Daniel M. Philbin

Histamine Release during Morphine and Fentanyl Anesthesia

High doses of morphine produce peripheral vasodilation and frequently significant hypotension. These effects are thought to be due, in part, to the release of histamine. One putative advantage of high-dose fentanyl anesthesia is its relatively small effect on peripheral vascular resistance. In a randomized study, the authors examined the possibility that the hemodynamic differences between morphine and fentanyl might be attributable to histamine release. Fifteen patients were studied prior to coronary artery bypass surgery. Subjects received an infusion of morphine (1 mg·kg−1, iv at 100 Amg-·kg−1·min−1 [n – 8]) or fentanyl (50 μg·kg−1 at 5 μg·kg−1·min−1 [n = 7]). Patients in the morphine group had an average 750 per cent peak increase in plasma histamine accompanied by a significant decrease in mean arterial pressure (-27 mmHg) and systemic vascular resistance (-520 dyne·s·cm−1). The greatest decrease in systemic vascular resistance occurred in those patients with the highest levels of plasma histamine (r = −0.81). Patients in the fentanyl group had no change in plasma histamine and no decrease in arterial pressure or systemic vascular resistance. Cardiac output and heart rate were comparable between the two groups. Differences in the release of histamine account for most, if not all, of the different effects of morphine and fentanyl on the peripheral vasculature.

Pulsatile and Nonpulsatile Cardiopulmonary Bypass: Review of a Counterproductive Controversy

In the controversy over pulsatile and nonpulsatile perfusion, most authors have failed to recognize the fundamental physical differences between the two methods. Pulsatile perfusion is polymorphic and its form varies with both the pulsatile source and the vascular system being perfused; nonpulsatile perfusion is by definition unvarying and uniform. While many studies of hemodynamics, metabolism, organ function, microcirculation, and histology show benefits derived from pulsatile perfusion, others do not. The simplest explanation for these conflicts is that different investigators employ different forms of pulsatile perfusion, only some of which are effective. Failure to quantitate adequately the pulsatile components of flow in these studies prevents differentiation between effective and ineffective forms of pulsatile flow and makes comparison of studies difficult. Future research in this area should be directed toward definition of effective pulsatile perfusion by adequate measurement of the pulsatile components of perfusion.

Fentanyl and Sufentanil Anesthesia Revisited: How Much is Enough?

This study was undertaken to determine if fentanyl and sufentanil could produce dose-related suppression of hemodynamic and hormonal responses to surgical stimulation. Eighty patients scheduled for elective CABG were studied in two consecutive protocols: protocol I was a randomized double-blind study of 40 patients who received a single dose of fentanyl (50 or 100 micrograms/kg) or sufentanil (10, 20, or 30 micrograms/kg). Hemodynamic measurements and hormonal concentrations (renin, aldosterone, cortisol, and catecholamines) were determined before and after induction and after intubation and sternotomy. Protocol II was an open randomized study of 40 patients who received sufentanil in one of four doses: 30 micrograms/kg as a single dose, 10 micrograms/kg plus infusion 0.05 microgram.kg-1.min-1, 20 micrograms/kg plus infusion 0.1 microgram.kg-1.min-1, or 40 micrograms/kg plus infusion 0.2 microgram.kg-1.min-1. Hemodynamic measurements and plasma sufentanil and catecholamine concentrations were determined before and after induction and after intubation, sternotomy, and aortic cannulation. Both protocols defined a hemodynamic response as a 15% or more increase in systolic blood pressure (SBP) from control and a hormonal response 50% or more increase over control. During protocol I, 18 patients had a hemodynamic response (average increase in SBP 22.6 +/- 2%) and 35 patients had a total of 59 hormonal responses. During protocol II, 24 patients had a hemodynamic response (average increase in SBP - 31 +/- 3%) and there were 15 catecholamine responses. There were no differences between dose groups in either protocol. It was concluded that in these dose ranges, suppression of hemodynamic or hormonal stress responses is not related to opioid dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study.

