Edward D. Staples

Effect of ventilation on acid-base balance and oxygenation in low blood-flow states.

Objectives: To investigate how minute ventilation affects the partial pressure of end‐tidal CO2 and arterial and mixed venous pH, Pco2, Po2, and the concentration of bicarbonate during low blood‐flow states. We tested the null hypothesis that acid‐base conditions during low rates of blood flow are not significantly different when minute ventilation is doubled or halved. Design: Prospective, experimental, animal study. Setting: University hospital laboratory. Subjects: Domestic swine. Interventions: We studied ten anesthetized and mechanically ventilated swine (weight, 43 to 102 kg) in a new model of controlled systemic and pulmonary blood flow in which each animal was maintained on ventricular assist devices. After electrical induction of ventricular fibrillation, ventricular assist device blood flow was decreased in steps. At each decrease, control minute ventilation, two times the control minute ventilation (hyperventilation), and onehalf the control minute ventilation (hypoventilation) were administered; each ventilatory change was maintained for 6 mins. Measurements and Main Results: Aortic, pulmonary arterial and central venous pressures, ventricular assist device blood flow, and endtidal CO2 were recorded continuously. Acid‐base conditions were studied at three different mean blood flow rates: 49%, 30%, and 12% of baseline prearrest cardiac index. Arterial pH and Pao2 and mixed venous pH varied directly ( p < .003) with minute ventilation, while Paco2 and mixed venous Pco2, and end‐tidal CO2 varied inversely ( p < .0001) with minute ventilation. Mixed venous Po2 was not significantly related to minute ventilation ( p = .6). Paco2 and arterial bicarbonate; mixed venous pH, mixed venous Po2, and mixed venous bicarbonate, and end‐tidal CO2 varied directly (p < .001) with blood flow, while mixed venous Pco2 varied inversely with blood flow (p < .05). Arterial pH was not significantly related to blood flow ( p = .3). When minute ventilation changed from hyperventilation to hypoventilation at a mean blood flow rate of 49%, mean arterial pH decreased 0.22 ± 0.06 (p < .05), mean Paco2 increased 28 ± 6 torr (3.7 ± 0.8 kPa) (p < .05), and mean Pao2 decreased 99 ± 77 torr (13.2 ± 10 kPa); mean mixed venous pH decreased 0.11 ± 0.02, mean mixed venous Pco2 increased 16 ± 2.2 torr (2.1 ± 0.3 kPa) (p < .05), and mean mixed venous Po2 did not change; mean endtidal CO2 increased 18 ± 2 torr (2.4 ± 0.3 kPa) ( p < .05). The effect of changes in minute ventilation on blood gases and end‐tidal CO2 was similar for mean blood flow rates of 30% and 12% of baseline cardiac index. Conclusions: During low rates of blood flow similar to those rates found in shock and cardiopulmonary resuscitation, alterations in minute ventilation significantly influenced end‐tidal CO2 and both arterial and mixed venous pH and Pco2. These findings may have clinical importance in improving the treatment of shock and cardiac arrest. (Crit Care Med 1994; 22:1827–1834)

End-tidal carbon dioxide during extremely low cardiac output

STUDY OBJECTIVE A number of studies have shown that expired CO2 concentration is closely related to cardiac output, but that cardiac output was not controlled as an independent variable. In addition, the partial pressure of end-tidal CO2 (PETCO2) during extremely low cardiac output has not been reported. The objective of the present study was to measure PETCO2 during well-controlled, very low blood flow rates under conditions of constant minute ventilation. DESIGN Ten anesthetized, intubated, and mechanically ventilated swine (weight, 43 to 102 kg) were placed on two ventricular assist devices in order to control cardiac output. Minute ventilation was measured and kept constant. Ventricular assist device output (measured with an ultrasonic flow probe); PETCO2; and aortic, pulmonary artery, and central venous pressures were recorded continuously. INTERVENTIONS After electrical induction of ventricular fibrillation, pump output was decreased in steps. MEASUREMENTS AND MAIN RESULTS Cardiac index ranged from 0 to 5,371 mL/min/m2; 59% of PETCO2 measurements were made at cardiac indexes of less than 1,313 mL/min/m2 (30 mL/min/kg). The relationship of PETCO2 levels to cardiac index was determined with linear regression analysis; P < .05 was statistically significant. PETCO2 correlated significantly with cardiac index (P < .0001). The best-fit line by least-squares analysis produced the equation: PETCO2 = 4.98 + 0.012 [cardiac index] (r2 = .82). CONCLUSION Under conditions of constant minute ventilation, PETCO2 correlated closely with cardiac index over a large range of blood flow rates, including extremely low rates.

Abnormal neuroendocrine responses during exercise in heart transplant recipients.

