Management of earthquake-related acute renal injury

Abstract

This frontier will highlight the principles of diagnosis and management of earthquake crush syndrome and related acute kidney injury (AKI) based on our two recently published highly accessed collective review articles. Continuous prolonged pressure of the rubble on injured muscles following earthquakes may cause crush injuries. When the patient is extricated and the compressed muscles are relieved, an ischemia–reperfusion injury, with systematic serious metabolic disturbances, occurs. This includes hyperkalemia, rhabdomyolysis, and AKI. AKI is caused by three mechanisms. Prerenal factors include: (1) Hypovolemia due to bleeding; (2) Dehydration due to lack of water; (3) Ischaemia-reperfusion injury; and (4) Cardiac depression caused by released toxins. Renal factors include the nephrotoxic effects of the uric acid and bilirubin, tubular casts obstructing the tubules, or the direct deposition of phosphorus and calcium inside the kidneys. Pelvic fractures may cause urethral rupture with postrenal obstruction. The management principles of crush syndrome and AKI include: (1) Proper fluid therapy to maintain adequate urine output; (2) Preventing and treating hyperkalemia; and (3) Renal replacement therapy when indicated in cases of severe hyperkalemia, severe acidemia, volume overload, or severe uremia. Recognizing these conditions and treating them timely and properly will save many patients.

Key Words: Acute kidney injury; Earthquake injury; Trauma management; Rhabdomyolysis; Crush syndrome; Renal dialysis

Core Tip: The causes of earthquake-related acute kidney injury (AKI) include: (1) Prerenal include bleeding, dehydration, ischaemia-reperfusion injury, or cardiac depression; and (2) Renal include nephrotoxic effects of the uric acid and bilirubin, tubular casts obstructing the tubules, or intra-renal deposition of phosphorus and calcium. Pelvic fractures may cause urethral rupture with postrenal obstruction. The management principles of crush syndrome and AKI include: (1) Proper fluid therapy to maintain adequate urine output; (2) Preventing and treating hyperkalemia; and (3) Renal replacement therapy when indicated in cases of severe hyperkalemia, severe acidemia, volume overload, or severe uremia.

BIOGRAPHY

Professor Fikri M Abu-Zidan (Figure 1) is an international scholar in acute care and trauma surgery, disaster medicine, point-of-care ultrasound, and applied medical statistics and research methodology. During his 43-years career, he has made major contributions to trauma management, education and research in Kuwait, Sweden, New Zealand, Australia, and United Arab Emirates. He has contributed to more than 520 publications in books and refereed international journals. He presented more than 800 invited lectures and scientific abstracts and received more than 40 national and international awards for clinical, research and educational activities. He chaired the organization committees of seven successful international conferences on trauma management, critical care, and prevention. Currently, he serves as the Statistical Consultant for the World Society of Emergency Surgery, as the Statistical Editor for the World Journal of Emergency Surgery, and as the Biostatistics Editor for European Journal of Trauma and Emergency Surgery. He has served as the Chair of the Human Research Ethics Committee of United Arab Emirates University (2017-2019). He developed numerous innovative approaches in his research, educational and clinical activities. He has been extensively involved in medical research for more than 40 years. This resulted in developing practical workshops on medical research methods and writing that have been running globally in different countries. This mingles his extensive clinical, research, statistical, and educational experience into very attractive and educational workshops in which he shares his research design, statistical analysis, and editing with academic staff and clinical researchers.

Figure 1  Fikri M Abu-Zidan, MD, FACS, FRCS, PhD, Dip Applied Statistics, Professor of Disaster Medicine, Consultant of Statistics and Research Methodology, Department of Surgery, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates. Fikri M Abu-Zidan, Statistical and Research Methodology Consultant, The World Society of Emergency Surgery, Bologna, Via Cracovia 23, Italy.

Dr Kamal M Idris (Figure 2) is a Consultant Critical Care Physician who has been trained in Sudan and South Africa. He is currently the chair of the Intensive Care Unit at Burjeel Royal Hospital at Al-Ain, United Arab Emirates. He is a dynamic physician with extensive experience in managing severe trauma, crush syndrome and its renal complications. He was the leading intensivist in Al-Ain, having a population of more than 700000 inhabitants, during the coronavirus disease 2019 pandemic during which he showed extraordinary devotion and commitment by taking care of very sick patients. He demonstrated proficiency in forming and leading multi-disciplinary teams during disaster situations through proper communication, incorporating values and integrity, transparency, and fairness thereby providing quality of care, based on Evidenced-based Medicine. He has a deep interest in training, mentorship and teaching juniors, and conducting research in critical care.

