Hypercoagulability After Resection of Thoracic Malignancy: A Prospective Evaluation.

BACKGROUND: Rates of venous thromboembolism are increased in thoracic malignancy; however, coagulation patterns are not established. We hypothesize that patients with esophageal and lung malignancy have similar hypercoagulable pre- and postoperative profiles as defined by rotational thromboelastometry (ROTEM). METHODS: Prospective study was conducted in 47 patients with esophageal and lung cancer undergoing surgical resection. ROTEM evaluated pre/postoperative coagulation status. RESULTS: Patients with thoracic malignancy were hypercoagulable by ROTEM, but not by conventional coagulation tests. Preoperative hypercoagulability was higher in lung versus esophageal cancer (64 vs. 16%, p = 0.001). Lung cancer patients that were hypercoagulable preoperatively demonstrated decreased maximum clot firmness (MCF) (p = 0.044) and increased clot time (p = 0.049) after surgical resection, suggesting reversal of hypercoagulability. Resection of esophageal cancer increased hypercoagulability (16 vs. 56%, p = 0.002) via elevated MCF (reflecting platelet activity). Hypercoagulability remained at follow-up clinic for both lung and esophageal cancer patients. CONCLUSIONS: Hypercoagulability in patients with lung malignancies reversed following complete surgical resection, whereas hypercoagulability occurred only postoperatively in those with esophageal malignancies. In both, hypercoagulability was associated with fibrin and platelet function.

The Perceived Consequences of Gold Mining in Postwar El Salvador: A Qualitative Study.

OBJECTIVES: We investigated themes related to the health and environmental impacts of gold mining in El Salvador. METHODS: Over a 1-month period in 2013, we conducted focus groups (n = 32 participants in total) and individual semistructured interviews (n = 11) with community leaders until we achieved thematic saturation. Data collection took place in 4 departments throughout the country. We used a combination of criterion-purposive and snowballing sampling techniques to identify participants. RESULTS: Multiple themes emerged: (1) the fallacy of economic development; (2) critique of mining activities; (3) the creation of mining-related violence, with parallels to El Salvador's civil war; and (4) solutions and alternatives to mining activity. Solutions involved the creation of cooperative microenterprises for sustainable economic growth, political empowerment within communities, and development of local participatory democracies. CONCLUSIONS: Gold mining in El Salvador is perceived as a significant environmental and public health threat. Local solutions may be applicable broadly.

Pediatric emergency department thoracotomy: a large case series and systematic review.

BACKGROUND/PURPOSE: The emergency department thoracotomy (EDT) is rarely utilized in children, and is thus difficult to identify survival factors. We reviewed our experience and performed a systematic review of reports of EDT in pediatric patients. METHODS: Patients age ≤18 years who received an EDT from 1991 to 2012 at our institution and all published case series were reviewed. Data analyzed include age, sex, mechanism of injury (MOI), injury patterns, presence of vital signs (VS) or signs of life (SOL) in the field/ED, return of spontaneous circulation (ROSC), and survival. RESULTS: A total of 252 patients were analyzed. 84% were male. 51% sustained penetrating injuries, and median age was 15 years. Upon arrival, 17% had VS, and 35% had SOL. After EDT, 30% experienced ROSC. The survival rate was 1.6% for blunt trauma, 10.2% for penetrating injuries, and 6.0% overall. CONCLUSION: Survival of pediatric patients following EDT is comparable to recent analyses in adults. Children who sustain blunt injury and are without SOL have been uniformly unsalvageable. Children who sustain penetrating trauma and have SOL or are without SOL for a short time prior to arrival have been salvageable. There are no reported EDT survivors less than 14 years of age following blunt injury.

Decreased mortality after prehospital interventions in severely injured trauma patients.

