In Search of Rationality: Hospital Management of Covid-19

REMDESIVIR

Remdesivir may be considered for fever (>38 C) at day 7 as 27.8% of patients with persistent fever develop hypoxia with 11.1% requiring intensive care¹. Remdesivir otherwise is not considered to be effective in non-hypoxic patients² and 5 days of treatment is no worse than 10 days³. The main beneficial effect  is a reduction  in the duration of symptoms⁴ and though there is a signal of improved mortality this has not been statistically significant. A systematic review and guidelines are available from the ACP^5,6. These suggest a 5 day course in hypoxic hospitalised patients not on invasive ventilation less than 10 days from onset of illness. If the patient deteriorates and is intubated while on Remdesivir extending the course to 10 days may be useful. The NIH⁷ and IDSA⁸ guidelines are similar. On the contrary the WHO – Solidarity trial⁹ showed no benefit from Remdesivir and consequently the WHO guidelines¹⁰ do not recommend Remdesivir.

DEXAMETHASONE

Dexamethasone 6 mg IV improves mortality when started in patients requiring oxygen or higher levels of respiratory support as conclusively shown in the Recovery – dexamethasone trial¹¹ and confirmed by a WHO sponsored meta-analysis¹².The level of SpO2 at which Dexamethasone should be started is unclear – IDSA guidelines⁸ say <94% while the WHO¹³ guidelines state <90%. The NIH guidelines¹⁴ do not specify a SpO2 level. We recommend starting Dexamethasone when resting SpO2 is persistently <94%.

There is a signal for harm if patients without hypoxia are treated with steroids¹¹ and as such this is discouraged by all guidelines^8,13,14.

In Covid – ARDS patients with PaO2/FiO2 < 200 Dexamethasone 20mg daily for 5 days and 10mg daily for 5 days maybe used as in the successful CoDEX trial in Covid patients¹⁵ which was based on the dosage showing  mortality benefit in the non-covid Dexa-ARDS trial¹⁶. Roughly any patient requiring more than 6 LPM nasal oxygen to keep Spo2 90% should be considered for the higher dose Dexamethasone strategy.

The duration of treatment for both low and high dose Dexamethasone is not more than 10 days with no need for tailing off. If a patient moves from low to high dose Dexamethasone because of deterioration the total number of days of Dexamethasone treatment may be more than 10.

TOCILIZUMAB

The Recovery trial¹⁷ and REMAP-CAP¹⁸ trials have confirmed mortality benefit from administration of Tocilizumab. Lower levels of success have been demonstrated in the EMPACTA trial with improvement in a composite outcome but not mortality¹⁹. The CORIMUNO-19²⁰, COVACTA²¹, BACC-BAY²², the Coalition covid-19 Brazil VI Investigators²³ and theRCT-TCZ-COVID-19 trial²⁴ did not show any benefit. There is strong evidence from these trials that Tocilizumab does not work without concomitant steroids or during  established invasive ventilation . All these RCTs have been reviewed by the NIH²⁵, NICE²⁶  and IDSA⁸ guidelines groups and all groups have given recommendations in favour of Tocilizumab in all patients with raised inflammatory markers and within 24-48 hours of requiring HFNC, NIV/CPAP or invasive ventilation. The IDSA and NICE in addition recommend it in progressively hypoxic patients even on conventional oxygen while the NIH agree that some patients in the conventional oxygen group probably benefit from it but is not sure how those patients should be selected. None of the trials used IL6 to target treatment. The WHO is in the process of reviewing the literature on Tocilizumab with a metanalysis²⁷ and have not made any recommendation at this time. A separate metanalysis²⁸ of all the above trials has confirmed a mortality benefit.

Patients with rising CRP, IL6 and low or stable Procalcitonin with progressive hypoxia despite steroid use should be considered for Tocilizumab. Values of CRP>100 or IL6 >80 and Procalcitonin <1 should be viewed with particular concern.

• We have however personally seen patients with IL6 >80 who were not hypoxic and who improved without any intervention and decreased their IL6 to <10 in 48 hours.
• Our inclusion of Procalcitonin levels in our calculations is based on the fact that it is usually less than 1.1 in “pure” covid²⁹. If Procalcitonin is raised we focus our attention on bacterial coinfection and avoid Tocilizumab..
• 400 mg (8mg/kg) single dose once has been most used, with occasional use of a second dose within 24 hours.
• Repeat testing of IL6 levels are not useful after using Tocilizumb as it can increase IL6 levels for weeks.
• Significant liver disease is a contraindication to its use.

ANTICOAGULATION

Standard dose prophylaxis is indicated in all hospitalised patients as it reduces mortality³⁰. The INSPIRATION RCT conclusively shows that intermediate dose prophylaxis is of no benefit in any patient group³¹. The preliminary report of the ATTACC/REMAP-CAP/ACTIV4A³² RCT in critically ill covid patients (defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes) suggests that full anticoagulation increases mortality in these patients. A similar finding was seen in the large STOP-COVID database review³³. In view of this, empirical full anticoagulation in the critically ill patient is to be avoided except in proven or strongly suspected VTE. The preliminary report of the same group of full anticoagulation in moderately ill covid patients – as yet unpublished in any form –has been discussed in two reviews^34,35 and there is cautious optimism that it improves outcome. The interim results are available on the internet³⁶. Interestingly D-Dimer levels have no bearing on outcomes regarding anticoagulation in this study. Post discharge DVTs are no more than similar non-covid patient series^37–39 and post discharge thromboprophylaxis is unlikely to be beneficial. The ACCP guidelines⁴⁰ concur with standard thromboprophylaxis, no benefit to intermediate dose thromboprophylaxis or D-Dimer stratified thromboprophylaxis and no extended thromboprophylaxis post discharge.

All patients with Spo2 persistently less than 94% receive

• 5 days of IV Remdesivir (within day 10 of symptom onset)
• 10 days of 6 mg Dexamethasone IV/oral (usually after day 7 of symptom onset)
• 40 mg of Enoxaparin s/c daily
• Consider Tocilizumab in progressively hypoxic patients despite steroids guided by Procalcitonin /IL6/CRP levels

 In patients requiring >6LPMNC to maintain SpO2 90%

• Consider 20 mg Dexamethasone for 5 days then 10 mg Dexamethasone for 5 days
• Consider Tocilizumab(within 48 hours of starting NIV/CPAP/HFNC/Invasive ventilation )

• D-Dimer stratification, Intermediate dose or post discharge thromboprophylaxis is not recommended
• Full dose anticoagulation for critically ill patients (in the absence of proven or strongly suspected VTE) is not recommended
• Remdesivir is not recommended on patients established on mechanical ventilation but maybe considered for patients with persistent fever at day 7
• Seek expert opinion re full anticoagulation in moderately hypoxic patients

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