Figure 2  Kamal Idris, Senior Consultant of Critical Care, Chair, Department of Critical Care, The Intensive Care Unit, Burjeel Royal Hospital, Al-Ain 67006, United Arab Emirates.

Professor Arif Alper Cevik (Figure 3) is an Emergency Medicine Academic Professor at United Arab Emirates University, interested in trauma, point-of-care ultrasound, international emergency medicine, and medical education. With a strong commitment to advancing emergency medicine worldwide, he has played a key role in education, research, and curriculum development. He is the founder and director of the International Emergency Medicine Education Project (iem-student.org), an initiative dedicated to providing high-quality educational resources for medical students and professionals globally. Additionally, he serves as the chair of the International Federation for Emergency Medicine Core Curriculum and Education Committee, where he contributes to shaping international standards for emergency medicine training. Professor Arif Alper Cevik is also a board member of both the Asian Society for Emergency Medicine and the Emirati Board of Emergency Medicine, where he works on policy development, academic initiatives, and the promotion of best practices in the field.

Figure 3  Arif Alper Cevik, Professor of Emergency Medicine, Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates.

INTRODUCTION

Earthquakes are natural disasters that occur without prior alarm and may have catastrophic damage with high toll of injury and death[1,2]. They may injure up to 10% of the affected population[3]. Most fatal historical earthquakes occurred in a land belt extending from Turkey in the west till Japan in the east. Two recent consecutive earthquakes that occurred in Turkey in February 2023 caused the death of more than 56 thousand victims[4,5]. The majority of earthquake-related deaths occur within the first few hours[6]. Those who reach the hospitals alive within 24 hours usually have severe crush injuries[7-9].

Earthquake-injured patients may be trapped under the rubble within confined spaces for days. This is a challenge for proper resuscitation while being under the rubble. The survival of these patients will depend on multiple factors including the severity of injury, the time spent under the rubble, the environmental conditions, availability of water and food, and finally proper resuscitation[3]. Crush injury is caused by continuous severe pressure on body muscles by rubble for long periods which may lead to extensive muscle necrosis[10]. It occurs in about 10% of the patients having soft-tissue trauma[11] while crush syndrome occurs in 3% (range 1.2%-16.4%) of the patients (Table 1)[12-19]. Patients with bilateral limb injuries have more than double serum creatinine phosphokinase (CPK) and death rates compared with those patients having unilateral limb injuries, indicating that severity of crush injury is related to the muscle mass injured[20]. Crush syndrome occurs after the extrication of patients. It has high mortality because of its systemic complications caused by the reperfusion injury including renal failure and sepsis[3,21].

Table 1 Crush syndrome incidence as reported by different studies on earthquake injuries.

Ref.	Earthquake	Country	Year	Severity Richter scale	Crush syndrome
Phalkey et al[12]	Gujarat	India	2001	7.9	5.8%
Dai et al[13]	Wenchuan	China	2008	8	9.3%
Yang et al[14]	Wenchuan	China	2008	8	3.9%
Min et al[15]	Wenchuan	China	2008	8	2.9%
Min et al[15]	Yushu	China	2010	7.1	2.4%
Bar-On et al[16]	Haiti	Haiti	2010	7	1.2%
Guner et al[17]	Van	Turkey	2011	7.2 and 5.7 (twin)	1.2%
Giri et al[18]	Nepal	Nepal	2015	7.8 and 7.3 (twin)	3%
Özdemir et al[19]	Kahramanmaras	Turkey	2023	7.8 and 7.6 (twin)	16.4%

Multiple reports have highlighted the lack of knowledge of those involved in treating earthquake victims including the pathophysiology and management of crush injuries[22,23]. This communication, which is based on our two recently published highly accessed collective reviews[24,25], aims to highlight the principles of diagnosis and management of acute kidney injury (AKI) caused by earthquake crush syndrome.

PATHOPHYSIOLOGY OF CRUSH SYNDROME

Relieving muscles after a prolonged period of compression of more than an hour may cause ischemia-reperfusion injury. This leads to the release of toxins, potassium, lactic acid, and myoglobin to the systemic circulation targeting distant organs[23,26,27]. The sudden release of large amounts of potassium into the circulation may induce cardiac arrythmias and arrest[28]. The breakdown of muscular myoglobin and its release into the bloodstream is called rhabdomyolysis. This may lead to renal impairment with subsequent accumulation of more toxic materials in the blood (Figure 4)[24]. The diagnosis of rhabdomyolysis depends on three components: (1) Presence of a swollen crushed limb; (2) Dark urine (red to brown) which may mimic hematuria; and (3) Increased CPK concentration which is the most sensitive diagnostic component of crush injury. CPK peaks 1-3 days after injury and usually decreases within 5 days. Crush injury rhabdomyolysis is defined as “the raise of serum CPK higher than 5 times the upper normal limit (around 1000 U/L)”[3,29].