BACKGROUND: We test the hypothesis that prehospital interventions (PHIs) performed by skilled emergency medical service providers during ground or air transport adversely affect outcome in severely injured trauma patients. METHODS: Consecutive trauma activations (March 2012 to June 2013) transported from the scene by air or ground emergency medical service providers were reviewed. PHI was defined as intubation, needle decompression, tourniquet, cricothyroidotomy, or advanced cardiac life support. RESULTS: In 3,733 consecutive trauma activations (71% blunt, 25% penetrating, 4% burns), age was 39 years, 74% were male, Injury Severity Score (ISS) was 5, and Glasgow Coma Score (GCS) was 15, with 32% traumatic brain injury (TBI) and 7% overall mortality. Those who received PHI (n = 130, 3.5% of the trauma activations) were more severely injured: ISS (26 vs. 5), GCS (3 vs. 15), TBI (57% vs. 31%), Revised Trauma Score (RTS, 5.45 vs. 7.84), Trauma and Injury Severity Score (TRISS, 1.32 vs. 4.89), and mortality (56% vs. 5%) were different (all p < 0.05) than those who received no PHI. Air crews transported 22% of the patients; more had TBI, blunt injury, high ISS, and long prehospital times (all p < 0.05), but mortality was similar to those transported by ground. In the most severely injured patients with signs of life who received a PHI, the ISS, prehospital times, and proportions of TBI, blunt trauma, and air transport were similar, but mortality was significantly lower (43% vs. 23%, p= 0.021). CONCLUSION: In our urban trauma system, PHIs are associated with a lower incidence of mortality in severely injured trauma patients and do not delay transport to definitive care. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; therapeutic study, level IV.

Differences between blunt and penetrating trauma after resuscitation with hydroxyethyl starch.

BACKGROUND: The purpose of this study was to test the hypothesis that a single bolus of 6% hydroxyethyl starch (HES 450/0.7 in lactated electrolyte injection) during initial resuscitation has a differential effect in blunt and penetrating trauma patients. METHODS: Consecutive admissions to the trauma service were reviewed. Patients who died within 24 hours were excluded. Multivariate analysis defined individual predictors for the primary outcomes, acute kidney injury (AKI) and mortality within 90 days. Data were expressed as mean ± SD, and significance was assessed at p < 0.05. RESULTS: There were 1,410 patients (76% male; mean ± SD, age 43 ± 18 years; 68% blunt trauma; mean ± SD Injury Severity Score [ISS] 14 ± 11; AKI, 4.4%; and mortality, 3.4%). HES (0.5-1.5 L) was administered to 216 patients (15.3%). After multiple logistic regression, HES remained a significant independent predictor of AKI after blunt trauma (odds ratio [OR], 2.54; 95% confidence interval [CI], 1.24-5.19; area under the receiver operating characteristic curve [AUROC], 0.809) but not penetrating trauma (OR, 0.90; 95% CI, 0.23-3.60; AUROC, 0.849). In separate logistic regression models, HES was a significant predictor of mortality after blunt trauma (OR, 3.77; 95% CI, 0.91-0.97; AUROC, 0.921) but not penetrating trauma (OR, 0.72; 95% CI, 0.13-3.94; AUROC, 0.904). CONCLUSION: HES is an independent risk factor for AKI and death after blunt, but not penetrating, trauma, which underscores a fundamental difference between these two injury types. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Initial hematocrit predicts the use of blood transfusion in the pediatric trauma patient.

PURPOSE: Initial hematocrit (Hct) is generally not considered a marker of acute blood loss because it is assumed that physiologic response of fluid conservation to hemorrhage is delayed. We challenged this idea by theorizing that admission Hct correlates with conventional signs of shock and predicts the use of blood transfusion during resuscitation of pediatric trauma patients. METHODS: Data from 1928 pediatric admissions (<18 years) at a Level I trauma center (2000-2012) were compared using standard statistical analyses and logistic regression modeling to identify factors associated with blood transfusion during initial trauma resuscitation. RESULTS: Overall mortality rate was 3.5%, with a transfusion rate of 10.7%. Factors significantly associated with transfusion were initial Hct, Glasgow Coma Score, base deficit, and injury severity score (all p<0.001). Initial Hct is a stronger predictor for transfusion (area under receiver operator curve (AUC: 0.728) compared to age-specific tachycardia (AUC: 0.689), age-specific hypotension (AUC: 0.673), and altered mental status (AUC: 0.654)). On multivariate analysis, initial Hct was an independent predictor (OR [95% CI]: 2.94 [1.56, 5.52]) along with hypotension (6.37 [2.95, 13.8]), base deficit (4.14 [1.38, 12.4]), and tachycardia (3.07 [1.62, 5.81]). CONCLUSIONS: Initial Hct correlates significantly with conventional signs of shock and is a strong independent predictor for blood transfusion with better predictability than other clinical factors.