BackgroundOsmotic and neural factors stimulate neuroendocrine activity during exercise. In contrast to excitatory mechanisms, afferent information from cardiac mechanoreceptors inhibits integrative centers in the hypothalamus and medula oblongata, which serves to buffer neuroendocrine activity. Orthotopic cardiac transplantation results in the loss of afferent information from cardiac mechanoreceptors. Thus, transplantation possibly results in exaggerated neuroendocrine responses when patients are physically active. Methods and ResultsWe measured the neuroendocrine response to moderate and strenuous exercise performed at the same relative intensity in 11 heart transplant recipients (50±14 years old) 18±12 months after transplantation and 11 control subjects matched with respect to sex, age, and body size. Plasma levels of norepinephrine, vasopressin, renin activity, atrial natriuretic peptide, angiotensin II, and aldosterone were measured at rest, during a maximal graded exercise test, and during submaximal exercise at 40% and 70% of peak power output on a cycle ergometer (W). Plasma renin activity and atrial natriuretic peptide were elevated at rest in heart transplant recipients (p≤0.05). Heart rate (%HR. reserve), rating of perceived exertion, and reductions in plasma volume (%δ from rest) at the conclusion of the three exercise conditions did not differ between heart transplant recipients and control (p≥0.05). Relative changes in neuroendocrine hormones were similar (p≥0.05) in heart transplant recipients and control during exercise at 40% of peak power output. Relative changes in plasma norepinephrine, vasopressin, atrial natriuretic peptide, and plasma renin activity were greater (p≤0.05) in heart transplant recipients during exercise at 70%of peak power output and the graded exercise test. ConclusionsWe interpret these data as a possible indication of ablation of cardiac mechanoreceptor afferents and unopposed neuroendocrine stimulation in heart transplant recipients. Furthermore, chronic neuroendocrine hyperactivity is likely in ambulatory heart transplant recipients. Although cyclosporine nephrotoxicity is implicated in the development of hypertension, our data suggest that chronic neuroendocrine hyperactivity, which alters renal volume regulation, also contributes to the incidence and severity of hypertension in heart transplant recipients.

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection

Background. Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). Methods. Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher’s exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. Results. Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P =0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P =0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. Conclusions. Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts

BACKGROUND A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Susceptibility of lung transplants to preformed donor-specific HLA antibodies as detected by flow cytometry.

BACKGROUND Preformed anti-HLA antibodies are known to have the potential to induce early graft damage in organ transplant recipients. However, in lung transplant recipients, little information exists about the significance of preformed antibodies directed to either class I or class II HLA antigens. METHODS A two-color flow cytometry cross-match was performed in 92 consecutive lung transplant recipients using serum obtained immediately before transplantation. The presence of preformed antibodies was correlated with the incidence of severe graft dysfunction manifested as pulmonary infiltrates and severe hypoxemia with onset in the first few hours after transplantation. RESULTS Six patients (6.5%) had low-level anti-donor IgG antibodies detected by flow cytometry, four against T and two against B lymphocytes. Three patients (50%) developed severe graft dysfunction with pulmonary infiltrates and hypoxemia. Two patients responded to treatment, but the third, who had an antibody highly specific for HLA-DR11, died at 48 hr after transplant. Results of histopathologic studies in this patient are consistent with hyperacute rejection and support a pathogenic role of these antibodies. In contrast, of 86 (93.5%) cases with a negative flow cytometry cross-match, only 4 (5%) had severe but reversible early graft dysfunction with pulmonary infiltrates and hypoxemia, attributed to ischemia-reperfusion injury (P<0.005). CONCLUSIONS Class II, and perhaps class I HLA antibodies at relatively low concentrations represent a risk factor for severe early pulmonary graft dysfunction, with the potential to progress to hyperacute rejection and death.

Exercise-induced hypoxemia in heart transplant recipient

Objectives. The purpose of this study was to determine whether heart transplantation has an adverse effect on pulmonary diffusion and to investigate the potentially deleterious effects of impaired pulmonary diffusion on arterial blood gas dynamics during exercise in heart transplant reciplents. Background. Abnormal pulmonary diffusing capacity is reported in patients after orthotopic heart transplantation. Abnormal diffusion may be caused by cyclosporlne or by the persistence of preexisting conditions known to adversely affect diffusion, such as congestive heart failure and chronic obstructive pulmonary disease. Methods. Eleven patients (mean age 50 ± 14 years) performed pulmonary function tests 3 ± 1 months before and 18 ± 12 (mean ± SD) months after heart transplantation. Transplant patients were assigned to groups with diffusion > 70% (n = 5) or diffusion < 70% of predicted values (n = 5). The control group and both subsets of patients performed 10 min of cycle exercise at 40% and 70% of peak power output. Arterial blood gases were drawn every 30 s during the 1st 5 min and at 6, 8 and 10 min. Results. Significant improvements in forced vital capacity (17,4%), forced expiratory volume in 1 s (11.7%) and diffusion capacity (6.6%) occurred in the patients; however, posttransplantation vital capacity, forced expiratory volume and diffusion were lower (p ≤ 0.05) compared with values in 11 control subjects. Changes in blood gases were similar among groups at 40% of peak power output. At 76% of peak power output, arterial blood gases and pH were significantly (p ≤ 0.05) lower in transplant patients with low diffusion (arterial oxygen pressure 15 to 38 mm Hg below baseline) than in patients with normal diffusion and control subjects. Cardiac index did not differ (p ≥0.05) between transplant patients with noramal and low diffusion at rest or during exercise. Posttransplantation mean pulmonary artery pressure was significantly related to exercise-induced hypoxemia (r = 0.71; p = 0.03). Conclusions. Abnormal pulmonary diffusion observed in patients before heart transplantation persists after transplantation with or without restrictive or obstructive ventilatory defects. Heart transplant recipients exprience exercise-induced hypoxemia when diffusion at rest is < 70% of predicted. Our data also suggest that abnormal pulmonary gas exchange possibly contributes to diminished peak oxygen consumption in some heart transplant recipients; however, direct testing of this hypothesis was beyond the scope of the present study. This possibility needs to be investigated further.

