Rescue and salvage of casualties suffering from the crush syndrome after mass disasters.

Extensive muscle crush injury culminating in the crush syndrome (CS) is often lethal unless promptly and vigorously treated. The causes of death in the CS are extreme hypovolemic shock, hyperkalemia, hypocalcemia, metabolic acidosis, acute myoglobinuric renal failure, and the compartment syndrome. Treatment consists of early massive volume replacement, preferably administered in the field, followed by forced alkaline solute (mannitol) diuresis. With this regimen, it is possible to increase substantially the survival of lives and limbs and to prevent acute myoglobinuric renal failure in patients suffering from the CS. Preliminary experience suggests that intravenous hypertonic mannitol is protective also to the injured muscle and can be used as a noninvasive adjunct in the management of compartment syndrome in humans. Moreover, by preserving muscular integrity, mannitol can conceivably reduce sarcolemmal leakage of the nephrotoxic myoglobin urate and phosphate and thus further defend kidney function. Furthermore, mannitol reduces the plasma pool of these nephrotoxic metabolites by increasing urinary elimination.

Josep Trueta (1897-1977): military surgeon and pioneer investigator of acute renal failure.

The great Spanish military and orthopedic surgeon J. Trueta gained his field and clinical experience in the Spanish civil war (1936-1939) and in Britain during World War II. As part of his major contribution to traumatology, he searched for the causes of the characteristic oliguria of combat casualties. For this purpose he studied the effect of induced ischemic myopathy on renal perfusion in the rabbit. He and his coworkers demonstrated conclusively that in this model there was an extreme renal cortical vasoconstriction with preservation of the medullary circulation. This early first demonstration of posttraumatic vasomotor nephropathy was independently confirmed 20 years later in the USA when 'preferential renal cortical ischemia' was demonstrated in acute renal failure in man. Thus, Trueta discovered in the early 40s the circulatory component of acute renal failure as part of his monumental contribution to military medicine.

Hyperbaric oxygen: a novel modality to ameliorate experimental colitis.

BACKGROUND: Hyperbaric oxygen (HBO) has been suggested to be beneficial in inflammatory bowel disease but the mechanisms responsible for its therapeutic effects have not been elucidated. AIM: To assess the effect of HBO treatment on colonic damage in two models of experimental colitis, and to examine whether this effect is mediated by modulation of NO synthesis. METHODS: Colitis was induced by either flushing the colon with 2 ml 5% acetic acid or intracolonic administration of 30 mg trinitrobenzenesulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol. Rats were exposed to HBO (100% oxygen at 2.4 atmosphere absolute) for one hour twice on the day of colitis induction and once daily thereafter. Control rats were treated only with acetic acid or TNB. Rats were killed 24 hours after acetic acid administration or one and seven days after TNB treatment. The colon was isolated, washed, and weighed, the lesion area was measured, and mucosal scrapings were processed for determination of myeloperoxidase (MPO) and NO synthase (NOS) activities, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) generation. RESULTS: In control rats exposed for seven days to HBO, colonic NOS activity was significantly decreased by 61%, compared with its activity in untreated rats (2.93 (0.17) nmol/g/min). HBO significantly reduced by 51 and 62% the extent of injury induced by acetic acid and TNB respectively. The protection provided by HBO was accompanied by a significant decrease in colonic weight, PGE2 generation, MPO, and NOS activities. In acetic acid colitis, LTB4 generation was also significantly decreased. CONCLUSIONS: (1) HBO effectively decreases colitis induced by acetic acid and TNB. (2) The decreased NOS activity induced by HBO suggests that reduction in NO generation may be among the mechanisms responsible for the anti-inflammatory effect of HBO. (3) HBO may be considered in the treatment of patients with refractory inflammatory bowel disease.

Acute renal failure complicating muscle crush injury.

Extensive skeletal muscle injury, whether caused by mechanical crush or by extreme physical exertion, is incompatible with life, unless treated early and vigorously. The immediate cause of morbidity is leakiness of the sarcolemmal membrane to cardiotoxic or nephrotoxic cations and metabolites (K, PO4, myoglobin and urate) of the sarcoplasma, and rapid massive uptake by the muscles of extracellular fluid, sodium and calcium, leading to profound hypovolemic and hyocalcemic shock. Casualties who survive the early steep of hyperkalemia and arterial hypotension are susceptible to myoglubinuric acute renal failure owing mainly to the combination of renal vasoconstriction, nephrotoxicity, and tubular obstruction by myoglobin plugs and urate. Management includes immediate (prehospital) intravenous volume replacement followed by mannitol-alkaline diuresis. The alkali regimen ameliorates the acidosis associated with shock and the hyperkalemia, and protects against the nephrotoxicity of myoglobin and urate by alkalinization of the urine. Mannitol, through its impermeant hyperoncotic properties, decompresses and mobilizes muscle edema and promotes renal tubular flow, thus flushing myoglobin plugs and enhancing urinary elimination of nephrotoxic metabolites. With this regimen and when necessary also with the use of dialysis, a substantial salvage of lives, limbs, and kidney function has been achieved recently compared with invariable mortality for casualties who were buried for 3 to 4 hours or more in the early 1940s (World War 2).

Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide.

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.

Involvement of nitric oxide system in experimental muscle crush injury.

Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.

Management of shock and acute renal failure in casualties suffering from the crush syndrome.

Widespread muscle crush injury is often associated with profound hemodynamic shock and myoglobinuric acute renal failure (ARF). The main reason for the shock is rapid uptake by the injured muscles of a substantial portion of extracellular fluid. The shock is aggravated by NO-dependent vasodilation in the injured muscles and by hyperkalemia and hypocalcemia, which suppress the entire cardiovascular tree. Treatment consists of early massive volume replacement and forced alkaline solute (mannitol) diuresis. With this regimen it is possible to increase survival of life and limbs, and prevent myoglobinuric ARF. Our preliminary experience suggests that i.v. hypertonic mannitol is protective also to the injured muscle and can be used as a noninvasive adjunct in the management of compartment syndrome in man. Moreover, by preserving muscular integrity, mannitol can conceivable reduce leakage of the nephrotoxic myoglobin and urate and thus further defend kidney function.

History of the crush syndrome: from the earthquakes of Messina, Sicily 1909 to Spitak, Armenia 1988.

Man-made or massive natural disasters may be followed by 'epidemics' of the muscle crush syndrome. The first descriptions of the crush syndrome were in the German-language literature following the earthquake of Messina in 1909 and World War II. On the threshold of World War II, the English-language literature was still unaware of the crush syndrome. During the London Blitz in 1940, Bywaters clearly delineated the pathogenesis of the crush syndrome and established guidelines for the management of casualties. The experience from the war in southern Lebanon in 1982 showed that early volume repletion can prevent acute renal failure in casualties with the crush syndrome. Following the major earthquake at Spitak in 1988, massive international relief effort helped to rescue and salvage many casualties. International preparedness contingency plans will increase the survival of future casualties suffering from crush injury.

Differential regulation of renal regional blood flow by endothelin-1.

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure.

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (-30%) and medulla (-23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.

Acute renal failure following massive mannitol infusion and enalapril treatment.

We report a patient with reversible acute oligoanuric renal failure. Intravenous mannitol 25% was infused to treat intracranial edema, during chronic administration of ACE inhibitors for arterial hypertension. Serum creatinine level rose to 5.6 mg/dl from a previous value of 1.2 mg/dl. Measured and calculated serum osmolalities were 310 and 280 mosm/kg respectively. We postulate that the association of afferent arteriolar constriction due to mannitol induced tubulo-glomerular imbalance and efferent dilatation due to ACE inhibitors provoked a sharp reduction in glomerular filtration rate. Alternatively, mannitol infusion may have caused tubular cell swelling with luminal obstruction.

Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects.

The association between obstructive jaundice and postoperative acute renal failure has been originally described more than eight decades ago and is now a well-established clinical phenomenon. Acute renal failure occurs in 8 to 10% of patients requiring surgery for relief of obstructive jaundice and contributes to eventual mortality in 70 to 80% of those who develop it. A major factor that may underlie the susceptibility to renal failure in patients with obstructive jaundice is cardiovascular instability manifested as systemic hypotension and defective vascular reactivity. This article outlines the scope of the clinical association between jaundice and renal failure and reviews the clinical and experimental studies that have contributed to our understanding of the underlying pathophysiologic mechanisms for this phenomenon. A growing body of evidence emanating from these studies indicates that bile constituents (e.g., bile acids, bilirubin, cholesterol) do not exert a direct nephrotoxic effect. Rather, the retention of bile during cholestatic jaundice has deleterious effects on cardiovascular function and on blood volume. This, in turn, sensitizes the kidney to prerenal failure and acute tubular necrosis in postsurgical patients with obstructive jaundice. The institution of prophylactic measures based on the appreciation of these underlying pathogenic mechanisms may result in an improvement in the overall prognosis of jaundiced patients undergoing surgery.

Differential effect of endothelin-1 on renal regional blood flow: role of nitric oxide.

This study evaluated the effects of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively) and the interactions with other local vasoactive systems in the regulation of renal regional blood flow. CBF and MBF were measured simulataneously by laser-Doppler flowmetry in anesthetized Wistar rats. Administration of ET-1 (1.0 nmol/kg, i.v.) produced a decrease in CBF (delta = -20%) and at the same time increased MBF (delta = +24%). In the presence of nitric oxide (NO) blockade by L-NAME, the vasodilatory effect of ET-1 on MBF was completely blocked and actually reversed (delta = -19%), whereas the cortical vasconstrictor effect was potentiated (delta = -31%). Cycloxygenase inhibition with indomethacin attenuated the vasodilator effect of ET-1 on MBF (delta = +12%) but did not affect the changes in CBF. Therefore, ET-1 exerts a differential effect on intrarenal regional blood flow, i.e., a decrease in CBF and an increase in MBF. The medullary vasodilator action of the peptide is dependent on an intact NO system and, to a lesser extent, on prostaglandin synthesis.

