Resuscitation: Benefits of ATP, Glucose, and Sodium

Also see:
ATP Regulates Cell Water
Arachidonic Acid’s Role in Stress and Shock
Lactate Paradox: High Altitude and Exercise
Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution
Sodium Deficiency and Stress

“I have written previously about several dramatically effective treatments for shock that were developed in the last fifty years–for example intravenous ATP, concentrated solutions of sodium chloride or glucose, and the morphine/endorphin-blocker, naloxone. Theoretical reasons have kept some of these techniques from being used as widely as would be appropriate, but gradually the success of the methods is forcing some people to rethink their theories.” -Ray Peat, PhD

“In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic, but simple hypertonic solutions of glucose and salt are probably safer, and are very effective.” -Ray Peat, PhD

Am J Physiol. 1980 Nov;239(5):H664-73.
Hyperosmotic NaCl and severe hemorrhagic shock.
Velasco IT, Pontieri V, Rocha e Silva M Jr, Lopes OU.
Intravenous infusions of highly concentrated NaCl (2,400 mosmol/l; infused volume 4 ml/kg; equivalent to 10% of shed blood), given to lightly anesthetized dogs in severe hemorrhagic shock, rapidly restore blood pressure and acid base equilibrium toward normality. No appreciable plasma volume expansion occurs for at least 12 h, indicating that fluid shift into the vascular bed plays no essential role in this response. Initial effects wee sustained indefinitely; long term survival was 100%, compared to 0% for a similar group of controls treated with saline. Hemodynamic analysis of the effects of hyperosmotic NaCl showed that these infusions substantially increase mean and pulse arterial pressure, cardiac output and mesenteric flow, whereas heart rate was slightly diminished. These effects immediately follow infusions with no tendency to dissipate with time (6-h observation). We conclude that hyperosmotic NaCl infusions increase the dynamic efficiency of the circulatory system, enabling it to adequately handle oxygen supply and metabolite clearance, despite a critical reduction of blood volume.

Am J Physiol. 1987 Oct;253(4 Pt 2):H751-62.
Hyperosmotic sodium salts reverse severe hemorrhagic shock: other solutes do not.
Rocha e Silva M, Velasco IT, Nogueira da Silva RI, Oliveira MA, Negraes GA, Oliveira MA.
Severe hemorrhage in pentobarbital-anesthetized dogs (25 mg/kg) is reversed by intravenous NaCl (4 ml/kg, 2,400 mosmol/l, 98% long-term survival). This paper compares survival rates and hemodynamic and metabolic effects of hypertonic NaCl with sodium salts (acetate, bicarbonate, and nitrate), chlorides [lithium and tris(hydroxymethyl)aminomethane (Tris)], and nonelectrolytes (glucose, mannitol, and urea) after severe hemorrhage (44.5 +/- 2.3 ml/kg blood loss). Sodium salts had higher survival rates (chloride, 100%; acetate, 72%; bicarbonate, 61%; nitrate, 55%) with normal stable arterial pressure after chloride and nitrate; near normal cardiac output after sodium chloride; normal acid-base equilibrium after all sodium salts; and normal mean circulatory filling pressure after chloride, acetate, and bicarbonate. Chlorides and nonelectrolytes produced low survival rates (glucose and lithium, 5%; mannitol, 11%; Tris, 22%; urea, 33%) with low cardiac output, low mean circulatory filling pressure, and severe metabolic acidosis. Plasma sodium, plasma bicarbonate, mean circulatory filling pressure, cardiac output, and arterial pressure correlated significantly with survival; other parameters, including plasma volume expansion or plasma osmolarity, did not. It is proposed that high plasma sodium is essential for survival.

