Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications

Editor—The extraordinary number of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections worldwide has made it inevitable that patients who have recovered from COVID-19 will present for anaesthesia and surgery. Recent data indicate that in the USA alone, approximately one-third of the population had been infected by the end of 2020.¹ With this in mind, we read with interest the recent correspondence by Silvapulle and colleagues² underscoring the wide range of symptoms that often follow recovery from COVID-19 and the complexity of considering residual physiologic abnormalities when assessing perioperative risk. They note that patients suffering from ‘long COVID’ have been reported to exhibit demonstrable abnormalities in several biomarkers as well as cardiac, neurological, haematologic, renal, hepatic, and endocrine impairment. Based on current evidence, the authors suggest that patients previously experiencing mild COVID-19 but without clear evidence of these sequelae can be regarded as having minimal additional perioperative risk. In this context, the relatively young person who suffered mild COVID-19 a year earlier and complains of exertional fatigue but admits to being sedentary and unfit, and has no objective evidence of cardiopulmonary disease or other organ dysfunction will likely raise little concern.

Although the morbidity and mortality associated with severe COVID-19 have appropriately received considerable attention, most SARS-CoV-2 infections result in relatively mild, self-limited symptoms not requiring hospitalisation. Nonetheless, some of these patients subsequently experience persistent fatigue and reduced exercise capacity that is not attributable to cardiopulmonary impairment diagnosed by conventional means.³ Several mechanisms have been proposed including anaemia, deconditioning, and red blood cell abnormalities.⁴ However, many of the studies describing these mechanisms were conducted in patients after hospitalisation, within a few months of recovery.

A central focus of perioperative management has always been maintenance of systemic oxygen delivery (DO₂) and tissue perfusion. Toward this end, research has defined how the fundamental relationships between DO₂, tissue oxygen consumption (VO₂), and oxygen extraction (EO₂) shift from the intraoperative setting where VO₂ tends to be reduced, to the postoperative period when VO₂ increases.⁵ Although a range of postoperative complications have been linked to suboptimal tissue DO₂,^{6 , 7} the incidence of these complications appears relatively low in relation to the documented incidence of perioperative hypoxaemia,^{8 , 9} particularly when considered in light of potential coincidence with other common factors such as anaemia, hypovolaemia, and transient hypotension. A contributing factor may be that, as with most physiological systems, evolutionary pressure has yielded compensatory mechanisms for reduced DO₂ to many organs. Under most circumstances, when DO₂ is low, VO₂ is maintained by augmented EO₂ to prevent tissue hypoxia.¹⁰ This compensatory EO₂ reserve persists until limits that vary among tissue beds are reached and VO₂ becomes DO₂-dependent. Ultimately, in the perioperative setting where alterations in regional VO₂/DO₂ balance occur with regularity, it is probable that this EO₂ reserve is working continuously ‘behind the scenes’ for organ protection.

But what if this seemingly occult protective mechanism is impaired? Clinical experience imparts heightened suspicion of tissue vulnerability in patients with defined end-organ dysfunction or risk factors for reduced functional reserve such as aging, smoking, diabetes mellitus, or hypertension. But how does this affect that relatively young person who admits to being sedentary and unfit but has no objective evidence of cardiopulmonary disease, and whose only other notable medical history is mild COVID-19 a year earlier? A recent report proposed the existence of a specific ‘long COVID phenotype’ with exertional intolerance and dyspnoea despite normal pulmonary function,¹¹ raising the question of whether there is more to this patient than meets the eye.

Recently published data indicate that this may well be the case. Singh and colleagues⁴ performed invasive cardiopulmonary exercise testing (iCPET) on 10 patients (mean age=48 yr; range, 28–79 yr; nine out of 10 female) with persistent exertional limitation 11 (1) months after mild COVID-19. None of the patients had abnormalities evident on chest CT imaging, pulmonary function testing, or resting echocardiogram, and all had normal haemoglobin levels. Study results were compared with those of a matched control group of 10 patients with normal exercise capacity and no history of COVID-19. As shown in Table 1 , relative to control patients at rest, DO₂ was the same for post-COVID-19 patients but VO₂ and systemic EO₂ were modestly reduced. At peak exercise, when functional reserve mechanisms normally increase both DO₂ and EO₂, the difference in VO₂ and EO₂ between control and post-COVID-19 patients was more profound. Importantly, this disparity occurred despite a peak exercise response for heart rate and DO₂ that was similar for both groups. These results indicate that exercise capacity was primarily limited by impaired systemic EO₂ of such severity that what should have been an adequate increase in DO₂ was insufficient to allow for an increase in VO₂. Although patients who are deconditioned can exhibit impaired EO₂ with exercise,¹² preservation of the capacity to increase heart rate and cardiac output adequately at peak exercise in post-COVID-19 patients makes deconditioning a less likely singular explanation for their exercise limitation. In fact, several patients included in the study had already completed supervised exercise rehabilitation programs by the time of their iCPET. The lack of objective evidence for the presence of other factors such as anaemia, impaired cardiac or pulmonary function, or superimposed non-COVID infection suggests a possible microvascular/molecular abnormality. It is worth noting the overlap between the clinical presentations of patients with post-COVID-19 exercise limitation and patients with myalgic encephalitis/chronic fatigue syndrome.¹³ The causal hypothesis of myalgic encephalitis/chronic fatigue syndrome has also been linked to preceding infection including human herpes virus, enterovirus, influenzae, Epstein–Barr virus (EBV), and Borrelia burgdorferi.^{14 , 15}

