K Katyayani and R Kapoor present a case study of severe hypothermia, complicated by cardiac arrest secondary to accumulation of uremic toxins in a patient with known stage four kidney disease secondary to renovascular hypertension
Uremic syndrome is known to occur in patients with advanced kidney disease and one of the presenting symptoms, apart from fluid and electrolyte imbalance, can be hypothermia. What is uncommon though is the primary presentation of uremic syndrome being profound hypothermia. We report a case of severe hypothermia complicated by cardiac arrest secondary to accumulation of uremic toxins in a patient with known stage 4 kidney disease secondary to renovascular hypertension. This case emphasises the need to be vigilant, especially in elderly patients with chronic renal disease, who are at higher risk of suffering from age-related impairments to their thermoregulatory system and therefore more likely to present with hypothermia complicating uremia. Uremic syndrome, despite being a rare cause of hypothermia, with early diagnosis and effective management can lead to excellent patient recovery within a short space of time.
Uremic syndrome is a manifestation of end stage kidney disease and, as such, most patients are commenced on renal replacement therapy long before the clinical signs and symptoms of uremic syndrome manifest. This makes patients presenting acutely with uremic syndrome a somewhat uncommon occurrence. Although hypothermia is associated with uremic syndrome, severe hypothermia is rare. Humans have a remarkable ability to maintain a relatively constant core body temperature of 36.5-37.5°C, irrespective of the environment due to the presence of an effective thermo-regulatory system. Severe hypothermia i.e. a temperature below 28° C can cause significant morbidity and mortality. The causes are varied with exposure to cold stress, especially during winter being one of the commonest. Other causes include sepsis, endocrine disorders, hypoglycaemia and DKA. Though the pathophysiology and management of uremic syndrome has been extensively researched, the evidence regarding hypothermia in uremic syndrome is limited. Accumulation of Endogenous cryogens in uremic syndrome has been thought to induce peripheral vasodilatation and supress shivering metabolism, thus inducing falls in body temperatures . We report a case of a patient with known stage 4 kidney disease secondary to reno-vascular hypertension who presented with hypothermia and suffered a cardiac arrest which were both secondary to accumulation of uremic toxins.
A 60-year-old retired gentleman was brought into accident and emergency by ambulance with worsening confusion and reduced responsiveness. He had a body mass index (BMI) of 42, a background history of hypertension, and chronic kidney disease (CKD) stage 4 secondary to hypertension induced renovascular disease. He was noncompliant with his regular antihypertensive medications, which included calcium channel blockers and beta blockers. He was also non-compliant with nephrology appointments.
On presentation, he was bradycardic with a heart rate between 30-35 beats/min and hypotensive. Although his GCS was 11/15 (E3V3M5) he was profoundly hypothermic with a temperature of 280 C with a tympanic thermometer. The hypothermia was not associated with shivering. There was no history of exposure to cold environment to explain the finding of severe hypothermia.
Arterial blood gas done on arrival confirmed a significant metabolic acidosis with a lactate of 7.7 mmol/L.
Active rewarming was commenced with forced air warming device. In view of the hypotension, 500 micrograms of intravenous atropine was administered, but no response to the heart rate was noted. In addition to supplemental oxygen and warm fluid resuscitation, routine blood tests including a full blood count, electrolytes and renal and liver function tests were requested. Over the next thirty minutes he became unresponsive and suffered a witnessed asytolic cardiac arrest. Cardio pulmonary resuscitation (CPR) was commenced immediately and return of spontaneous circulation was achieved after two cycles of CPR and 1 mg intravenous adrenaline. He immediately regained consciousness and could maintain a patent airway throughout, though he remained bradycardic and hypotensive with worsening metabolic acidosis. The patient also received one dose of empirical broad-spectrum antibiotics as sepsis was considered as one of the differential diagnosis. He was noticed to be anaemic with an Hb of 60 gm/L and in acute kidney injury with a urea of 48mmol/L and creatinine of 1099 mmol/L.
He was transferred to the intensive therapy unit (ITU), where invasive monitoring and inotropes were commenced with active rewarming continued. As his blood pressure stabilised on inotropes he was commenced on continuous veno-venous hemofiltration (CVVHF). A focused bedside echocardiography was performed to rule out cardiogenic shock and confirmed well-functioning right and left ventricles with no evidence of pericardial effusion.
On renal replacement therapy over the next 10 hours his heart rate spontaneously recovered to 86 beats/min. Antibiotics were discontinued as the infective markers were within normal limits and no focus of infection was identified. Over the following 12 hours his temperature normalised, inotropes were weaned off, he was tolerating oral intake, but remained on CVVHF. During his stay on the ITU septic screen, thyroid function tests, random cortisol levels and trans-thoracic echocardiography were all within normal limits. His illness and brief cardiac arrest were attributed to hypothermia and bradycardia secondary to uremic syndrome.
