In vivo time-resolved brain phosphorus nuclear magnetic resonance.

Methods used to obtain and quantify high-quality time-resolved dog brain phosphorus nuclear magnetic resonance (31P NMR) spectra are described. In eight animals the normoxic dog brain spectra showed 10% of total phosphorus in ATP, 14% in phosphocreatine (PCr), and 38% in brain phospholipids containing phosphodiesters. The chemical shift between PCr and inorganic phosphate, 5.09, corresponded to an intracellular brain pH of 7.2. During hypoxia, PCr declined to 0.5 +/- 0.3 (n = 8) of starting levels, prior to any changes in brain ATP. Simultaneous recording of the EEG was obtained in two animals. During hypoxia, progressive PCr depletion was associated with progressive slowing of the EEG, which was essentially silent before significant changes occurred in brain ATP. Finally, the brain 31P NMR spectrum and pH were measured at 90-s intervals, and the sequential changes that followed respiratory arrest were monitored in one dog until high-energy phosphate depletion was complete.

Glomerular and tubular function in non-oliguric acute renal failure.

Glomerular and tubular function were evaluated in 30 non-oliguric patients with increasing azotemia following open heart surgery. Fractional clearances (theta) of test solutes relative to that of inulin were determined. In 16 patients, theta dextran (radius 22 to 30 A) exceeded unity, a finding attributed to inulin backleak through necrotic tubules. These patients were classified as having acute renal failure; 14 subsequently required dialysis. In the remaining patients (N = 14), theta dextran was normal. These patients were considered to have prerenal failure; all recovered spontaneously. clearance of inulin (Cin) was lower in acute renal failure than in prerenal failure (12 +/- 2 versus 18 +/- 2 ml/min/1.73 m2; p less than 0.025). The apparent difference in glomerular filtration rate when Cin is used as an index was abolished, however, when Cin in acute renal failure was corrected for tubule backleak of inulin. In acute renal failure, fractional clearance of p-aminohippurate (theta PAH) was 7.1 +/- 1.0, and fractional excretion of potassium (FEk) was 160 +/- 18 percent. These findings strongly suggest that secretory ability in both proximal and terminal tubule augments, respectively, is preserved in acute renal failure. Compared with prerenal failure, the urine-to-plasma inulin ratio was lower (U/Pin = 10 +/- 1 versus 25 +/- 4; p less than 0.005) and FENa was higher (FENa = 5.1 +/- 1.5 versus 0.5 +/- 1.0 percent; p less than 0.01) in acute renal failure.

Neurologic dysfunction following cardiac operation with low-flow, low-pressure cardiopulmonary bypass.

A prospective 6 month study of all patients undergoing cardiac operation with cardiopulmonary bypass (CPB) was undertaken to determine the incidence of neurologic and neuropsychological dysfunction following low-flow, low-pressure CPB. Among 204 patients who underwent cardiac operation with CPB, there were seven deaths (3.4%), six who developed new motor deficits (2.9%), and 35 (17.2%) who exhibited some neurologic or neuropsychological dysfunction at discharge. When compared to the 169 patients with no evidence of neurlogic or neuropsychological dysfunction at discharge, these 35 were older (65 +/- 10 versus 55 +/- 12 years), had a lower incidence of coronary artery bypass grafting as the sole surgical procedure (29% versus 55%), a higher mortality rate (11.4% versus 1.8%), and prolonged CPB (140 +/- 45 versus 107 +/- 38 minutes). The mean arterial pressure (MAP) during CPB was similar in the two groups (51 +/- 7 versus 49 +/- 7 torr), and an index of time at low pressure, torr x minutes below 50 (TM less than 50), was also similar in the two groups (589 +/- 591 versus 554 +/- 478 TM less than 50). The incidence of postoperative neurologic and neuropsychological complications appears comparable to that in reports from institutions employing high CPB flow and maintaining high CPB MAP. Our results suggest that CPB pressure, per se, is not the major determinant of postoperative neurologic and neuropsychological dysfunction.

