Samuel R. Powers

Opsonic α2 Surface Binding Glycoprotein Therapy During Sepsis

: A pronounced depletion of an opsonic protein for hepatic reticuloendothelial (RE) phagocytosis has been demonstrated in critically ill trauma patients. This opsonic alpha(2) surface binding (SB) glycoprotein has immunologic identity and a similar amino acid composition to cold insoluble globulin (CIg). Since CIg can be concentrated in cryoprecipitate, it was utilized as a readily available source of opsonic alpha(2)SB glycoprotein for replacement therapy after injury with documented hypoopsonemia. Six septic patients (2 multiple trauma, 2 thermal burn, and 2 intra-abdominal abscess) were studied to test whether cryoprecipitate infusion would restore this humoral component. Pre- and posttherapy opsonin levels were determined by bioassay and electroimmunoassay. In all patients, severe opsonin depletion was reversed following cryoprecipitate infusion. All patients had a rapid improvement in febrile state, normalization of leukocyte levels, and improvement in pulmonary function as evidenced by decreasing requirements for end expiratory pressure at lowered levels of inspired oxygen. One patient was studied more extensively and demonstrated an increase in cardiac output, limb blood flow, total body and limb oxygen delivery, total body and limb oxygen consumption and a progressive decrease in pulmonary shunt fraction. Thus, opsonic alpha(2)SB glycoprotein deficiency can be reversed by cryoprecipitate infusion in critically ill septic injured patients. Replacement of this humoral factor may be an important therapeutic modality in prevention of multiple organ failure, but it should be administered only after documentation of hypoopsonemia in traumatized patients.

Deficits in reticuloendothelial humoral control mechanisms in patients after trauma.

Plasma opsonic activity as expressed by an alpha-2-globulin which stimulates hepatic Kupffer cell phagocytosis, and thus modulates RES clearance, was determined in patients at varying intervals following whole-body trauma. Plasma opsonic activity decreased markedly following trauma in both nonsurviving (NS) and surviving (S) trauma patients as compared to an age- and sex-matched group of healthy volunteers. The initial post-traumatic hypoopsonemia (0-72 hr) was more severe (p less than 0.01) in nonsurviving patients than surviving patients. Survivors following trauma manifested restoration of opsonin levels with a definite transient rebound hyperopsonemia during the recovery phase (11-30 days); nonsurviving patients exhibited persistent systemic alpha-2-globulin opsonic deficiency. On the basis of previous animal and human studies, the presently observed humoral deficits following trauma in patients could contribute to impairment of reticuloendothelial Kupffer cell clearance of blood-borne particulate matter such as fibrin, damaged platelets, and other altered autologous tissue. The importance of post-trauma RES dysfunction to survival following severe injury warrants further investigation and clinical consideration.

Increased Creatinine Clearance following Cryoprecipitate Infusion in Trauma and Surgical Patients with Decreased Renal Function

Deficiency of opsonic alpha 2 surface binding (SB) glycoprotein (cold-insoluble globulin, plasma fibrinectin) is related to depressed reticulendothelial function as well as to multiple organ failure after tissue injury and sepsis. Cryoprecipitate (250 ml), extracted from 10 units of human plasma, was infused over 60 minutes into 11 hypo-opsonemic patients with decreased renal function. Cardiac output, mean arterial pressure, creatinine clearance, and limb blood flow were measured before and at intervals of 14 to 20, 35 to 44, and 60 to 66 hours following cryoprecipitate infusion. Before infusion, the mean creatinine clearance was 30 +/- 4 ml/min/M2 body surface area (BSA) and increased to 40 +/- 6 ml/min/M2 BSA at 14 to 20 hrs (p < 0.05); to 40 +/- 4 ml/min/M2 BSA at 35 to 44 hrs (p < 0.05); and to 40 +/- 5 ml/min/M2 BSA at 60 to 66 hrs (p < 0.05). In contrast, mean arterial pressure and cardiac index at each time interval showed no significant changes from the pretreatment values of 81 +/- 6 mm Hg and 3.4 +/- .2 L/min/M2 BSA, respectively. Limb blood flow increased significantly at 4 hours and returned to control values by 35 to 44 hours. Thus cryoprecipitate infusion to critically ill trauma and surgical patients with depressed renal function may improve glomerular filtration rate independently of mean arterial pressure or cardiac output. This improved renal function may be related to increased reticuloendothelial clearance of blood-borne particulates and/or improved microcirculatory function and lends support to the concept that RES failure may be involved in the etiology of multiple organ failure secondary to combined tissue injury and sepsis.

Detrimental effects of removing end-expiratory pressure prior to endotracheal extubation.

Patients recovering from acute respiratory insufficiency are usually not extubated until they can ventilate adequately while breathing spontaneously at ambient end-expiratory pressure (T-tube). It is hypothesized that this period of T-tube breathing might be detrimental to gas exchange since the endotracheal tube abolishes the expiratory retard produced by the glottis and thereby inhibits the patients ability to maintain adequate functional residual capacity (FRC). To test this hypothesis, pulmonary function of 17 patients was compared during T-tube breathing and Continuous Positive Airway Pressure (CPAP) and after extubation. Intrapulmonary shunt was higher (p less than 0.05) and arterial PO2 and FRC were lower (p less than 0.05) during T-tube breathing than during CPAP or after extubation. In contrast, shunt, PaO2 and FRC were similar during CPAP and after extubation. Furthermore, after extubation there was an increase (p less than 0.05) in mean expiratory airway pressure as compared to T-tube breathing. A comparison of patients extubated from T-tube with patients extubated from CPAP showed no difference in postextubation shunt, PaO2 or FRC. These data suggest that endotracheal intubation should be accompanied by low levels of CPAP and that patients should be extubated directly from CPAP. The practice of placing patients in T-tube prior to extubation should be abandoned as unnecessary and potentially harmful.