Novel prehospital monitor with injury acuity alarm to identify trauma patients who require lifesaving intervention.

BACKGROUND: A miniature wireless vital signs monitor (MWVSM, www.athena.gtx.com) has been designed according to US Special Operations Command specifications for field monitoring of combat casualties. It incorporates an injury acuity algorithm termed the Murphy Factor (MF), which is calculated from whatever vital signs are available at the moment and changes in the last 30 seconds. We tested the hypothesis that MF can identify civilian trauma patients during prehospital transport who will require a lifesaving intervention (LSI) upon hospital admission. METHODS: From December 2011 to June 2013, a prospective trial was conducted in collaboration with prehospital providers. The MWVSM detects skin temperature, pulse oximetry (SpO2), heart rate (HR), pulse wave transit time, and MF. LSIs included: intubation, tube thoracostomy, central line insertion, blood product transfusion, and operative intervention. Prehospital MWVSM data were compared with simultaneous vital signs (SaO2, systolic blood pressure (SBP), and HR) from a conventional vital signs monitor. Sensitivity, specificity, negative predictive value, positive predictive value, and area under the receiving operating characteristic curves were calculated. RESULTS: Ninety-six trauma patients experienced predominantly blunt trauma (n = 80, 84%), were mostly male (n = 79, 82%), and had a mean ± SD age of 48 ± 19 years and an Injury Severity Score (ISS) of 10 (17). Those who received an LSI (n = 48) had similar demographics but higher ISS (18 vs. 5) and mortality (23% vs. 0%) (all p < 0.05). The most common LSIs were intubation (n = 24, 25%), blood product transfusion (n = 19, 20%), and emergency surgery (n = 19, 20%). Compared with HR > 100 beats/min, SBP < 90 mm Hg, SaO2 < 95% alone or in combination, MF > 3 during the entire transport time had the largest area under the receiving operating characteristic curves (0.620, p = 0.081). MF greater than 3 had a specificity of 81%, sensitivity of 39%, positive predictive value of 68%, and negative predictive value of 57% for the need for LSI. CONCLUSION: A single numeric value has the potential to summarize overall patient status and identify prehospital trauma patients who need an LSI. Prehospital monitoring combined with algorithms that include trends over time could improve prehospital care for both civilian and military trauma. LEVEL OF EVIDENCE: Prospective observational, level II.

Long-term coagulation changes after resection of thoracoabdominal malignancies.

BACKGROUND: The purpose of this study was to evaluate the long-term coagulation status of patients undergoing malignancy resection. STUDY DESIGN: A prospective observational trial was conducted with informed consent in 52 patients (age 66 ± 10 years and 60% male) with thoracoabdominal tumors (pancreas [n = 18, 35%], esophagus [n = 13, 25%], liver [n = 7, 14%], stomach [n = 6, 12%], bile duct [n = 3, 6%], retroperitoneal [n = 3, 6%], and duodenum [n = 2, 4%]) with 6- to 12-month follow-up. Coagulation was evaluated with rotational thromboelastography (ROTEM) on whole blood and with a panel of hemostatic markers on stored plasma. RESULTS: Maximum clot firmness (MCF) in the intrinsic, extrinsic, and fibrinogen pathways increased immediately postoperatively and then decreased by 9.2 ± 4.1 months (p < 0.05). Markers of thrombin generation (prothrombin fragment 1 + 2, fibrinolysis [D-dimer], and endothelial activation [coagulation factor VIII]) were elevated at all time points. The ROTEM pattern depended on histologic type and cancer location. All esophageal tumors were adenocarcinoma and demonstrated similar patterns to the overall population, with MCF differences over time in all 3 pathways (all p < 0.05). Regarding tumors of the pancreas or liver, there were no statistically significant differences when comparing all 3 time periods, but there were time-related differences when evaluating only primary adenocarcinomas of the liver (all p < 0.05). Three patients (6%) developed venous thromboembolism (VTE) and had decreased clot formation time, increased angle, and increased MCF (all p < 0.05). CONCLUSIONS: Cancer patients at risk for VTE can be identified with a point-of-care ROTEM test and may benefit from additional anticoagulation. Biomarkers reflecting different functional hemostasis activity groups (fibrinolysis, thrombin generation, and endothelial activation) confirm the ongoing prothrombotic state. The ROTEM demonstrated increased hypercoagulability postoperatively, which returned to baseline in long-term follow-up. Reversal of cancer-induced hypercoagulability occurred in some patients and varied with tumor histology and location.

