Monitoring intravascular volumes to direct hypertensive, hypervolemic therapy in a patient with vasospasm

The common therapeutic approach to patients, who develop vasospasm following subarachnoid hemorrhage, is usually composed of hypertension, hypervolemia, and hemodilution (HHH). This therapy often leads to cardiopulmonary complications, including significant heart failure and pulmonary edema. We describe a 40-year-old woman who developed vasospasm 8 days after surgery for clipping an aneurysm, following a large subarachnoid hemorrhage. The patient required HHH therapy with a very high blood pressure to optimize her clinical neurologic status, but she started to develop pulmonary edema resulting from this therapy. This manifested as a need for increasing oxygen to maintain a normal arterial saturation. To avoid further hemodynamic compromise, we used a new monitor of cardiac function to measure intravascular volumes and quantify pulmonary edema to help titrate the fluid management of a patient in severe vasospasm. We conclude that monitoring volumes with the PiCCO cardiac monitor can help make clinical decisions in patients requiring HHH. This enables maintaining a hypertensive and hypervolemic state while avoiding cardiopulmonary complications such as heart failure and pulmonary edema. It may also help prevent the need for mechanical ventilation in these situations.     

In vitro phamacology of MK-996, a new potent and selective angiotensin II (AT1) receptor antagonist

MK-996 (N-((4′-((5,7-Dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl) (1,1′-biphenyl)-2-yl) sulfonylbenzamide) interacted in a competitive manner with rabbit aortic angiotensin II (All) receptors as determined by Scatchard analysis of specific binding of [¹²⁵l]-Sar¹lle⁸-All. MK-996 also exhibited high affinity at All receptors in several tissues from different animal species (K_i = 0.1–0.4 nM). In vitro functional assays utilizing All-induced aldosterone release in rat adrenal cortical cells demonstrated further that MK-996 acts as a competitive, high affinity antagonist of All (pA₂ = 10.3) and lacks agonist activity. MK-996 also potently inhibited All-induced contractile response in isolated rabbit aorta and pulmonary artery with a reduction in maximal response. The specificity of MK-996 for All receptors was demonstrated by its lack of activity (IC₅₀> 1 μM) in several other receptor binding assays and its inability to affect in vitro functional responses produced by other agonists. MK-996 demonstrated a very high selectivity for the AT₁ compared to AT₂ receptor subtype (AT₂ IC₅₀ ≥ 2 μM). Direct binding studies using [³H]-MK-996 in rat adrenal indicated specific binding of [³H]-MK-996 is saturable and of high affinity (K_d = 0.47 nM). The specific [³H]-MK-996 binding in rat adrenal represents binding to pharmacologically relevant AT₁ receptors as demonstrated by the similar K_i values for various All agonists and antagonists in inhibiting specific ³H-MK-996 and [¹²⁵l]-All binding to AT₁ receptors. Dissociation rate studies of specific [³H]-MK-996 binding indicated a t1/2 of 103 min. This slow dissociation may account for the reduction in maximal responses to All in MK-996 treated isolated blood vessels.     

Pain and analgesia: considerations for the elderly in critical care

A large percentage of patients in critical care are older than 65 years old. Pain is a problem common to the elderly receiving critical care. Effective management of pain is accomplished through collaboration between nursing and medicine. Understanding physiologic changes experienced with aging and anticipated changes in functional abilities is necessary to the development of a pain-management plan and to providing comprehensive nursing care. Pharmacologic analgesia will be a part of the pain-management plan, with consideration given to the effects on the elderly.     

Inositol phosphate formation in the human squamous cell carcinoma line SCC-12 F: studies with bradykinin, the calcium ionophore A23187, and sodium fluoride

The phospholipase C (PLC)-mediated hydrolysis of membrane phosphoinositides is an important signal transduction pathway coupled to the cell-surface receptors for several hormones and growth factors. In addition, PLC activity can be modulated by changes in intracellular calcium and activation of GTP binding proteins. In this report, differential activation of PLC in the human keratinocyte cell line SCC-12F was studied as judged by specific patterns of inositol phosphate formation. Several hormones and growth factors previously shown to stimulate PLC in a variety of cell types were screened for activity in SCC-12F cells. Only bradykinin was active, stimulating the PLC-dependent generation of inositol (1,4,5) triphosphate (Ins(1,4,5)P3). Ins(1,4,5)P3 was rapidly metabolized to inositol(1,4)biphosphate (Ins(1,4)P2) and inositol(1,3,4,5)tetrakisphosphate (Ins(1,3,4,5)P4), and subsequently degraded to inositol monophosphates. The response elicited by bradykinin was concentration dependent (EC50 value of 50 nM), suggesting involvement of a specific bradykinin receptor. Treatment of these cells with the calcium ionophore A23187 appeared to result in the direct formation of Ins(1,4)P2 without Ins(1,4,5)P3 as precursor. Treatment of the cells with AIF4-, a putative activator of GTP binding proteins, resulted in the generation of inositol monophosphates as the major metabolites in the absence of detectable Ins(1,4,5)P3 formation. Taken together, these observations suggest that the PLC complex present in SCC-12F cells can be differentially activated to yield either Ins(1,4,5)P3, Ins(1,4)P2, or InsP. The observed effects may be due to a direct PLC-dependent hydrolysis of the appropriate membrane phosphoinositide.