The effects of carbon dioxide on pulmonary mechanics in hyperventilating, normal volunteers.

Transpulmonary pressure, air flow, and end-tidal carbon dioxide levels were measured in normal human volunteers during hypocapnic, eucapnic, and hypercapnic hyperventilation. Respiratory rate and tidal volumes were well matched at a minute ventilation of 52 L. on three inspired gas mixtures: 21 per cent oxygen and 79 per cent nitrogen; 5 per cent carbon dioxide, 21 per cent oxygen and 74 per cent nitrogen; and 12 per cent carbon dioxide, 21 per cent oxygen and 67 per cent nitrogen. Respiratory rate, tidal volume, lung compliance, resistance, and resistive work per liter were calculated with a digital computer. In 13 experiments in 7 normal volunteers, no net bronchoconstriction or bronchodilatation was observed when eucapnic hyperventilation was compared to hypocapnic or hypercapnic hyperventilation. During hyperventilation of this degree, a change in bronchomotor tone owing to alteration in arterial or alveolar PCO2 either does not occur or else is masked by other reflexes or mechanical factors acting on the bronchi.

An analysis of potential physiological predictors of respiratory adequacy following cardiac surgery.

More than 50 potential physiological and clinical predictors of postoperative respiratory adequacy were examined in an attempt to identify those few variables which, singly or in combination, best predicted the outcome of the first trial of spontaneous respiration following cardiac surgery. This trial was initiated when patients seemed hemodynamically stable and relatively alert following surgery. Analysis of data from 124 patients identified the following useful predictors: forced vital capacity, total lung capacity, and maximal mid-expiratory flow rate from preoperative pulmonary function tests; resting cardiac index from preoperative cardiac catheterization; postoperative compliance and resistance measured by a computer-based monitoring system; postoperative vital capacity per kilogram, and maximum inspiratory force, measured at the bedside prior to the weaning trial. Stepwise linear discriminant analysis indicated that vital capacity per kilogram and maximum inspiratory force were the most useful predictors, the dividing line between successes and failures being represented by a vital capacity per kilogram of 15 ml. and a maximum inspiratory force of 28 cm. H2O. Mean values of successes were 18.3 +/- 7 ml. per kilogram and 30.7 +/- 9 cm. H2O and, for failures, 11.9 +/- 4 ml. per kilogram and 24.3 +/- 8.4 cm H2O. These physiological variables assess patient effort acting upon an abnormal pulmonary system. Measurements of passive pulmonary mechanics, cardiac function, and the measurement of arterial blood gases were suprisingly poor predictors.

Sequential pathophysiological changes characterizing the progression from renal dysfunction to acute renal failure following cardiac operation.

Sequential pathophysiological data were analyzed from 14 patients who exhibited similar severe depression of cardiac and renal function within 24 hours of cardiac operation. Seven patients exhibited postoperative renal dysfunction (defined by a minimum postoperative clearance of inulin [Cin] between 20 ml/min/1.73 m2 and one-half normal) and seven progressed from renal dysfunction to acute renal failure (ARF) (Cin less than or equal to ml/min/1.73 m2). In ARF patients depression of cardiac function was profound and persistent from postoperative days 1 to 7. Urine flow remained greater than 1 ml/min, and serum creatinine rose progressively. The Cin declined progressively during the first postoperative week. The ratio or urinary to plasma osmolality fell, and the fractional excretion of sodium (FENa) and potassium (FEK) increased substantially. By contrast, in renal dysfunction patients definite hemodynamic improvement occurred and renal function remained stable. Increased FENa in renal dysfunction was associated with hemodynamic improvement, weight loss, and stable fractional potassium excretion. These data provide unique documentation of the indices of hemodynamic and renal function associated with the progression to postoperative ARF. The central role of sustained profound depression of cardiac function in this progression appears to be the primary factor in the lethality of postoperative ARF.

Recovery of cardiopulmonary reflexes in monkeys undergoing heart-lung transplantation.