High doses of morphine can produce significant cardiovascular effects generally attributed to histamine release. The authors examined the possibility that H1 and H2 histamine antagonists might prove beneficial in preventing these responses. In a randomized double-blind study, four groups of 10 patients each received 1 mg/kg morphine and either a placebo, diphenhydramine (H1), cimetidine (H2), or both of the histamine antagonists. The morphine-placebo group demonstrated a marked elevation in plasma histamine levels (880 ± 163 to 7437 ± 2684 pg/ml), a decrease in systemic vascular resistance (SVR) (15.5 to 9.0 l torr/(1 ± min−1) and diastolic BP (71 ± 3 to 45 ± 4 torr) and an increase in cardiac index (CI) (2.4 ± 0.2 to 3.0 ± 0.21·min−1·m−2). The administration of either cimetidine or diphenhydramine with morphine provided minimal protection. Those patients who received morphine and both antagonists demonstrated significant attenuation of these responses (CI 2.5 ± 0.2 to 2.5 ± 0.1 1·min−1·m−2; SVR 17.4 to 14.6 torr/(1·min−1) although plasma histamine levels showed a comparable increase (1059 ± 222 to 7653 ± 4242 pg/ml). These data demonstrate directly that many of the hemodynamic effects of morphine can be attributed to histamine release. They further demonstrate that significant hemodynamic protection can be obtained by the use of histamine antagonists and the combination of H1 and H2 antagonists is superior to either given alone.

Diazepam-Fentanyl Interaction-Hemodynamic and Hormonal Effects in Coronary Artery Surgery

Diazepam has been reported to produce hypotension when administered with anesthetic doses offentanyl. Twenty patients undergoing coronary bypass surgery were randomly assigned to one of four treatment groups: group 1, no diazepam; groups 2, 3, and 4, 0.125, 0.25, and 0.5 mg·kg−1 of diazepam, respectively. All patients then received 50 μg·kg−1 fentanyl at 400 μg·min−1 and 0.4 mg·kg−1 metocurine at 2 mg·min−1. Hemodynamic parameters were recorded and blood was sampled for measurement of plasma catecholamine and histamine concentrations. Heart rate, cardiac index, stroke volume index, central venous pressure, pulmonary arterial and wedge pressures, and pulmonary vascular resistance did not change significantly in any group. Patients in groups 2–4 had significant decreases in mean arterial pressure and systemic vascular resistance during fentanyl infusion. These hemodynamic changes were accompanied by decreases in plasma epinephrine and norepinephrine levels. These hemodynamic and hormonal changes did not occur in patients given fentanyl only. Plasma histamine levels did not change significantly in any group. Caution should be used when diazepam in doses as small as 0.125 mg·kg−1 are combined with high-dose fentanyl anesthesia.

Hemodynamic and hormonal responses to hypothermic and normothermic cardiopulmonary bypass

Normothermic cardiopulmonary bypass (CPB) is used in cardiac surgery at some institutions. To compare hemodynamic and hormonal responses to hypothermic (29 degrees C) and normothermic nonpulsatile CPB, 20 adults undergoing coronary artery bypass graft and/or aortic valve replacement were studied. Hemodynamic measurements and plasma hormone concentrations were obtained from preinduction to the third postoperative hour. The two groups were given similar amounts of anesthetics and vasodilators. Systemic vascular resistance increased only during hypothermic CPB, and heart rate was higher at the end of hypothermic CPB. Postoperative central venous pressure and pulmonary capillary wedge pressure were lower after hypothermic CPB. Oxygen consumption decreased by 45% during hypothermic CPB, did not change during normothermic CPB, but increased similarly in the two groups after surgery; mixed venous oxygen saturation (SvO2) was significantly lower during normothermic CPB. Urine output and composition were similar in the two groups. In both groups, plasma epinephrine, norepinephrine, renin activity, and arginine vasopressin concentrations increased during and after CPB. However, epinephrine, norepinephrine, and dopamine were 200%, 202%, and 165% higher during normothermic CPB than during hypothermic CPB, respectively. Dopamine and prolactin increased significantly during normothermic but not hypothermic CPB. Atrial natriuretic peptide increased at the end of CPB and total thyroxine decreased during and after CPB, with no difference between groups. This study suggests that higher systemic vascular resistance during hypothermic CPB is not caused by hormonal changes, but might be caused by other factors such as greater blood viscosity. A higher perfusion index during normothermic CPB might have allowed higher SvO2.

Antidiuretic and Growth Hormone Responses during Coronary Artery Surgery with Sufentanil-Oxygen and Alfentanil-Oxygen Anesthesia in Man

Antidiuretic hormone (ADH), growth hormone (GH), and cardiovascular responses to large (anesthetic) doses of alfentanil (1.2 ± 0.02 mg/kg) and oxygen and sufentanil (13.1 ± 0.4 μg/kg) and oxygen were measured before and during surgery (including cardiopulmonary bypass) and at the end of surgery in 29 patients undergoing coronary artery bypass surgery. The data demonstrate that alfentanil-O2 and sufentanil-O2 result in little change in cardiovascular dynamics throughout anesthesia and surgery, and also prevent changes in plasma levels of ADH and GH at all times during the study. Our findings contrast with previous studies with other anesthetics, including fentanyl, in which plasma levels of ADH and GH become markedly elevated during bypass. The results suggest that alfentanil and sufentanil may block hormonal stress responses to surgical stimulus better than fentanyl does. The clinical significance of the difference in ADH and GH responses during fentanyl and during alfentanil or sulfentanil anesthesia remains to be determined. However, this difference may provide part of the explanation why alfentanil and sufentanil-O2 anesthesia require less frequent employment of other anesthetic adjuvants and are easier to use than fentanyl during coronary artery surgery.