Carcinoid tumor of the lung and type-1 multiple endocrine neoplasia associated with persistent hypercalcemia: a case report.

The clinical and laboratory data, and histologic, electron microscopic and immunocytochemical findings of a carcinoid tumor of the lung associated with parathyroid hyperplasia and persistent hypercalcemia are described. The carcinoid tumor consists of uniform cuboidal cells with regular round vesicular nuclei and eosinophilic granular cytoplasm. The tumor cells were chromogranin and neuron-specific enolase positive. The CAT scan of the abdomen revealed an adrenal mass, 3 cm in diameter, and an enlarged body in the pancreas. Our patient is still suffering from hypercalcemia and renal colic, despite repeated parathyroid gland removal, and enucleation of the lung mass. Recent parathyroid scintigraphy with Tc revealed an enlarged parathyroid gland. The thoracic CAT scan is normal. We believe that our patient is suffering from multiple endocrine neoplasia type-1 with persistent hypercalcemia due to hyperparathyroidism.

Circulatory disturbance and renal dysfunction in liver disease and in obstructive jaundice.

The appearance of hepatorenal syndrome in a patient with acute or chronic liver disease is associated with a dismal outcome. Thus, management of HRS remains a formidable challenge to the aggressiveness and perseverance of the physician. The best treatment for HRS remains prevention based on avoidance of circulating volume contraction or the use of nephrotoxic drugs. Treatment for established HRS remains a frustrating experience with recovery being rare. A successful liver transplantation is currently the only definitive treatment that can reverse HRS. As this procedure is being performed with increasing frequency and encouraging results, a new window of hope has been opened for these patients.

Cardiac function and responsiveness to beta-adrenoceptor agonists in rats with obstructive jaundice.

The function and role of the heart and the contribution of cardiac beta-adrenoceptors in the pathogenesis of circulatory failure in obstructive jaundice were studied in the 3-day bile duct-ligated (BDL) rat using three different techniques to measure cardiac function and beta-adrenoceptor activity, number, and affinity. The techniques were the pithed rat preparation, the isolated working heart preparation, and a competitive radioligand binding assay for beta-adrenoceptors. The results of these experiments were compared with those obtained in 3-day bile duct-manipulated (sham operated; SO) rats. Impaired indexes of basal cardiac contractility were observed in the BDL pithed rats and isolated working hearts. In these two preparations, responsiveness to norepinephrine and the beta-adrenoceptor agonists, isoproterenol and dobutamine, was unaffected by bile duct ligation. The affinity and number of cardiac beta-adrenoceptors in membranes from the hearts of SO and BDL rats were not significantly different from each other. These experiments have established for the first time that the 3-day BDL rat has a cardiac myopathy associated with intact responsiveness to beta-adrenoceptor agonists, a normal unchanged affinity and number of cardiac beta-adrenoceptors.

Acute renal failure in casualties of mass disasters.

Human-made and seismic catastrophes continue to extract a heavy toll in lives. Many survivors with extensive muscle injury succumb to preventable causes such as shock, extreme hyperkalemia or acute renal failure (ARF). Others may lose limbs because of the compartment syndrome. Early treatment of such casualties, starting in the field, may increase salvage of lives and limbs, and prevent ARF. The treatment consists of aggressive volume and bicarbonate replacement followed by forced solute alkaline diuresis. If myoglobinuric ARF has occurred, solute load should not be given, and regular hemodialysis (HD) is indicated. If mass casualties have occurred in remote regions and HD cannot be immediately provided, continuous arteriovenous hemofiltration (CAVH) may temporarily substitute for HD. CAVH has the distinct advantage of simplicity, and does not require electricity, pumps or delivery systems. It is effective in eliminating potassium and relieving circulatory congestion without causing hypotension.

Hypokalemic flaccid paralysis as the presenting symptom of autoimmune interstitial nephropathy.

We describe a patient who presented dramatically with life-threatening hypokalemic flaccid paralysis. Following resuscitation, extensive investigation showed that the patient had lupus erythematosus (SLE) and Sjogren's syndrome (SS) of which she was unaware. A search for the cause of the profound hypokalemia led to the finding of obligatory renal potassium wasting due to distal renal tubular acidosis (RTA), secretory type. The acid base status of the patient showed hyperchloremic metabolic acidosis compatible with distal renal tubular acidosis. Our case is a further proof that patients with "overlap syndrome" (SLE-SS) may have RTA, which may lead to life-threatening hypokalemia. Others have shown that the SLE-SS complex may occasionally be complicated by hyperkalemia. Thus, an autoimmune disease that is relatively common may present with devastating electrolyte abnormalities.