Lung vascular permeability after reversal of fibronectin deficiency in septic sheep. Correlation with patient studies.

Plasma fibronectin deficiency and opsonic dysfunction exist in critically ill septic surgical, trauma, and burn patients with multiple organ failure. Fibronectin deficiency can be reversed by infusion of fresh plasma cryoprecipitate. The influence of therapy with human cryoprecipitate on lung vascular permeability in septic sheep with plasma fibronectin deficiency following surgery was evaluated. Additionally, selected studies on pulmonary function in septic surgical and trauma patients after infusion of plasma cryoprecipitate were completed. In patients, ventilation-perfusion balance appeared to improve as measured by the multiple inert gas elimination technique. With the lung lymph fistula preparation in fibronectin deficient sheep, infusion of human plasma cryoprecipitate (10 units; 250 ml) delayed the onset and minimized the increase in lung vascular permeability during postoperative Pseudomonus sepsis (5 × 109 bacteria, I.V.; 5 × 1010 bacteria, I.P.). For example, in a first group of sheep, the transvascular protein clearance (TPC) at 2 hrs in septic sheep (n = 4) treated with only saline (volume control) was 20.1 ± 3.1 ml/hr, compared to 11.23 ± 0.83 ml/hr in the sheep (n = 4) treated with fibronectin-rich cryoprecipitate (p < 0.05). In a second group of sheep, cryoprecipitate depleted of fibronectin by affinity chromatography was used as the control solution. It also did not manifest this protective effect with respect to lung vascular permeability. Thus, at 2 hrs the lymph flow (Qlym) was 30.2 ml/hr and the transvascular protein clearance (TPC) was 18.0 ml/hr in septic sheep given fibronectin-deficient cryopre cipitate. In contrast, in the fibronectin-rich cryoprecipitate treated sheep, the Qlym was 14.8 ml/hr and the TPC was 8.12 ml/hr. It is suggested that fibronectin may influence lung vascular integrity during sepsis following surgery and trauma.

Cardiopulmonary adjustments following single high dosage administration of methylprednisolone in traumatized man.

Pharmacologic doses of methylprednisolone sodium succinate were administered to 10 critically ill patients when the steroid was the only variable. Measurements of respiratory and circulatory physiologic parameters were obtained in all patients prior to injection and at 30 and 90 minutes following injection of methylprednisolone sodium succinate. A significant increase in Cardiac Index was seen (P less than .01) which appeared to be in association with a decrease in pulmonary vascular resistance (P less than .01) at a time when physiologic shunting of blood through the lungs increased (P less than .01). These changes imply improved perfusion of non- or poorly ventilated portions of the lungs. Four of ten patients demonstrated removal of lactate by the lung during the control period. Following methylprednisolone sodium succinate injection, 9 of 10 patients demonstrated production or a washout of lactate from the lungs.

Hypertonic mannitol in the therapy of the acute respiratory distress syndrome.

Increased pulmonary artery pressure, an increase in pulmonary vascular resistance and an increase in physiologic dead space are consistent findings in patients with post-traumatic respiratory distress. Since mannitol has been shown to decrease renal vascular resistance following trauma, the effect of a bolus injection of 100 ml of 25% solution of this drug on pulmonary hemodynamics and physiologic dead space was investigated in 11 patients who had suffered multiple trauma. Five minutes after the injection, pulmonary vascular resistance fell (p less than .01), cardiac index increased (p less than .001) and physiologic dead space decreased (p less than .05). In contrast, the administration of 40 mg of furosemide produced no significant change in any of these parameters. Mannitol rapidly equilibrates in the extracellular space and exerts an osmotic effect across cell membranes. We postulate that the beneficial response to mannitol on the pulmonary vascular resistance and the improved perfusion of ventilated regions of the lung is due to a reduction in cell swelling and is not explainable by its diuretic effect. Improvement in the distribution of perfusion of pulmonary blood flow by mannitol may be a useful aid in the treatment of the post-traumatic form of the respiratory distress syndrome.

Increased glomerular filtration rate following mannitol administration in man

In contrast to previous findings in normal man, we found that mannitol increased the glomerular filtration rate (GFR) in seriously ill patients. The increase in GFR following hypertonic mannitol administration was greater than the proportional increase in cardiac output.

Mannitol-vasopressin interactions in the splenectomized dog

Summary Experiments were carried out in 46 splenectomized dogs demonstrating that the intravenous administration of mannitol will produce an increase in urinary flow under all conditions of water loading. It was also demonstrated that the intramuscular administration of vasopressin will not significantly alter the expected course of events except when high water loading has been carried out; in that case a significant increase in urinary flow is noted. Further experiments have indicated that the renal blood flow, measured directly, is consistently greater in the high water load, mannitol- and vasopressin-treated dog than in the high water load, mannitol- but not vasopressin-treated animal. A very high urinary excretion of chlorides was also noted in the vasopressin-treated, mannitolized, high water load animals.

Uneven ventilation of the lung following trauma.

AbstractVentilatory function of the lungs has been studied in 13 posttrauma patients using a two compartment analysis. The analysis is based upon a model of the lung which describes a nitrogen washout curve in terms of fast and slowly ventilated compartments. Data output from a digital computer provides values that compare the fractions of the alveolar ventilation and volume of the two compartments. All patients on initial investigation had large identifiable slow spaces. Subsequent evaluation at a time of clinical improvement showed that the ventilation of the slow space had increased significantly (P < .003), whereas no change was evident in the volume fraction. The ventilation to volume ration of the slow space, measured on these two separate occasions increased in twelve of the patients studied. An increase in this ratio correlated with improvement in the patients clinical condition.