Plasma Antidiuretic Hormone Levels in Cardiac Surgical Patients during Morphine and Halothane Anesthesia

The effects of halothane and morphine anesthesia on plasma antidiuretic hormone (ADH) levels and urinary flow were determined in 18 patients undergoing elective open-heart operations. Patients were divided into three groups of six each: Group I, halothane, 0.5 per cent; Group II, morphine, 1 mg/ kg; Group til, morphine, 2 mg/kg. In addition, all patients received nitrous oxide - oxygen, 50 per cent each. Measurements of mean blood pressure; heart rate; urinary flow, osmolality and electrolytes; and plasma ADH (by radioimmunoassay) we remade prior to induction of anesthesia, 15 and 30 min after induction, and 15 and 30 min after surgical incision. Control values for ADH were comparable in all groups (about 3 pg/ml). There was no significant change in any group after induction of anesthesia. After surgical incision ADH levels increased significantly in Group I (102 ± 29 pg/ml), and Group II (42.6 ± 25 pg/ml), but not in Group III (14.5 ± 7 pg/ml). The increase of plasma ADH was significantly higher in Group I than in Group II or III. Variations in urinary (low were not significant throughout the study. These data demonstrate that neither morphine nor light halothane anesthesia stimulates high levels of ADH secretion. They suggest that the increase in ADH with surgical stimulation is a stress response that can be attenuated by deeper morphine anesthesia. The ADH levels arc beyond the physiologic range for antidiuretic action on the kidney, and may represent a vasopressor response. Variations in urinary flow were not ADH-related.

Attenuation of the stress response to cardiopulmonary bypass by the addition of pulsatile flow.

The effect of pulsatile flow during cardiopulmonary bypass on the hormonal stress response was studied in 26 patients. Thirteen had routine bypass and 13 had pulsatile bypass with an average pulse pressure of 30 mm Hg. Plasma vasopressin levels were significantly elevated during bypass in both groups, but were lower with pulsation (66 ± 11 vs 36.3 pg/ml, p < 0.05). Epinephrine levels increased in both groups during bypass, but were higher after bypass (1179 ± 448 vs 713 ± 140 pg/ml, p < 0.05) and in the recovery room (1428 ± 428 vs 699 ± 155 pg/ml, p < 0.05) in the nonpulsatile group. The same response was noted in the norepinephrine levels (924 ± 225 vs 465 ± 90 pg/ml, p < 0.05; 1915 ± 491 vs 717 ± 112 pg/ml, p < 0.05). There were no significant changes in renin activity in either group, but the increase after cardiopulmonary bypass was greater in the nonpulsatile group (2.0 ± 0.7 vs 1.36 ± 0.4 ng/mI/hr, NS). These data suggest that pulsatile flow significantly attenuates the vasopressin and catecholamine stress response to cardiopulmonary bypass. This may explain the increased flow requirements and better tissue perfusion and organ function and the decreased incidence of postoperative hypertension after bypass using pulsatile flow.

The influence of sufentanil on endocrine and metabolic responses to cardiac surgery.

Sufentanil is a new synthetic opioid 5–10 times as potent as fentanyl. This study evaluated the endocrine and metabolic responses to cardiac surgery in 10 patients anesthetized with 20 μ/kg of sufentanil and air-O2. With the exception of prolactin, there were no significant changes in the concentrations of any of the hormones or substrates measured before cardiopulmonary bypass. No changes occurred at any time during the study in insulin or growth hormone concentrations and only plasma cortisol increased significantly 1 h after surgery. Blood glucose increased significantly at the end of cardiopulmonary bypass and remained elevated throughout the remainder of the study period. ADH also increased during bypass, although the increase only reached significance (P < 0.05) at the end of surgery. Marked increases in concentrations of nonesterified fatty acids and decreases in levels of triglycerides occurred immediately before and during bypass. These changes are attributed to the effect of heparin on lipoprotein lipase activity. Highly significant (P < 0.01) increases occurred in plasma lactate concentrations during cardiopulmonary bypass. This is attributed to use of Ringers lactate solution in the oxygenator prime. Very large increases in catecholamine concentrations occurred during cardiopulmonary bypass. Thus, although sufentanil prevents the endocrine and metabolic responses to surgery before cardiopulmonary bypass, even the use of a large dose is ineffective in preventing these responses during or after bypass.