After heart-lung transplantation in primates, cardiopulmonary reflexes were tested and shown to be present. The Hering-Breuer and cough reflexes were tested, as well as responses to an inhaled respiratory stimulant, vasodilator, and an intravenous anticholinesterase and antimuscarinic agent. Recovery of these responses, except to the anticholinesterase agent, suggests that reinervation occurs in autotransplanted organs in primates. The Hering-Breuer reflex was present at 1.9 and 2.2 months after the operation in two animals subjected to autotransplantation. These cardiopulmonary reflex responses were also demonstrated in two allograft recipients studied at 15 and 16.9 months after the operation. Return of protective reflexes such as coughing may be an important mechanism to prevent aspiration pneumonitis and other complications in humans.

Acute renal failure following cardiac surgery.

In a prospective 6 month study of 204 patients requiring cardiac operations, five (2.5 percent) developed acute renal failure (ARF) and five (2.5 percent) had documented renal dysfunction (RD). Preoperative left ventricular dysfunction and prolonged cardiopulmonary bypass (CPB) were important predictors of subsequent RD/ARF; CPB pressure per se was not. Physiological and clinical studies in 51 selected patients studied over an 18 month period documented the effectiveness of low flow, low pressure CPB in preserving postoperative renal function. Twenty-two patients with nonazotemic postoperative courses demonstrated moderate depression of cardiac function while the glomerular filtration rate (GFR) was normal (98 +/- 30 ml./min/1.73 M.2) within 24 hours of operation. Seventeen high risk patients developed AFF (65 percent mortality rate) and 12 experienced severe RD without ARF (17 percent mortality). ARF (65 percent mortality rate) and 12 experienced severe RD without ARF (17 percent mortality). Eleven patients with ARF and 11 with RD were studied in the early postoperative period; at this time, all 22 patients demonstrated RD with equivalent severe depression of cardiac and renal function. Superposition of further hemodynamic or toxic insults upon ischemic kidneys was usually necessary for ARF to occur.

A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations.

A randomized, double-blind study was designed to evaluate the therapeutic effect and safety of prostacyclin (epoprostenol) in patients undergoing cardiopulmonary bypass. One hundred patients having isolated coronary bypass grafting received 300 units/kg of heparin and then either prostacyclin (12.5 ng/kg/min from heparinization until cardiopulmonary bypass, 25 ng/kg/min during bypass) or buffer/diluent in a similar manner. Standardized anesthetic, perfusion, and surgical techniques were used. Drug and placebo groups were similar in demographic data and bypass times, and there were no deaths. Activated coagulation time and platelet count were significantly higher during cardiopulmonary bypass in patients receiving prostacyclin. Platelet count remained significantly higher 24 hours after bypass in the active drug group. Immediately after operation, there was significantly less prolongation of bleeding time (1.3 versus 2.9 minutes; p = 0.009) in the patients receiving prostacyclin. Blood loss was significantly reduced during the first 4 hours postoperatively in the prostacyclin group (261 +/- 159 versus 347 +/- 197 ml; p = 0.02). There was no significant difference between the groups when total blood loss was compared (710 +/- 351 versus 869 +/- 498 ml; p = 0.07). Patients receiving prostacyclin required an average of 257 ml less blood transfused in the intensive care unit (p = 0.02). We conclude that the clinical impact of prostacyclin in patients undergoing coronary artery operations was demonstrable, but small. Prostacyclin may provide clinical benefits in patients undergoing cardiopulmonary bypass when there are contraindications to or other difficulties with blood transfusion. With prostacyclin, reduced heparin dose is possible and therefore reduced protamine requirement would offer a potential benefit of less cardiovascular depression immediately after bypass. However, the advantages offered by prostacyclin are not sufficient to recommend its routine use during cardiopulmonary bypass.

A prospective, randomized study of the effects of prostacyclin on neuropsychologic dysfunction after coronary artery operation.