Am J Physiol. 1981 Dec;241(6):H883-90.
Hyperosmotic NaCl and severe hemorrhagic shock: role of the innervated lung.
Lopes OU, Pontieri V, Rocha e Silva M Jr, Velasco IT
Infusions of hyperosmotic NaCl (2,400 mosmol/l; 4 ml/kg) were given to dogs in severe hemorrhagic hypotension by intravenous injection (72 expts) or intra-aortic injection (25 expts). In 46 experiments intravenous infusions were given during bilateral blockage of the cervical vagal trunks (local anesthesia or cooling). Intravenous infusions (without vagal blockade) restore arterial pressure, cardiac output, and acid-base equilibrium to normal and cause mesenteric flow to overshoot prehemorrhage levels by 50%. These effects are stable, and indefinite survival was observed in every case. Intra-aortic infusions of hyperosmotic NaCl produce only a transient recovery of arterial pressure and cardiac output but no long-term survival. Intravenous infusions with vagal blockage produce only a transient recovery of cardiac output, with non long-term survival. Measurement of pulmonary artery blood osmolarity during and after the infusions shows that a different pattern is observed in each of these three groups and strongly indicates that the first passage of hyperosmotic blood through the pulmonary circulation at a time when vagal conduction is unimpaired is essential for the production of the full hemodynamic-metabolic response, which is needed for indefinite survival.

Crit Care Med. 1992 Feb;20(2):200-10.
Resuscitation of intraoperative hypovolemia: a comparison of normal saline and hyperosmotic/hyperoncotic solutions in swine.
Pascual JM, Watson JC, Runyon AE, Wade CE, Kramer GC.
We compared a hypertonic saline-dextran solution (7.5% NaCl/6% dextran-70) with 0.9% NaCl (normal saline) for treatment of intraoperative hypovolemia. Fourteen anesthetized pigs (mean weight 36.3 +/- 2.1 kg) underwent thoracotomy, followed by hemorrhage for 1 hr to reduce mean arterial pressure to 45 mm Hg. A continuous infusion of either solution was then initiated and the flow rate was adjusted to restore and maintain aortic blood flow at baseline levels for 2 hrs.
Full resuscitation to initial values of aortic blood flow was achieved with both regimens, but the normal saline group required substantially larger volumes and sodium loads to maintain stable hemodynamic values. Normal saline resuscitation produced increases in right ventricular preload (central venous pressure) and afterload (pulmonary arterial pressure and pulmonary vascular resistance), resulting in increased right ventricular work.
Hypertonic saline-dextran solution resuscitation of intraoperative hypovolemia is performed effectively with smaller fluid and sodium loads, and is devoid of the deleterious effects associated with fluid accumulation induced by a conventional isotonic solution regimen.

Lancet. 1980 Nov 8;2(8202):1002-4.
Treatment of refractory hypovolaemic shock by 7.5% sodium chloride injections.
de Felippe J Jr, Timoner J, Velasco IT, Lopes OU, Rocha-e-Silva M Jr.
Injections of hyperosmotic (7.5%) sodium chloride (100-400 ml) were given to 12 patients in terminal hypovolaemic shock who had not responded to vigorous volume replacement and corticosteroid and dopamine infusions. Hyperosmotic sodium chloride promptly reversed the shock in 11 of these patients. The immediate effects of the NaCl injections were a moderate rise in arterial pressure, the resumption of urine flow, and recovery of consciousness. These effects tended to persist for a few hours. The hyperosmotic infusion also reduced isosmotic fluid requirement by 90%.

J Trauma. 1994 Mar;36(3):323-30.
A review of the efficacy and safety of 7.5% NaCl/6% dextran 70 in experimental animals and in humans.
Dubick MA, Wade CE.
Recent years have seen a renewed interest in the use of hypertonic-hyperoncotic solutions as plasma volume expanders for the treatment of hemorrhagic hypotension. In particular, a number of studies in experimental animals have addressed the efficacy and safety of small-volume infusions of 7.5% NaCl/6% dextran 70 (HSD). Employing models of fixed volume or fixed pressure hemorrhage, HSD has improved survival and reversed many of the hemodynamic, hormonal, and metabolic abnormalities associated with hemorrhagic shock. In the few human field trials completed to date, HSD has been shown to be potentially beneficial in hypotensive trauma patients who require surgery or have concomitant head injury. Extensive toxicologic evaluations and lack of reports of adverse effects in the human trials indicate that, at the proposed therapeutic dose of 4 mL/kg, HSD should present little risk.

