Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection

Impaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria, but severe orthostatic intolerance in Plasmodium vivax has been rarely reported [1‐3]. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min after a change from a reclining to upright posture, together with associated symptoms [4]. It can be a debilitating symptom in conditions characterized by autonomous nervous system dysfunction [5]. Symptoms are caused by decreased cerebral perfusion, including blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope [6]. On standing, the gravitational volume shift causes a redistribution of circulating blood, with pooling in the capacitance vessels below the diaphragm [7]. A normal compensatory haemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [4]. Preservation of an adequate blood pressure is ensured by a prompt rise in cardiac output, mainly through an increase in heart rate, and an increase in vascular resistance favoring the cerebral blood circulation [8]. In dysautonomic states, this response to circulatory redistribution is impaired, which may lead to a compromised cerebral blood flow. Orthostatic hypotension in acute Plasmodium falciparum infection has been well described and is related to a combination of persisting relative bradycardia and insufficient peripheral vasoconstriction [9]. A case of severe orthostatic hypotension in a patient with a P. vivax infection, mimicking severe malaria is described. Haemodynamic profiles and possible pathophysiological features are discussed.

Patient is a 32-year old previously healthy Thai female without a history of malaria and not taking any medication before the disease episode. Two weeks prior to admission she had travelled to a malaria endemic forested area in Kanchanaburi Province, Thailand for camping and hiking with friends and her 6-year-old son. Eight days prior to admission she developed a high-grade fever with headache and chills without localizing symptoms. She had a history of poor appetite, nausea and reduced oral intake without vomiting or diarrhoea. On admission, she had a fever of 39.8 °C, a pulse rate of 78 beats per minute and a blood pressure of 90/60 mmHg. Her weight was 49 kg which were 1 kg lower from her base line of 50 kg. Her consciousness was normal, conjunctivae were not pale and sclerae were not icteric. She had no cold or clammy skin and her capillary refill time was less than 2 s. The liver span was 10 cm in the mid-clavicular line and the spleen was normal in size on palpitation.

Initial complete blood count revealed anaemia with 31% haematocrit, as well as thrombocytopenia of 74,000/µL. Liver function tests revealed mild elevated aspartate aminotransferase and alanine aminotransferase of 60 U/L and 86 U/L, respectively. Blood sugar, creatinine, glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and urinary analysis were normal. Microscopic examination of a peripheral blood film showed an asexual stage P. vivax parasitaemia of 69,800 parasites/µL and the diagnosis was confirmed by a positive polymerase chain reaction (PCR) for P. vivax. In patients breathing spontaneously, inferior vena cava (IVC) collapsibility index measured by transthoracic echocardiogram is a predictor of fluid responsiveness when the value was more than 42% [10]. In this patient, IVC collapsibility index was 46%, which is predictive of a positive fluid responsiveness. She was admitted to the Hospital for Tropical Diseases and given 600 mg chloroquine orally and started on 5% dextrose in 0.9% Sodium Chloride infusion at a rate of 80 mL/h. After 10 h and infusion of 800 mL fluids, the patient complained of postural faintness while getting out of bed. At that moment, she had an upright blood pressure of 77/46 mmHg and a pulse rate of 103 beats/min which increased to 90/50 mmHg in the supine position. Her urine output was 0.5 to 1 mL/kg per an hour. After lying down, she had good consciousness, warm extremities and capillary refill less than 2 s. Her IVC collapsibility index was 31%. Twelve-lead electrocardiogram showed sinus tachycardia with a normal QTc interval.

She was initially diagnosed with severe Plasmodium vivax and given intravenous artesunate 2.4 mg/kg promptly followed by intravenous artesunate in the same dose after 12 h, which was repeated every 24 h for 5 days. Intravenous ceftriaxone was also started to cover potential concomitant bacterial septic shock awaiting blood culture results. Blood cultures obtained before start of antibiotics, however, remained without growth after which antibiotic therapy was discontinued on the 3rd day of admission. After transferring the patient to the intensive care unit, 400 mL normal saline was given over 1 h. After the fluid bolus, her blood pressure was 88/56 mmHg and her pulse rate was 74 beats/min in the supine position with falling to 77/50 mmHg and 72 beats/min while standing, and IVC collapsibility index of 16%, compatible with non-responsiveness to fluid resuscitation. Table 1 details her haemodynamic profiles during hospital admission. This prompted the start of intravenous norepinephrine at a dose of 0.13 µg/kg/min to maintain a blood pressure of 90/50 mmHg in an upright position. Her plasma lactate assessed at that moment was 1.8 mmol/L (normal value: < 2 mmol/L). Her morning serum cortisol on the next day was 32 µg/dL (normal level: > 6 µg/dL) making a diagnosis of primary or secondary adrenal insufficiency unlikely, and corticosteroids were not started. Haemodynamic monitoring by an ultrasound cardiac output monitor (USCOM) in the supine and upright position before receiving norepinephrine showed a marked drop in cardiac index from 3 L/min/m² in the supine position to 1.9 L/min/m² after standing for 3 min, despite adequate hydration. The upright positional drop in cardiac output in the upright position was explained by an absence of an increase in stroke volume, and an insufficient increase in heart rate (Table 1). This orthostatic hypotension persisted until 3 days after microscopically confirmed parasite clearance, necessitating continued vasopressor support with norepinephrine (Table 1) (Figs. 1, 2, 3, 4, 5 and 6). Orthostatic intolerance only resolved completely at the 12th day of follow up. After recovery, the patient received radical treatment with a 14-day course of (0.25 mg/kg daily) primaquine.