This randomized, double-blind study was designed to evaluate the effect of prostacyclin (epoprostenol) on the incidence and severity of postoperative neuropsychologic dysfunction in patients undergoing coronary artery operation. Four days before operation and 1 week after operation, 100 patients having coronary artery bypass grafting underwent detailed neurologic and psychologic examinations and computed tomographic scans of the brain. The psychologic examination was repeated 2 months after operation. During cardiopulmonary bypass, all patients received 300 U/kg of heparin and then either buffer-diluent or prostacyclin (12.5 ng/kg/min from the time of heparinization until onset of cardiopulmonary bypass and 25 ng/kg/min during cardiopulmonary bypass). No deaths or major neurologic complications occurred in this series. Ninety-six patients completed the psychologic and neurologic evaluations 1 week after operation; 74 of these patients were evaluated psychologically 2 months after operation. Psychologic testing demonstrated similar declines in postoperative performance in both the prostacyclin-treated and the control groups; these changes were no longer present in either group 2 months after operation. Results of neurologic examinations and computed tomographic scans of the brain were unchanged. We conclude that the administration of prostacyclin during cardiopulmonary bypass in patients undergoing routine coronary artery operation has no effect on perioperative cognitive changes.

Relationship between intracellular pH and energy metabolism in dog brain as measured by 31P-NMR.

The relationships between pHi (intracellular pH) and phosphate compounds were evaluated by nuclear magnetic resonance (NMR) in normo-, hypo-, and hypercapnia, obtained by changing fractional inspired concentration of CO2 in dogs anesthetized with 0.75% isoflurane and 66% N2O. Phosphocreatine (PCr) fell by 2.02 mM and Pi (inorganic phosphate) rose by 1.92 mM due to pHi shift from 7.10 to 6.83 during hypercapnia. The stoichiometric coefficient was 1.05 (r2 = 0.78) on log PCr/Cr against pHi, showing minimum change of ADP/ATP and equilibrium of creatine kinase in the pH range of 6.7 to 7.25. [ADP] varied from 21.6 +/- 4.1 microM in control (pHi = 7.10) to 26.8 +/- 6.3 microM in hypercapnia (pHi = 6.83) and 24.0 +/- 6.8 microM in hypocapnia (pHi = 7.17). ATP/ADP X Pi decreased from 66.4 +/- 17.1 mM-1 during normocapnia to 25.8 +/- 6.3 mM-1 in hypercapnia. The ADP values are near the in vitro Km; thus ADP is the main controller. The velocity of oxidative metabolism (V) in relation to its maximum (Vmax) as calculated by a steady-state Michaelis-Menten formulation is approximately 50% in normocapnia. In acidosis (pH 6.7) and alkalosis (pH 7.25), V/Vmax is 10% higher than the normocapnic brain. This increase of V/Vmax is required to maintain cellular homeostasis of energy metabolism in the face of either inhibition at extremes of pH or higher ATPase activity.

Monitoring in the operating room: current techniques and future requirements.

Review of a recent lawsuit and study of operating room cardiac arrests reveal that ventilatory problems are a major source of intraoperative morbidity and mortality. Tidal volume and airway gas composition are critical to the anesthesiologist who must determine the depth of an inhalation anesthetic. Yet, current instrumentation does not permit these variables to be measured conveniently. In this paper, current techniques for monitoring cardiovascular physiology are review, and considerable attention is focused on the problem of and the requirements for ventilatory monitoring in the operating room. The high dollar cost of infrequent untoward events is discussed, as well as the additional problem this creates because individual anesthesiologists may receive little positive reinforcement in encouraging the development of more sophisticated monitoring techniques.

Marginally effective medical care: ethical analysis of issues in cardiopulmonary resuscitation (CPR)

Outcomes from cardiopulmonary resuscitation (CPR) remain distressingly poor. Overuse of CPR is attributable to unrealistic expectations, unintended consequences of existing policies and failure to honour patient refusal of CPR. We analyzed the CPR outcomes literature using the bioethical principles of beneficence, non-maleficence, autonomy and justice and developed a proposal for selective use of CPR. Beneficence supports use of CPR when most effective. Non-maleficence argues against performing CPR when the outcomes are harmful or usage inappropriate. Additionally, policies which usurp good clinical judgment and moral responsibility, thereby contributing to inappropriate CPR usage, should be considered maleficent. Autonomy restricts CPR use when refused but cannot create a right to CPR. Justice requires that we define which medical interventions contribute sufficiently to health and happiness that they should be made universally available. This ordering is necessary whether one believes in the utilitarian standard or wishes medical care to be universally available on fairness grounds. Low-yield CPR fails justice criteria. Cardiopulmonary resuscitation should be performed when justified by the extensive outcomes literature; not performed when not desired by the patient or not indicated; and performed infrequently when relatively contraindicated.