Figure 4 The pathophysiology and mechanisms of the crush syndrome, rhabdomyolysis, and acute kidney injuries[24]. Citation: Abu-Zidan FM, Idris K, Cevik AA. Prehospital management of earthquake crush injuries: A collective review. Turk J Emerg Med 2023; 23: 199-210. Copyright ©The Author(s) 2023. Published by Wolters Kluwer (Supplementary material).

As a result of the ischemia-reperfusion injury, sodium, calcium and water enter the cell. The increased intracellular calcium concentration will initiate muscular contractions which consume the intracellular adenosine triphosphate as an energy source. This leads to mitochondrial damage and release of proteases and phospholipases. These enzymes augment the effects of oxidative stress to cause myolysis by damaging the phospholipids of the muscle cell membrane. The intracellular toxic metabolites are then released to the circulation[27,30]. These toxic metabolites will destroy the capillary endothelium increasing its permeability. Fluids can then move easily to the third space. Increased fluids in the muscle compartments which are surrounded by fascia like the legs may cause muscle compartment syndrome (Figure 4). Hypoperfusion will reduce oxygen saturation in the tissues leading to anaerobic metabolism with increased production of lactic acid. Furthermore, reperfusion is characterized by an inflammatory process. Activated leukocytes will further injure the tissues, releasing more toxins including myoglobulin and uric acid. Myoglobulin and uric acid may form renal tubule casts which obstruct the tubules and damage the kidneys[3,29,31](Figure 5). Crushed patients are at high risk of being shocked. This include: (1) Hypovolemic shock from hemorrhage; (2) Cardiac shock caused by hyperkalemia; (3) Distributive shock by losing fluid into the third space; and (4) Spinal shock caused by spinal cord injury. Circulatory shock increases the risk of AKI.

Figure 5 Histopathological findings of myoglobin casts (yellow arrows) of the renal tubules[31]. A: These casts are granular eosinophilic pigment casts on haematoxylin and eosin staining; B: They are weakly positive on Periodic acid–Schiff staining; C: Bright red on Masson trichrome staining; D: Immunohistochemistry for myoglobin confirmed the diagnosis. Note the normal glomeruli and the diffuse flattening of tubular epithelial cells. Citation: Islam SMJ, Karim I, Yasmin S. Myoglobin Cast Nephropathy, A Series of Five Cases. American J Pathol Res 2023; 2: 1-4. Copyright ©The Author(s) 2023. Published by SciVision Publishers LLC (Supplementary material).

AKI

AKI is a severe complication of earthquake crush injury which may occur in the few early days after the injury. Its severity is related to the magnitude of muscle damage and inappropriate fluid resuscitation[32]. Renal disaster is a term which was used following the Armenian 1988 earthquake so as to highlight the significance of earthquake-related AKI[27]. Timely proper fluid resuscitation is pivotal in preventing crush-related renal failure[33].

Up to 5% of earthquake injured patients develop AKI[34,35]. One third of crush syndrome patients develop AKI[30,34,36]. In Wenchuan 2008 earthquake, 42% of those who had crush syndrome developed AKI; 50% of them needed renal dialysis while 8% died[34]. In comparison, during Marmara 1999 earthquake, 18.3% had AKI, 68% of those needed renal dialysis, and 12% of those who were dialysed died[37]. In another study of Marmara 1999 earthquake, 12% of the patients had AKI and only 9% needed dialysis[38].

AKI is defined as “a 1.5-fold increase in serum creatinine or by 0.5 mg/dL or a decrease in glomerular filtration rate by 50%, and/or a reduction in urine output below 0.5 mL/kg/hour for more than 6 hours”[39]. The clinical presentation of AKI depends on its severity. It may start with an oliguric phase which is followed by a polyureic phase 1-3 weeks from the injury. There are three mechanisms for AKI to occur: Prerenal, intrarenal, or postrenal (Figure 4)[24]. Prerenal factors include: (1) Hypovolemia due to bleeding; (2) Dehydration due to lack of water; (3) Ischaemia-reperfusion injury following release of entrapment; and (4) Cardiac depression caused by released toxins. Renal factors include the nephrotoxic effects of uric acid and bilirubin, tubular casts obstructing the tubules, or the direct deposition of phosphorus and calcium inside the kidneys[3,27,29]. Pelvic fractures may cause urethral rupture with postrenal obstruction.

