Leonid Roytblat

Postoperative Pain: The Effect of Low-dose Ketamine in Addition to General Anesthesia

In a randomized, double-blind study, postoperative pain was assessed in 22 patients undergoing elective open cholecystectomy with two types of anesthesia: standardized general anesthesia (control group), and low-dose ketamine as an addition to the same method of general anesthesia, before surgical incision (ketamine group). After the operation we found that the time from the end of surgery to the first request for analgesic was longer in the ketamine group. Postoperatively, patients in both groups were treated with patient-controlled analgesia (PCA) in exactly the same way. The major difference in the study was the reduced dose requirement of morphine in the ketamine group compared with the control group after the operation. The mean dose of morphine given in patients of the control group during the first 24 h was 48.7 mg vs 29.5 mg in the ketamine group. Mean visual analog scale (VAS) and verbal rating scale (VRS) were higher in patients in the control group during the first 5 h after surgery (P < 0.02), but between 5 and 24 h after surgery VAS and VRS were not significantly different (P > 0.05). Our results indicate that postoperative pain can be decreased when ketamine in low doses is added to general anesthesia before surgical stimulation.

Ketamine Attenuates the Interleukin-6 Response After Cardiopulmonary Bypass

Cardiopulmonary bypass (CPB) has been proposed as a model for studying the inflammatory cascade associated with the systemic inflammatory response syndrome.Serum interleukin-6 (IL-6) concentration seems to be a good indicator of activation of the inflammatory cascade and predictor of subsequent organ dysfunction and death. Prolonged increases of circulating IL-6 are associated with morbidity and mortality after cardiac operations. In the present study, we compared the effects of adding ketamine 0.25 mg/kg to general anesthesia on serum IL-6 levels during and after elective coronary artery bypass grafting (CABG). Thirty-one patients undergoing elective CABG were randomized to one of two groups and prospectively studied in a double-blind manner. The patients received either ketamine 0.25 mg/kg or a similar volume of isotonic sodium chloride solution in addition to large-dose fentanyl anesthesia. Blood samples for analysis of serum IL-6 levels were drawn before the operation; after CPB; 4, 24, and 48 h after surgery; and daily for 6 days beginning the third day postoperatively. Ketamine suppressed the serum IL-6 response immediately after CPB and 4, 24, and 48 h postoperatively (P < 0.05). During the first 7 days after surgery, the serum IL-6 levels in the ketamine group were significantly lower than those in the control group (P < 0.05). On Day 8 after surgery, IL-6 levels were no different from baseline values in both groups. A single dose of ketamine 0.25 mg/kg administered before CPB suppresses the increase of serum IL-6 during and after CABG. Implications: In this randomized, double-blind, prospective study of patients during and after coronary artery bypass surgery, we examined whether small-dose ketamine added to general anesthesia before cardiopulmonary bypass suppresses the increase of the serum interleukin-6 (IL-6) concentration. Serum IL-6 levels correlate with the patients clinical course during and after coronary artery bypass. Ketamine suppresses the increase of serum IL-6 during and after coronary artery bypass surgery. (Anesth Analg 1998;87:266-71)

Ketamine attenuates neutrophil activation after cardiopulmonary bypass.

UNLABELLED Surgery is associated with activation of neutrophils and their influx into affected tissue. The pathogenic role of superoxide production generated by activated neutrophils has been documented repeatedly. Ketamine suppresses neutrophil oxygen radical production in vitro. In the present study, we compared the effect of adding small-dose ketamine to opioids during the induction of general anesthesia on superoxide production by neutrophils after coronary artery bypass grafting (CABG). Thirty-five patients undergoing elective CABG were randomized to one of two groups and prospectively studied in a double-blinded manner. The patients received either ketamine 0.25 mg/kg or a similar volume of saline in addition to large-dose fentanyl anesthesia. Blood samples were drawn before the operation, immediately after cardiopulmonary bypass, 24 and 48 postoperative h, and on postoperative Days 3-6. Functional capacity of neutrophils was assessed by superoxide generation after stimulation with phorbol 12-myristate 13-acetate, opsonized zymosan, or formyl-methionyl-leucyl-phenylalanine. The addition of small-dose ketamine to general anesthesia attenuates increased production of the superoxide anion (O2-) by neutrophils without chemical stimulation and after stimulation with phorbol 12-myristate 13-acetate, formyl-methionyl-leucyl-phenylalanine, and opsonized zymosan for 4-6 days after CABG. In addition, ketamine attenuated the percentage of neutrophils on postoperative Days 2-6. In the Control group, superoxide production significantly increased compared with the baseline value. By contrast, in the Ketamine group, this difference was not significant. IMPLICATIONS In a randomized, double-blinded, prospective clinical study, we compared the effect of adding small-dose ketamine to opioids during general anesthesia on superoxide production and showed that ketamine suppressed the increase of superoxide anion production by neutrophils after coronary artery bypass grafting.

Albumin or hetastarch improves neurological outcome and decreases volume of brain tissue necrosis but not brain edema following closed-head trauma in rats.