Medicina (B Aires). 1998;58(4):393-402.
Hypertonic saline resuscitation.
Rocha e Silva M.
Treatment of severe hemorrhage offers few theoretical problems, but in practice, severe blood loss usually occurs out of hospital, often in more or less inaccessible scenarios. Controversy rages over ideal fluid, ideal volume, and minimum O2 carrying capacity, but all agree that pre-hospital, isotonic resuscitation is unfeasible. The effects of highly hypertonic 7.5% NaCl (HS) was first described in 1980, when we showed that it induced immediate and long lasting hemodynamic restoration. The addition of 6% dextran-70 to (HSD) significantly enhances the duration and intensity of volume expansion, with no loss of hemodynamic effects. HS/HSD restores cardiac output, arterial pressure, base excess and oxygen availability, induce pre-capillary vasodialtion, moderate hyperosmolarity and hypernatremia, reversal of high glucose and lactate. It interferes with endocrine secretions when administered to animals in hemorrhagic hypotension. HS acts through transient plasma volume expansion, positive inotropic effect on cardiac contractility, precapillary vasodilation through a direct action on vascular smooth muscle. Expansion of circulating volume is part of the mechanism, the extra volume coming from the intracellular compartment fluid, especially from endothelial and red blood cells, which facilitate microcirculatory flow. The new field of interactions of hypertonicity with the immune mechanisms may provide insight into the long lasting effects of hypertonic solutions. Randomized double blind prospective studies on the effects of HS, or HSD, used as first treatment of shock show that both are safe and free from collateral, toxic effects. These studies show an early significant rise in arterial blood pressure and a non-significant trend towards higher levels of survival. HSD administration to patients about to undergo cardiopulmonary bypass for cardiac surgery results in higher cardiac output before, and immediately following cardiopulmonary bypass, as well as zero fluid balance.

Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 1):62-70.
Hyperosmotic-hyperoncotic solutions during abdominal aortic aneurysm (AAA) resection.
Christ F, Niklas M, Kreimeier U, Lauterjung L, Peter K, Messmer K.
A largely positive perioperative fluid balance during both elective and emergency abdominal aortic aneurysm repair (AAA) may put patients at risk of developing left ventricular failure and may thus contribute to morbidity. In the present paper we report on a prospective study using hyperosmotic-hyperonocotic solutions (HHS) infused during clamping of the aorta, for the prevention of declamping shock, and the associated reduction in perioperative fluid requirements. The major aim of this paper was to determine the efficacy of an HHS infusion when given over 20 minutes and to detect possible adverse effects of HHS. For perioperative fluid replacement 12 patients received crystalloid solutions with HHS [250 ml of 7.2% NaCl combined with either 6% Dextran (n = 3), 6% Hydroxyethylstarch (HES, n = 4) or 10% HES (n = 5)]. In 16 controls, crystalloids with 1000 ml of HES 10% were infused. Patients were invasively monitored and hemodynamic parameters frequently assessed during the operation, which were statistically analyzed in relation to the start of the fluid loading during clamping of the aorta. One patient showed an anaphylactoid reaction to HES, otherwise no side effects of HHS were observed during infusion (no hypotension, no pathological EKG changes). Plasma sodium and chloride concentration as well as osmolality rose resulting in an osmotic gradient and a desired intravascular volume expansion. Prior to declamping pulmonary capillary wedge pressure had increased to the desired value of > 13 mmHg and < 18 mmHg. Oxygen delivery was significantly elevated upon HHS and remained so post declamping, whereas no change was observed in controls. During clamping systemic vascular resistance was significantly decreased, but was unchanged in controls. The perioperative fluid balance of patients receiving HHS was 2471.0 +/- 948.6 ml, which was significantly less than + 3386.7 +/- 1247.9 ml of controls (P < 0.01). We suggest that HHS opens new perspectives in perioperative fluid management of both elective and emergency AAA repair, since hemodynamic parameters are improved and the overall fluid balance is less positive, thus decreasing the likelihood of edema formation. Moreover, the previously described positive microcirculatory effects of HHS may be particular beneficial in some high-risk patients.