MANAGEMENT OF CRUSH SYNDROME

A checklist for managing crush syndrome is shown in Table 2. Starting this management as early as possible will reduce the incidence and severity of AKI. Clinical examination should assess the shock status including reduced mental alertness, tachycardia, hypotension, pale cold extremities, dry mouth, and prolonged capillary refill time.

Table 2 Checklist for the management of acute crush syndrome.

Investigations
Blood tests: Complete blood count, arterial blood gas, creatinine phosphokinase, comprehensive metabolic panel
Coagulation profile: Prothrombin time, activated partial thromboplastin time, international normalized ratio, fibrinogen
Urine tests: Dipstick and urine sediments
The 12-lead electrocardiogram to assess findings for hyperkalemia or hypocalcemia
Management
Start aggressive intravenous fluids to maintain a urine output of around 200-300 mL/hour
Monitor potassium every 4 hours and manage hyperkalemia aggressively
Correct hypocalcemia only when symptomatic (tetany or seizures)
Consult a nephrologist when dialysis is indicated including volume overload, hyperkalemia, severe acidemia, and uremia

It is important to stress that serum creatinine concentration and urine output may not early diagnose AKI because they are affected by multiple factors including dehydration, age, and body mass. Serum creatinine increases when there is loss of more than 50% of the renal function. According, point-of-care biomarkers for early detecting AKI, like serum neutrophil gelatinase-associated lipocalin (NGAL) can be useful. NGAL is produced in neutrophils and the epithelium of the proximal convoluted tubules and can rise within 2 hours of the start of AKI[40]. There is increased interest in this promising biomarker for the diagnosis of AKI and guiding the renal replacement therapy in critically-ill patients[41]. Nevetheless, there are no clinical studies on its use on earthquake-injured patients, highlighting the need for running such studies in the future.

Effective, early and vigorous fluid management plays a crucial role in the prevention of AKI[33,35]. The recommendations for the management of crush victims in mass disasters state that: “Initiate early and rapid fluid resuscitation to ensure euvolemia in hypovolemic victims; maintain hydration in euvolemic victims with adequate urine output”[42]. It is recommended to use crystalloids and not colloids. Isotonic saline is preferred because of its availability, efficacy, does not contain potassium, and has low side effects. Vasopressors are to be used in cases of spinal shock. Fluid resuscitation during the first two hours should be started with a rate of 1 L/hour to 1.5 L/hour for adults and 10-20 mL/kg/hour for children and then reduced according to the response, aiming for a urine output of 200-300 mL/hour[21,42,43].

Continuous monitoring of patients is essential to assess their individualized fluid needs. This will depend on the clinical examination, hemodynamic monitoring, hourly urine output, age, and available resources[42]. Using ultrasound in evaluating the urinary bladder volume and measuring the diameter of inferior vena cava to assess the intravascular fluid status can be useful[44]. Urine output should be continuously measured by methods depending on the patient’s condition, whether to be collected by the patient, by a condom catheter, urethral catheter, or suprapubic catheter. Pitfalls that can affect urination include a pelvic fracture with complete urethral damage in which suprapubic catheterization should be inserted, or a spinal cord injury that causes urine retention despite a normal renal function[42].

It is recommended to administer sodium bicarbonate to raise urine pondus hydrogenii (pH) above 6.5 so as to prevent the deposition of uric acid and myoglobin in the renal tubules[3,45]. Mannitol, given with a maximum dose of 2 g/kg/day, helps to prevent myoglobulin-induced renal failure[43]. Nevertheless, it should be used cautiously, otherwise it may cause renal failure[46]. Monitoring serum potassium, blood pH, and electrocardiograms may prevent and treat cardiac arrhythmias. Potassium-binding resins should be used empirically to treat hyperkalemia[3] while inhaled antiasthmatic beta-2 adrenoceptor agonists are advised early during the rescue phase[43].

Ideally it is recommended to transfer severely injured patients directly to critical care units at well-equipped hospitals to be properly treated[47]. Nevertheless, some advocated establishing on-field critical care units with renal dialysis units close to the earthquake centre to manage earthquake severely injured patients[36]. Although these temporary dialysis units have advantages, they can treat less patients and need clean water sources[45]. Nevertheless, the latter option is difficult. Hospitals’ infrastructures near the earthquake centre can be damaged or may be unsafe[39]. Usually, acute hemodialysis demand is more than the available resources and even competes with the hemodialysis needs of chronic patients. The earthquake-injured AKI patients are often evacuated and transferred to distant facilities in the country[48]. This needs a proper national disaster response plan to manage this critical situation[2,48].

