LMWH dosing if there is evidence of any venous thrombosis or signs of
cytokine storm syndrome. Care should be taken to consider the patient’s renal function
while selecting the agent and the dose, and to individualize anticoagulation.
If the patient is on warfarin at admission (mechanical heart valves, atrial fibrillation,
etc.), it should be continued.
In case of any contraindications to pharmacological prophylaxis, mechanical thromboprophylaxis
should be used.
Supportive Therapies
At the time of writing this review, there has been no therapeutic agent approved for
use in COVID-19 patients. There has been interest in several potential agents and
trials are ongoing.
Corticosteroids
Usage of systemic corticosteroids in MERS resulted in increased viral shedding, delayed
viral clearance, and increased days on ventilator and mortality.[38]
[39]
[40]
[41] The World Health Organization, the Society for Critical Care Medicine, and the Infectious
Disease Society of America recommend against the routine use of systemic corticosteroids
in all COVID-19 positive patients.[34]
[35]
[42] If the patient has underlying chronic obstructive pulmonary disease or asthma, in
septic shock, or has severe ARDS; corticosteroids should be used.[34] Corticosteroids may also be used in severe COVID-19 with cytokine release syndrome
(CRS). We administer methylprednisolone 2 mg/kg/day for 5 days as mandated by government
guidelines.[43]
Hydroxychloroquine/Chloroquine
Hydroxychloroquine was developed and subsequently approved for the treatment of malaria
in 1955 while chloroquine was developed in the 1930s. The mechanism of action is believed
to be accumulation within lysosomes and alteration of the internal pH. Both hydroxychloroquine
(HCQS) and chloroquine inhibit SARS-CoV2 in vitro, but there is limited and good quality clinical data which show a clear benefit.
The U.S. Food and Drug Administration (FDA) has issued an emergency use authorization
while most clinical societies discourage use outside of a clinical trial.
The most concerning side effect of HCQS is QT prolongation and should be avoided in
patients having QTc prolongation at baseline, or on other drugs causing conduction
abnormalities.
We administer hydroxychloroquine 400 mg every 12 hours on the first day, followed
by 400 mg daily for 5 days.
A recent observational study has allayed fears to some extent about the side effects
of hydroxychloroquine usage in COVID-19 patients.[44] But in the absence of robust data, it is not recommended to use HCQS in all COVID-19
patients.
Azithromycin, a macrolide antibiotic has known immunomodulatory properties.[45] When combined with HCQS, it is thought to have a synergistic action on viral activity.
Caution should be exercised when combining both drugs as azithromycin also causes
QT prolongation.
Interleukin-6 Antagonists
Drugs such as tocilizumab, sarilumab, and siltuximab are interleukin (IL)-6 antagonists.
Tocilizumab has been approved as a therapy for CRS related to CAR-T cell therapy.
Since CRS is a common feature of severe COVID-19 infections (presence of persistent
fevers, elevated IL-6 and other cytokines, and elevated ferritin, D-dimer, and other
inflammatory markers), it follows that tocilizumab and other IL-6 antagonists have
a role to play. Indeed, case reports and observational studies have described the
use of tocilizumab in severe COVID-19 patients. The U.S. FDA has recently approved
a phase III trial for tocilizumab usage in COVID-19 and multiple RCTs are ongoing
to answer questions about its efficacy.
Ivermectin
Ivermectin is an FDA-approved and broad spectrum antiparasitic agent that has been
shown to have antiviral activity against a broad range of viruses, including SARS-CoV2
in vitro.[46] Indeed, a case has been made for the synergistic action of hydroxychloroquine and
ivermectin in COVID-19 infections.[47] More robust clinical data are still awaited before use in COVID-19 can be recommended.
Remdesivir
Remdesivir is a nucleotide analog that has in vitro activity against SARS-CoV2.[48] The U.S. FDA granted emergency use authorization for remdesivir for children and
adults with severe COVID-19 but is not available in India yet. There are ongoing trials
to ascertain its efficacy in treating COVID-19 with the current evidence inconclusive.
Preliminary results demonstrate a probable efficacy in treating COVID-19 infections,
but the target patient subset is unclear.
Remdesivir is not recommended in patients with alanine aminotransferase (ALT) levels
more than five times the upper limit of normal. The drug should be discontinued if
these ALT levels are breached. The drug should not be given in patients with an estimated
glomerular filtration rate <30 mL/min per 1.73 m2.
Lopinavir–Ritonavir
It is a combined protease inhibitor, primarily used for HIV, which has in vitro activity against SARS-CoV.[49] It appears to have minimal activity against SARS-CoV2.
Cao et al reported no significant difference in time to clinical improvement, reduction
in viral load, or 28-day mortality with lopinavir–ritonavir compared with standard
care in patients with severe COVID-19.
The use of lopinavir-ritonavir outside the context of a clinical trial is not recommended.
Convalescent Plasma
Convalescent plasma is plasma prepared from a patient who has recovered from an illness.
It is essentially a way to transfer passive immunity to a sick patient. A systematic
review to assess the effectiveness of this therapy in severe acute respiratory illness
of viral etiology concluded that convalescent plasma was effective in reducing mortality.[50]
Whether a recovered patient can donate plasma is dependent on several factors such
as consent for the procedure, blood type matching, antibody titers, and absence of
transmissible infections.
Ideally, convalescent plasma should be administered in the early stages of the disease
when the viral inoculum is low. Possibility of adverse effects such as volume overload,
transfusion reactions, antibody dependent enhancement of infections, etc. should also
be considered.
Plasmapheresis
While targeting the infectious agent, that is, the virus is inarguably important,
mitigation of the excessive host response is also a therapeutic target. The host response
is made up of a complex interplay between excessive cytokine release, endothelial
dysfunction, and hypercoagulability.[51]
[52] Plasmapheresis or therapeutic plasma exchange (TPE) acts on multiple levels of the
inflammatory cascade to mitigate the exaggerated immune response.[53]
Although just a single center and retrospective study, this study showed a mortality
benefit when TPE was used versus standard care in the subset where pneumonia was the
source of sepsis.[54] Similarly, Ma et al reported their encouraging experience of using TPE in patients
with severe COVID-19 infections with cytokine storm.[55]
Plasmapheresis seems to be a promising option in COVID-19 and awaits more robust data.
Blood Purification Devices
Several blood purification devices are available on the market that can remove both
endogenous and exogenous inflammatory mediators. The three most well known of these
devices are Oxiris, Toraymyxin, and Cytosorb. All three have varying efficacy and
adsorption capacity for the removal of cytokines and inflammatory mediators.[56]
The usage of such devices requires specialized equipment and expensive consumables
and have unproven efficacy in the management of COVID-19. Their routine usage cannot
be recommended at this time.