Table 1.

Baseline characteristics and relevant cardiopulmonary exercise data. Data are presented as %, mean (standard deviation), or median (inter-quartile range [IQR]). Data adapted from Singh and colleagues.⁴ FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; SaO₂, oxygen saturation in arterial blood; DO₂, oxygen delivery; VO₂, oxygen consumption; EO₂, oxygen extraction ratio, CPET, cardiopulmonary exercise testing.

	Post-COVID-19 (n=10)	Controls (n=10)	P-value
Characteristics
Age, yr (range)	48 (28–79)	48 (40–68)	0.87
Female/male	9/1	8/2	0.53
BMI (kg m−2)	28 (6)	24 (6)	0.11
Haemoglobin (g dl−1)	13.4 (1.1)	14.2 (1.4)	0.16
Interval time from acute infection (months)	11 (1)	Not applicable
Pulmonary function tests
FEV1 (% predicted)	97 (1)	100 (1)	0.34
FVC (% predicted)	96 (1)	104 (1)	0.19
FEV1/FVC (% predicted)	101 (3)	98 (5)	0.18
CPET – resting
SaO2 (%)	98 (IQR 97–98)	98 (IQR 97–98)	0.64
Mixed venous O2 saturation (%)	73 (3)	66 (6)	0.01
Stroke volume index (ml m−2)	36.3 (10.3)	40.3 (12.8)	0.44
Cardiac index (L min−1 m−2)	3.2 (0.6)	2.8 (0.5)	0.13
DO2 (ml kg−1 min−1)	1.41 (0.24)	1.24 (0.35)	0.23
VO2 (ml min−1 kg−1)	3.69 (0.5)	4.38 (0.8)	0.04
Systemic EO2 (ratio)	0.26 (0.03)	0.36 (0.01)	0.01
CPET – peak exercise
VO2 (ml min−1 kg−1)	16.7 (4.2)	33.5 (12.9)	0.001
Heart rate (% predicted)	84 (8)	84 (2)	0.85
SaO2 (%)	98 (IQR 98–98)	97 (IQR 97–98)	0.01
Mixed venous O2 saturation %)	50 (10)	22 (5)	<0.0001
DO2 (ml kg−1 min−1)	3.6 (1.4)	4.2 (1.5)	0.33
Systemic EO2 (ratio)	0.49 (0.1)	0.78 (0.1)	<0.0001
Cardiac index (L min−1 m−2)	7.8 (3.1)	8.4 (2.3)	0.59
Stroke volume index (ml m−2)	54.1 (20.8)	63.5 (22.2)	0.34

Given the broad heterogeneity of symptoms associated with COVID-19, the complexity of accurately measuring EO₂, and the fact that a substantial number of people have undoubtedly experienced mild but undiagnosed SARS-CoV-2 infection,¹ it is difficult (if not impossible) to define the incidence, much less the consequences, of impaired EO₂ reserve after mild COVID-19 in the surgical population. Ultimately, we agree with Silvapulle and colleagues² that at present the best approach to perioperative risk assessment in post-COVID-19 patients is tangible, objective evaluation of multiorgan sequelae. Nonetheless, clinicians should be aware that a deficit may exist that can mimic impaired tissue DO₂ despite normal cardiopulmonary function and haemoglobin level, and potentially enhance the adverse consequences of perioperative hypoxaemia, anaemia, or impaired tissue perfusion. We are just beginning to learn about the long-term sequelae of even mild COVID-19, underscoring the need to be vigilant to the potential for a broader perioperative impact of prior SARS-CoV-2 infection.

Declarations of interest

The authors declare no conflicts of interest.