Adenosine-induced atrioventricular block: A rapid and reliable method to assess surgical and radiofrequency catheter ablation of accessory atrioventricular pathways

Adenosine has been shown to inhibit anterograde and retrograde conduction through the atrioventricular (AV) node while having little or no effect on accessory pathway conduction. Its rapid onset of action and short half-life make it particularly suitable for repetitive measurements. In this study, the utility of adenosine was tested in assessing completeness of accessory pathway ablation. Sixteen patients with an accessory pathway were studied (eight surgical ablations, eight catheter ablations with radiofrequency energy). Before ablation, no accessory pathway was sensitive to adenosine. Twelve patients with pre-excitation showed high grade AV node block with maximal pre-excitation on the administration of adenosine during atrial pacing. Four patients with a concealed accessory pathway demonstrated high grade AV block without evidence of latent anterograde accessory pathway conduction. Preablation ventriculoatrial (VA) block was not observed in any of the 16 patients in response to adenosine during ventricular pacing. Immediately after accessory pathway ablation, all patients developed AV and VA block with the administration of adenosine during atrial and ventricular pacing, respectively. These findings were confirmed during follow-up study 1 week later. Atrioventricular block during atrial and ventricular pacing with adenosine affords a reliable and immediate assessment of successful pathway ablation.

Acute Neuropsychological Functioning Following Cardiosurgical Interventions Associated With the Production of Intraoperative Cerebral Microemboli

Coronary artery bypass graft (CABG) and valve replacement (VR) surgical patients underwent neuropsychological assessment 1–2 days prior to surgery; 7–10 days postsurgery; and 1 month following hospital discharge. A group of matched healthy controls was tested at identical intervals. Cerebral microemboli in both middle cerebral arteries were quantified during surgery using Doppler sonography. Neuropsychological testing results revealed that the CABG and VR groups did not differ from one another at any assessment point. However, surgical patients performed more poorly than healthy controls across all assessments. Surgical patients, as a group, demonstrated a mild decline in attentional functioning and learning efficiency at the 7–10 day follow-up, but these difficulties essentially returned to baseline by the 1-month follow-up. Intraoperative microemboli counts were not significantly associated with postsurgical neuropsychological functioning in either the CABG or VR group.

Superoxide Anion Generation, Superoxide Dismutase Activity, and Nitric Oxide Release in Human Internal Mammary Artery and Saphenous Vein Segments

Background: Internal mammary artery (IMA) as conduit for a coronary artery bypass graft (CABG) stays patent longer and more often than saphenous vein (SV). However, the pre cise differences in the biology of IMA and SV are unclear. Methods and Results: To examine inherent difference in superoxide anion, superoxide dis mutase (SOD) and nitric oxide (NO) formation in IMA and SV as a basis for differences in patency rates, we measured these parameters in vascular segments of patients undergoing CABG. Superoxide anion generation was measured by lucigenin chemiluminescence and reduction of cytochrome c, SOD by inhibition of pyrogallol auto-oxidation, and NO as nitrite/nitrate fluorometrically using 2-3-diaminonaphthalene as a probe. Generation of superoxide anion, SOD activity, and NO formation were all greater in the IMA than in the SV segments (IMA:SV = 2.6:1, 2.9:1, 1, and 3.0:1, respectively, all P < .01). There was a pos itive correlation between superoxide anion generation and SOD activity (r = 0.65, P < .05; r = 0.70, P < .05 in IMA and SV, respectively) and NO release (r = 0.68, P < .05; r = 0.75, P < .03 in IMA and SV, respectively). Western blot analysis showed no differences in SOD and NO synthase protein expression in IMA and SV segment homogenates. To examine whether greater superoxide anion generation, SOD activity, and NO formation are unique to IMA, we studied pulmonary artery (PA) and pulmonary vein (PV) segments taken from patients undergoing lung resection. Superoxide anion generation, SOD activity, and NO formation were also found to be greater in PA than in PV segments. Conclusions: Inherently greater superoxide anion generation and subsequently increased formation of SOD and NO release in IMA (vs SV) may be a factor in the greater patency of the former as CABG conduit. Because both IMA and PA are exposed to pulsatile stretch and carry blood at higher pressure than the SV and PV, it is likely that these 2 factors account for the observed differences.