Resuscitation. 1989;18 Suppl:S51-61.
Microcirculatory therapy in shock.
Messmer K, Kreimeier U.
The normal microvascular perfusion pattern is characterized by temporal and spatial variations of capillary flow. Local driving pressure, arteriolar vasomotion and endothelial cells are key-factors for local regulation of hydraulic resistance and fluid balance between the blood and tissue compartments. In shock, both the central and particularly the local mechanisms controlling microvascular perfusion are impaired. The microvascular perfusion pattern becomes permanently inhomogeneous due to lack of arteriolar vasomotion, changes of flow properties of blood, endothelial cell swelling and blood cell-endothelium interaction. Hence the objectives of primary shock therapy are to reestablish precapillary pressure, arteriolar vasomotion and to open the occluded microvascular pathways in order to reestablish the surface area needed for exchange of nutrients and drainage of waste product. These effects can not be achieved by vasoactive drugs, unless blood volume has been restored and blood fluidity improved by hemodilution. Whereas the necessary hemodilution can be achieved by conventional volume substitutes (colloids, crystalloids) restoration of vasomotion and reopening of narrowed capillaries can be obtained by small volume resuscitation using hyperosmotic/hyperoncotic salt dextran solution. The potential of this new concept for primary resuscitation and treatment of tissue ischemia is presently explored.

Am J Physiol. 1988 Sep;255(3 Pt 2):H629-37.
Dynamic fluid redistribution in hyperosmotic resuscitation of hypovolemic hemorrhage.
Mazzoni MC, Borgström P, Arfors KE, Intaglietta M.
A mathematical description of blood volume restoration after hemorrhage with resuscitative fluids, particularly hyperosmotic solutions, is presented. It is based on irreversible thermodynamic transport equations and known physiological data. The model shows that after a 20% hemorrhage, the rapid addition of a hypertonic (7.5% NaCl)-hyperoncotic (6% Dextran 70) solution amounting to one-seventh of the shed blood volume reestablishes blood volume within 1 min. Measurements of systemic hematocrit, hemoglobin concentration, and plasma osmolality taken from 13 experiments on anesthetized rabbits verify this prediction. The model shows that immediately after hyperosmotic infusion, water shifts into the plasma first from red blood cells and endothelium and then from the interstitium and tissue cells. The increase in blood volume is transitory; however, it occurs in a fraction of the time compared with isoosmotic fluids at the same infusion rate and is partially sustained by Dextran 70. We theorize that the concurrent hemodilution and endothelial cell shrinkage during hyperosmotic infusion lead to a decreased capillary hydraulic resistance, an effect that is even more significant in capillaries with swollen endothelium. Our results support the significant role of an osmotic mechanism during hyperosmotic resuscitation in quickly restoring blood volume with the added benefit of improved tissue perfusion.

Am J Physiol. 1977 Sep;233(3):R83-8.
Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock.
Chaudry IH, Sayeed MM, Baue AE
It has been shown that infusion of ATP-MgCl2 proved beneficial in the treatment of shock; however, it is not known whether this effect is due to improvement in the microcirculation or direct provision of energy or a combination of the above or other effects. To elucidate the mechanism of the salutary effect of ATP-MgCl2, we have now examined the in vitro uptake of ATP by liver and kidney of animals in shock. Rats were bled to a mean arterial pressure of 40 Torr and so maintained for 2 hrs. After the rats were killed, liver and kidney were removed and slices of tissue (0.3-0.5 mm thick) were incubated for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM MgCl2, and 5 mM [8-14C]ATP or 5 mM [8-14C]ADP, or 5 mM [8-14C]AMP, or 5 mM [8-14C]adenosine in 95% O2-5% CO2 and then homogenized. Tissue and medium samples were subjected to electrophoresis to separate and measure the various nucleotides. The uptake of [14C]ATP but not that of [14C]ADP or [14C]adenosine by liver and kidney slices from animals in shock was 2.5 times greater than the corresponding uptake by control slices. Thus, the beneficial effect of ATP-MgCl2 in shock could be due to provision of energy directly to tissue in which ATP levels were lowered.