The present study examined whether hemodilution with 20% human serum albumin (HSA) or 10% hydroxyethyl starch (HES) improved the outcome from closed-head trauma (CHT) in rats. Rats anesthetized with halothane were given one of three hemodilution solutions (i.e., 20% HSA, 10% HES, or control [0.9% saline]) after CHT or sham surgery. CHT was delivered using a weight drop impact of 0.5 J onto the closed cranium. The hemodilution solution (volume = 1% of body weight) was given just after determining the neurological severity score (NSS) at 1 hour following CHT. The NSS was determined again at 24, 48, and 72 hours following CHT. At 72 hours, brains were removed, and brain edema and brain tissue necrosis volume were determined. Solutions of 20% HSA and 10% HES significantly improved brain tissue necrosis volume (143 +/- 72 mm3 and 104 +/- 53 mm3 as compared to 271 +/- 65 mm3 in controls, mean +/- SD) and NSS (12 +/- 2 and 9 +/- 2 as compared to 15 +/- 2 in controls at 72 hours, median +/- range) but not brain edema. The hematocrit decreased similarly in all groups during hemodilution. Hemodilution with 20% HSA and 10% HES following CHT in rats did not decrease brain edema but did decrease brain tissue necrosis volume and NSS (improved neurological function), suggesting that the beneficial effect of hemodilution resulted not from decreased edema formation but rather from effects not measured in this study such as improved perfusion of the salvageable brain tissue surrounding the core injury.

Phenylephrine-induced hypertension does not improve outcome after closed head trauma in rats.

Phenylephrine-induced hypertension (increase of 30-35 mm Hg for 15 min) is reported to increase cerebral perfusion pressure and collateral flow to ischemic areas of the brain in a rat model of focal cerebral ischemia. In the present study, we examined whether phenylephrine-induced hypertension of similar magnitude and duration was beneficial in a rat model of closed head trauma (CHT). Forty-eight rats were randomized into four experimental conditions: CHT at time 0 min (yes/no), plus phenylephrine-induced hypertension (increase of 30-35 mm Hg for 15 min) at 65 min (yes/no). CHT was delivered using a weight-drop device (0.5 J). Outcome measures were neurological severity score (NSS) at 1, 4, and 24 h, and brain tissue specific gravity (microgravimetry) and injury volume (2,3,5-triphenyltetrazoium chloride) at 24 h. After CHT, NSS at 24 h (median +/- range) and brain tissue specific gravity (mean +/- SD, injured hemisphere) were 7 +/- 2 and 1.033 +/- 0.007 without phenylephrine and 8 +/- 2 and 1.035 +/- 0.005 with phenylephrine (P = 0.43), respectively. Tissue injury volume (mean +/- SD) was 335 +/- 92 mm3 without phenylephrine and 357 +/- 154 mm3 with phenylephrine (P > 0.62). The results of our study indicate that postinjury treatment with 15 min of phenylephrine-induced hypertension does not attenuate brain edema, reduce tissue injury volume, or improve neurological outcome after CHT in rats. Implications: Phenylephrine-induced hypertension is reported to increase cerebral perfusion pressure and blood flow in a rat model of focal cerebral ischemia. In our study, phenylephrine-induced hypertension did not decrease brain edema or tissue injury volume or improve neurological outcome in a rat model of closed head trauma. (Anesth Analg 1998;87:574-8)

Treatments to support blood pressure increases bleeding and/or decreases survival in a rat model of closed head trauma combined with uncontrolled hemorrhage.

UNLABELLED Hemorrhagic hypotension may aggravate the detrimental effects of head trauma on neurologic outcome. Our study examined whether using phenylephrine or large volumes of saline IV to increase mean arterial blood pressure (MAP) to 70, 80, or 90 mm Hg during the combination of head trauma and uncontrolled hemorrhage would improve neurologic outcome. Rats were assigned to one of 17 groups. In Groups 1-5, the variables were head trauma (yes/no), hemorrhage (yes/no), 0 or 3 mL saline per milliliter of blood lost, and no target MAP. In Groups 6-11, hemorrhage was or was not combined with head trauma, and large volumes of saline were given IV to achieve target MAPs of 70, 80, or 90 mm Hg. Groups 12-17 were similar to Groups 6-11 except that phenylephrine was used rather than saline to achieve target MAPs. Saline increased blood loss at 2 h to approximately 16 and 25 mL at a MAP of 80 and 90 mm Hg respectively, increased (worsened) the neurodeficit score but not cerebral edema at 24 h, and decreased survival rate at 2 and 24 h. Because phenylephrine was fatal for 62 of 63 rats, group mean values for blood loss, neurodeficit score, and brain tissue specific gravity could not be calculated. We conclude that supporting MAP with either phenylephrine or large volumes of saline worsened the neurodeficit score and/or survival and did not affect cerebral edema formation in our rat model of head trauma combined with hemorrhage. IMPLICATIONS The results of this study indicate that maintaining mean arterial blood pressure at 70, 80, or 90 mm Hg with either phenylephrine or large volumes of saline worsened the neurodeficit score and/or survival and did not affect cerebral edema formation in our rat model of head trauma combined with hemorrhage.

Effect of Ketamine on Inflammatory and Immune Responses After Short- Duration Surgery in Obese Patients

In non-obese patients ketamine decreases inflammatory responses and prevents overexpression of immune re- sponses. Its effect in obese patients is unknown. This prospective, blinded, randomized controlled trial was designed to determine the effect of ketamine on cytokines and immune cell responses after short-duration surgery in obese patients. Thirty-six patients received either ketamine 0.15 mg/kg IV prior to induction of general anesthesia, or an equal volume of normal saline. Cytokine concentrations and immune cell responses were determined pre-operatively and at 4, 24, and 48 h after operation. Interleukin (IL)-6 production was significantly greater in the control group (126.0 ± 18.8 ng/ml, mean ± SEM, n = 19) than in the ketamine group (57.9 ± 8.4 ng/ml) at 4 h. At other time periods IL-6 and tumor necrosis factor � increased and IL-2, lymphocyte proliferation, and natural killer cell cytotoxity decreased compared to pre-operative values in the control group but not in the ketamine group. We conclude that effects of ketamine on inflammatory and immune re- sponses after short-duration surgery in obese patients are similar to those previously reported in non-obese patients.