He made a good recovery and was discharged to the renal ward following a 44-hour stay on ITU. He was continued on regular haemodialysis and was discharged home after nine days of stay in hospital. He currently remains on regular haemodialysis and continues to do well.
Though severe hypothermia is a medical emergency and can be associated with severe morbidity and mortality, the causes can be varied. The treatment mainly involves active external rewarming by application of warm blankets, radiant heat or forced warm air directly to the skin. If the patients fails to respond to these measures active internal rewarming measures including invasive extracorporeal rewarming can be used.
At present in the UK there is a significant drive to increase awareness of sepsis. Therefore, when this patient first arrived at the hospital, the initial differential diagnosis was considered to be sepsis, which was soon ruled out. While the majority of septic patients are febrile, 10-20 per cent of patients could be hypothermic. The exact mechanism of sepsis-induced hypothermia is not clearly known. Previous studies hypothesised a lack of pro-inflammatory cytokines, especially interleukin (IL)-6 and tumour necrosis factor (TNF)-α, though recent studies suggest elevated levels of fractalkine, marker of endothelial activation, may play a role .
In our patient renal function tests performed as part of the routine work up confirmed acute kidney injury with uremic syndrome as the cause for the presenting symptoms. The term “uremia” was introduced in 1840 by Piorry and L’ H’eritier which literally meant urine in the blood . They believed manifestations of renal failure were due to poisoning of blood from reabsorption of urine. Today, the term uremic syndrome is used to describe the impairment of several biochemical and physiological functions associated with deteriorating renal function . Urea was one of the earliest retention product to be recognised while Oxalic acid, beta -2 microglobulin, PTH, guanidines are examples of other recognised uremic toxins. The compounds that accumulate in the highest concentrations, were identified first and have been most widely studied. Remarkable progress has been made in the research of uremic toxins and at present there are 152 solutes listed in the European Uremic Tox database . Uremic solutes are classified based on their physio-chemical characteristics and removal by dialysis into three groups  as described in the table below:
However Uremic syndrome is complex with multi-organ involvement with varied signs and symptoms, and all these complications cannot be traced back to dysregulation of any one single compound. Dialysis forms the mainstay of treatment while other forms of renal replacement can be used as well. Renal transplant is the only form of definitive treatment. The clearance of uremic retention solutes is however varied and depends on their molecular weight, protein binding and sequestration in blood and other tissues.
Though the pathophysiology of organ system involvement in uremic syndrome is widely researched, the literature regarding uremia and hypothermia in humans is limited. Kluger et al  in 1981 conducted an experimental study in rabbits to study the effects of injection of endogenous cryogen on body temperature. They concluded that injection of human urine in rabbits led to a fall in temperature, because of peripheral vasodilatation in thermo-neutral environment and suppression of shivering without vasodilatation in cold environment. They also hypothesised that endogenous cryogens in the urine could act on the thermoregulatory system and lower the thermoregulatory set point .
A similar in vitro study in rats by Hohegenner et al hypothesised that uremic hypothermia is secondary to a reduction in metabolic rate and that the direct action of toxic substances at the cellular level might be contributory . However, there is a lack of experimental studies reproducing uremic signs and symptoms by raising solute levels in animals or humans. One report which looked at the association of uremic syndrome with hypothermia in uremic patients, found that in eight out of ten patients, temperature normalised after initiation of haemodialysis . Similar normalisation of temperature with haemodialysis was noted in uremic cats and dogs .
There are case reports of hypothermia associated with acute renal failure in patients with diabetic nephropathy and malnutrition [8-9]. However, in these cases reduced muscle mass leading to impaired shivering thermogenesis has been thought to be an important co-factor contributing to hypothermia. Recent evidence suggests that the mitochondrial uncoupling proteins (UCAP-1) are upregulated in brown adipose tissue following exposure to cold stress, however it is far scarcer in adults compared to neonates .
Although our patient was not malnourished, shivering thermogenesis was impaired. One explanation could be a loss of muscle mass, despite a high BMI, leading to impaired shivering. Obesity is reported to have detrimental effects on the functioning of skeletal muscles. Evidence suggests that obese individuals have reduced maximum muscle strength relative to body mass and can cause functional limitations especially in the elderly .
This case emphasises that not all hypothermia is sepsis related and there is a need to be vigilant in patients with renal disease who are non- compliant with their treatment. It is also worth exploring more unusual causes of severe hypothermia especially when the history, signs and symptoms don’t quite add up. Though Uremic syndrome is easily diagnosed with a combination of clinical and biochemical markers, a high index of suspicion in patients with chronic renal failure will prevent delays in managing a relatively easily treatable condition. Acknowledgements: Published with the written consent of the patient, and verbal consent of his partner.
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AUTHORS: Dr K Katyayani ST6 Anaesthetics, King’s College Hospital NHS Foundation Trust, Dr R Kapoor Consultant Intensivist and Anaesthetist, Kent and Canterbury Hospital, East Kent Hospitals NHS Foundation Trust.