CONTROL OF SEPSIS

Prophylactic antibiotics should be administered to earthquake-injured patients who have open fractures or contaminated wounds according to these principles: (1) Administer antibiotic(s) to the right patient, at the appropriate dose, time, route, and duration; (2) Start targeted treatment as soon as possible based on the results of bacterial culture and sensitivity; and (3) Control the source of sepsis, this may include repeated debridement of necrotic tissues[49-51]. The recommendations for the management of crush victims in mass disasters state that: “Assume all open wounds are contaminated. Consider surgical debridement, in addition to antibiotics, in the presence of necrosis or significant infection. Obtain cultures prior to initiation of antibiotics. Administer tetanus toxoid to all patients with open wounds, unless in those who have definitely been vaccinated within the last 5 years”[42]. Patients with heavily contaminated wounds and those who have been injured before 12 hours, especially obese patients, should receive tetanus human immunoglobulin[42].

RENAL REPLACEMENT THERAPY

AKI can be prevented or reversed with appropriate fluid administration, medical therapy, and renal dialysis when indicated[39]. The risk of developing AKI increases with delayed or inadequate fluid therapy[7]. Severe complications including acute respiratory distress syndrome, sepsis, limb fasciotomy or amputation are more common among patients having AKI[52]. Managing shock and sepsis especially during the oliguric phase is pivotal for improving the renal function[42]. In the recent Turkey earthquake of 2023, 20%-60% of those who had crush injury needed dialysis, of whom more than half died[20,53,54].

The timing of renal replacement therapy and starting it as early as possible when indicated is very important. Initial high hyperkalemia, low bicarbonate and base excess are risk factors for death[55]. One of the essential components of disaster response is triage[42]. AKI patients have a life-threatening condition and should be triaged in the red zone. Those who have crush syndrome with swollen limbs, low urine output, or dark urine should have priority to be transferred quickly to facilities having renal replacement therapy. Nevertheless, medical and fluid therapy should be started in the field.

Available resources have a major impact on methods of renal replacement therapy and their frequency. The guidelines for managing crushed patients in earthquakes state that: “Although continuous renal replacement therapy or peritoneal dialysis can be used depending on availability and patient needs, prefer intermittent hemodialysis as the first choice of renal replacement therapy”[42]. Peritoneal dialysis has many advantages which are: (1) It is technically easy; (2) Does not need running water or electricity; and (3) It can be started quickly. Nevertheless, it needs large amounts of sterile dialysate, and it has the risk of infection[45]. A recent small sample size randomized controlled clinical trial (70 patients) showed that continuous veno-venous hemodialysis with high cutoff dialyzer and regional citrate anticoagulation improved myoglobin clearance[56]. Intravenous fluid administration should be carefully assessed when AKI has been diagnosed. The indications for renal replacement therapy are shown in Table 3 which are severe hyperkalemia, severe acidemia, volume overload, and uremia. When there is rapid onset of severe hyperkalemia, dialysis may need to be done two or more times a day to control it.

Table 3 Indications for renal replacement therapy.

Indications
Serum potassium concentration > 6.5 mmol/L or its rapid rise
Pondus hydrogenii ≤ 7.1 (severe acidosis)
Blood urea nitrogen concentration > 30 mmol/L
Serum creatinine concentration > 700 μmol/L
Uremic symptoms (hypervolemia, encephalopathy, and pericarditis)
Continued oliguria (200 mL/12 hours) or anuria (50 mL/12 hours) despite adequate fluid resuscitation

Oral or rectal sodium polystyrene sulfonate (Kayexalate) can prevent hyperkalaemia by reducing potassium intestinal absorption. It is used to prevent or treat hyperkalemia in combination with renal dialysis. Its side effects include nausea, vomiting, hypokalemia, or rarely bowel necrosis[42]. Intravenous acetazolamide is useful when arterial pH becomes more than 7.45 following bicarbonate administration[42]. Allopurinol (xanthine oxidase inhibitor) reduces free oxygen radicals and uric acid. Accordingly, it has a potential to prevent crush-related AKI. Nevertheless, allopurinol cannot be recommended to treat rhabdomyolysis and AKI at this stage because of lack of strong evidence[57-59]. Accordingly, it was not included in the guidelines for the management of earthquake-related AKI[21,42].

CONCLUSION

Continuous prolonged pressure of the rubble on injured muscles following earthquakes may cause crush syndrome, and acute renal injury. The management principles of these complications include: (1) Proper fluid therapy to maintain adequate urine output; (2) Preventing and treating hyperkalemia; and (3) Renal replacement therapy when indicated in cases of severe hyperkalemia, severe acidemia, volume overload, or severe uremia.