Prog Clin Biol Res. 1989;299:19-31.
ATP-MgCl2 and liver blood flow following shock and ischemia.
Chaudry IH.
The information available indicates that following hepatic ischemia and reflow, there is decreased tissue ATP levels, decreased tissue and mitochondrial magnesium levels, and decreased mitochondrial capability. Associated with these changes are altered cellular functions. Administration of ATP-MgCl2 following ischemia significantly improves total and microcirculatory blood flow, tissue and mitochondrial magnesium levels, tissue ATP stores, cellular functions, and the survival of animals. In contrast to ATP-MgCl2, administration of ATP or MgCl2 alone after ischemia was ineffective in improving cellular functions and tissue and mitochondrial magnesium levels. ATP-MgCl2 therefore appears to be a promising adjunct to the treatment of shock and ischemia.

Magnesium. 1986;5(3-4):211-20.
The role of ATP-magnesium in ischemia and shock.
Chaudry IH, Clemens MG, Baue AE.
Although much is known about the role of Mg in cardiomyopathies of different etiology, very little is known about the changes in hepatic Mg levels following hemorrhagic shock or ischemia to the liver. Information available indicates that tissue and mitochondrial Mg levels may be altered following shock and ischemia and that such alterations may be responsible for the depressed cellular function during those conditions. MgCl2 administration following shock or ischemia was ineffective in improving tissue and mitochondrial Mg levels and cellular functions. Administration of ATP complexed with MgCl2, however, increased tissue and mitochondrial Mg levels, tissue ATP stores and cellular functions and proved beneficial for the survival of animals. ATP-MgCl2 administration also increased cardiac output while decreasing myocardial as well as total body O2 consumption. The potential mechanisms of the beneficial effects of ATP-MgCl2 are discussed. ATP-MgCl2 can be given safely to humans and it decreases myocardial O2 consumption and increases cardiac output without producing hypotension. A clinical trial of ATP-MgCl2 in patients with various adverse circulatory conditions is underway at our institution.

Surgery. 1975 Jun;77(6):833-40.
Evidence for enhanced uptake of adenosine triphosphate by muscle of animals in shock.
Chaudry IH, Sayeed MM, Baue AE.
Although it has been shown that infusion of adenosine triphosphate (ATP)-magnesium chloride (MgCl2) proved beneficial in the treatment of shock, it is not known whether this effect is due to improvement in the microcirculation or to direct provision of energy. In searching for the mechanism of this, we have now examined the in vitro uptake of ATP by soleus muscle of animals in shock. Rats were bled to a mean arterial pressure of 40 mm. Hg and so maintained for 2 hours. Following death the two soleus muscles from each animal were removed and incubated in Krebs-HCO3 buffer containing 10 mM. of glucose, 5 mM. (8–14C) of ATP, 5 mM. (8–14C) of ADP, or 0.5 mM. (8–14C) of adenosine, and 5 mM. of MgCl2 for 1 hour under an atmosphere of 95 percent O2 to 5 percent CO2. Following homogenization and centrifugation, samples of the muscle extract and the medium were subjected to electrophoresis to separate the various nucleotides. The concentrations of the several nucleotides in medium and muscle were calculated from the radioactivity observed in each fraction. The uptake of 14-C-ATP by muscles from animals in shock was three times greater than was the uptake by control muscles. This leads us to conclude that the beneficial effect of ATP-MgCl2 to animals in shock could be due to provision of energy directly to tissues in which ATP levels were lowered

Surgery. 1966 Jan;59(1):66-75.
Protective effect of ATP in experimental hemorrhagic shock.
Sharma GP, Eiseman B.

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