In this report, three cases of imported malaria complicated by severe ARDS supported with ECMO are presented. Severe ARDS may be a complication of P. falciparum, P. vivax or P. ovale infections. In accordance with the WHO guidelines the presence of ARDS is a defining criterion for severe malaria . In all three cases, oxygenation and CO2 clearance through the membrane ECMO lung allowed the compliance to protective ventilation of the native lung with low tidal volumes (<6 ml/kg IBW) and low-fractional oxygen concentrations, limiting ventilator-induced lung injury . However, permissive hypercapnia is frequently necessary to allow low tidal volume protective ventilation in severe ARDS. This could be potentially harmful in patients with severe malaria, given that cerebral oedema with elevated intracranial pressures can complicate cerebral malaria  and that hypercapnia causes cerebral vasodilatation and intracranial pressure elevation. Moreover, microvascular congestion and sequestration of parasitized red blood cells was shown to be a common feature in cerebral malaria, leading to impaired tissue perfusion that may cause diffuse cerebral ischemia and increased intracranial blood volume . The use of ECMO in patients with severe malaria, allowing strict control of patient’s PaCO2, potentially limits intracranial pressure elevation.
Fluid management is crucial in patients with severe malaria. Taking into account that in these patients pulmonary edema secondary to increased pulmonary vascular permeability has been shown to be frequent, unpredictable and exacerbated by fluid loading, a conservative strategy of fluid management was followed in all three patients before and after ECMO initiation . Moreover, a liberal strategy of fluid management in acute lung injury has been previously associated with prolonged duration of mechanical ventilation and intensive care .
ECMO is not without risks and there are no definitive criteria for ECMO treatment in adult ARDS. Therefore, ECMO should only be considered in adult patients with malaria and severe ARDS refractory to conventional treatment. The recently conducted CESAR trial showed favourable results of ECMO referral for adult patients with severe ARDS . In that context, the same inclusion (Murray score >3.0 or pH <7.20) and exclusion (high pressure (>30 cm H2O of peak inspiratory pressure) or high FiO2 (>0.8) ventilation for more than seven days; intracranial bleeding; any other contraindication to limited heparinization) criteria for ECMO consideration in malaria and severe ARDS were used in the present case series.
Severe imported malaria is an important problem in the western world due to the increasing number of travellers returning from endemic countries who are non-adherent to malaria chemoprophylaxis . Most imported cases occur in non-immune patients in whom malaria can rapidly progress to severe disease, with mortality as high as 20 to 35%, even with adequate anti-malarial treatment . ARDS may develop in isolation or as part of a severe multisystem illness and often occurs within a few days of starting treatment when parasitaemia is falling . The pathogenesis of ARDS in malaria is not fully understood, though it may involve parasite sequestration in the pulmonary vasculature and up-regulation of pro-inflammatory cytokines, and may persist even after parasite clearance . However, parasite sequestration in the pulmonary vasculature seems to be relevant only for P. falciparum infection, given that in P. vivax malaria there is no substantial lung sequestration. Severe ARDS in patients with malaria has a poor prognosis, with mortality as high as 69 to 95% in observational ICU case series [22, 25]. Severe ARDS most commonly complicates P. falciparum infection and is rarely a complication of P. vivax or P. ovale infection. This could be related to differences in cyto-adhesion of infected erythrocytes [26–29]. However, it should be stressed that it is difficult to definitely establish malaria as the sole etiology for severe ARDS, fully excluding bacterial co-infection. Nevertheless, no documentation of bacterial co-infection was found despite extensive microbiology specimen collection and culture at ICU admission. This could support the assumption that malaria was the most probable cause for severe ARDS in the three cases presented in this report.
Risk factors associated with the development of ARDS in malaria include advanced age, lack of specific immunity, immunocompromised status, and pregnancy. A high parasitic burden is not necessary . In this case series, patients were either semi-immune or non-immune and parasitaemia was less than 4% in all patients.
There are only two prior cases reported separately on the use of ECMO for severe ARDS in patients with malaria, as well as one case on the use of extracorporeal carbon dioxide elimination [5, 12, 13]. In both cases of ECMO use, P. falciparum was identified as the causal organism and ECMO was instituted within seven days for refractory hypoxaemia, but only one patient survived [5, 12]. In the case of extracorporeal carbon elimination use, P. falciparum was also identified as the causal organism and extracorporeal carbon elimination was instituted on the 17th day, being discontinued after twelve days. The patient was weaned from mechanical ventilation and successfully discharged home . In the present case series, one of the two patients that initiated ECMO after more than seven days of IMV did not survive. Patients with ARDS who have been receiving IMV with excessively high plateau pressures or high fractions of inspired oxygen for more than seven days may be less likely to benefit from ECMO [31–35]. Earlier initiation of ECMO, for these or other reasons, has been associated with better outcomes in some, but not all, observational studies [33, 36–38].
Patients with severe forms of malaria are highly susceptible to bacterial infections and concomitant antibacterial therapy is recommended [2, 39]. All the three patients presented in this case series received adequate antimicrobial therapy, though one patient developed nosocomial infections and ultimately died of sepsis, despite appropriate antibacterial coverage.
ECMO-related complications in the present case series included cannula migration into a hepatic vein, which was identified by transesophageal echocardiogram and corrected at the bedside. Thrombus formation in the oxygenator was ultimately the cause for oxygenator exchange in one patient. However, the rate of thrombosis-associated oxygenator failure requiring device exchange is low, even at low levels of anticoagulation . Major bleeding complications, as occurred in one patient, are less frequent in the era of modern ECMO technology, given the ability to maintain circuit integrity at lower levels of anticoagulation, but they may still occur, especially in the setting of pre-existing thrombocytopaenia or coagulopathy.
In conclusion, severe ARDS can complicate P. falciparum, P. vivax, and P. ovale infection. In regions where the technology is available, ECMO referral should be considered for patients with malaria complicated by severe ARDS refractory to conventional treatment. Taking into account the limited experience with ECMO in severe malaria yet, its use should be performed in experienced ECMO centers. In fact, severe malaria can cause haemolysis, disseminated intravascular coagulation and low platelets, which might be exaggerated by the use of extracorporeal devices.