Effect of the intra-aortic balloon pump upon postoperative renal function in man.

Fifty-seven postoperative cardiac surgical patients receiving intra-aortic balloon pump (IABP) support were selected for detailed hemodynamic and renal function measurements on the basis of depressed cardiac and/or renal function. Eleven patients developed acute renal failure while receiving maximal IABP support and 10 during, or after withdrawal of IABP support. To define further the relationship between IABP support and renal function, 17 patients underwent simultaneous assessment of hemodynamic and renal function under varying conditions of IABP support. These studies, performed just before IABP withdrawal, demonstrated slight, clinically insignificant, improvement in hemodynamic and renal function with increased IABP support. Arterial pressure recordings, performed above and below the intra-aortic balloon in 8 patients, revealed no significant pressure gradient across the balloon whether single- or double-chambered. In addition, the balloon pulse waveform was always evident in the femoral artery. Importantly, the intra-aortic balloon did not interfere demonstrably with renal function, nor did it decrease renal perfusion pressure, in spite of its suprarenal position. Therefore, improvement in systemic perfusion from IABP support in the early postoperative period will result in improved renal perfusion.

Albuminuria and the permselective properties of the glomerulus in cardiac failure.

Fractional dextran clearances (theta D) were used to ascertain whether the albuminuria accompanying cardiac failure (CF) has a hemodynamic basis. In 17 patients with grade-IV CF in whom GFR and effective renal plasma flow (ERPF) were depressed to 58 +/- 7 and 215 +/- 20 ml/min/1.73 m2, respectively, theta D was elevated relative to normal control subjects over the Stokes-Einstein radius (r) interval of 28 to 46 Angstrom. For dextran of equivalent size to albumin (r = 36 Angstrom), the rate of urinary excretion (UD36V) was not increased because elevated theta D36 was offset by the depressed GFR. In contrast, urinary albumin excretion (UalbV) was increased to 82 +/- 35 microgram/min. Thus, for albuminuria in CF to have the hemodynamic basis suggested by elevation of theta D requires that (I) the fractional clearance for anionic albumin be disproportionately enhanced relative to uncharged dextran by reduced glomerular plasma flow and/or (2) that glomerular electrostatic barrier function be impaired in CF. In seven patients with minimal change nephropathy, UD36V was similar to that in CF, but UalbV was 40 times greater than that in CF. Thus, if glomerular electrostatic barrier function is impaired in CF, such dysfunction is trivial by comparison with minimal change nephropathy.

Transtubular leakage of glomerular filtrate in human acute renal failure.

Ten postcardiac surgical patients with acute renal failure (ARF) were infused with inulin and dextran 40. Plasma and urine were then submitted to gel-permeation chromatography to ascertain the apparent fractional clearance profile for the dextrans. Compared to normal volunteer controls, the fractional clearance profile was substantially elevated for dextran molecules in the Einstein-Stokes radius (r) range 20-40 A. For the smaller molecules (r = 20-28 A), fractional dextran clearance in ARF was frequently in excess of unity. A simple mass conservation model which assumes that the "true" fractional dextran clearance profile for the glomerulus (in Bowman's space) in ARF is the same as that for normal controls, when applied to the experimental observations, revealed that in ARF, on the average, 50% of filtered inulin is lost by tubular backleakage. Furthermore, the model permitted an estimate of the permeability properties of the damaged tubular wall. This indicated tubular permeability not unlike that of the normal glomerulus to dextran molecules with r less than 30 A, but relative impermeability to larger dextran molecules.