Do all trauma patients benefit from tranexamic acid?

BACKGROUND: This study tested the hypothesis that early routine use of tranexamic acid (TXA) reduces mortality in a subset of the most critically injured trauma intensive care unit patients. METHODS: Consecutive trauma patients (n = 1,217) who required emergency surgery (OR) and/or transfusions from August 2009 to January 2013 were reviewed. At surgeon discretion, TXA was administered at a median of 97 minutes (1-g bolus then 1-g over 8 hours) to 150 patients deemed high risk for hemorrhagic death. With the use of propensity scores based on age, sex, traumatic brain injury (TBI), mechanism of injury, systolic blood pressure, transfusion requirements, and Injury Severity Score (ISS), these patients were matched to 150 non-TXA patients. RESULTS: The study population was 43 years old, 86% male, 54% penetrating mechanism of injury, 25% TBI, 28 ISS, with 22% mortality. OR was required in 78% at 86 minutes, transfusion was required in 97% at 36 minutes, and 75% received both. For TXA versus no TXA, more packed red blood cells and total fluid were required, and mortality was 27% versus 17% (all p < 0.05). The effects of TXA were similar in those with or without TBI, although ISS, fluid, and mortality were all higher in the TBI group. Mortality associated with TXA was influenced by the timing of administration (p < 0.05), but any benefit was eliminated in those who required more than 2,000-mL packed red blood cells, who presented with systolic blood pressure of less than 120 mm Hg or who required OR (all p < 0.05). CONCLUSION: For the highest injury acuity patients, TXA was associated with increased, rather than reduced, mortality, no matter what time it was administered. This lack of benefit can probably be attributed to the rapid availability of fluids and emergency OR at this trauma center. Prospective studies are needed to further identify conditions that may override the benefits from TXA. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Hypercoagulability and other risk factors in trauma intensive care unit patients with venous thromboembolism.

BACKGROUND: Thromboelastography (TEG) on hospital admission can identify hypercoagulable trauma patients at risk for venous thromboembolism (VTE), but the value of TEGs obtained after multiple interventions, including tranexamic acid (TXA), has not been defined. We test the following hypotheses. (1) TEG on intensive care unit (ICU) admission can help stratify patients screened with Greenfield's risk assessment profile (RAP) for VTE. (2) TXA is a VTE risk factor, and its effect on fibrinolysis can be identified with TEG. METHODS: Trauma patients who survived to the ICU with RAP ≥ 10 received serial venous duplex ultrasound examinations and blood samples for coagulation analysis at admission to the ICU and weekly thereafter. RESULTS: Six hundred seventy-eight patients were screened and 121 were enrolled; 76% blunt injury, Injury Severity Score (ISS) 27, 13% mortality. Thromboprophylaxis was administered to 90% of the patients and was started a median of 2 days after hospital admission. VTE was detected in 28% (n = 34) of the patients (27 deep vein thrombosis and 7 pulmonary emboli) and occurred a median 10 days after admission. Twenty-nine percent (n = 10) of VTE occurred within 2 days of admission. Most variables were similar between those with and without VTE, but the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score > 2 (59% vs. 39%, p = 0.050). Upon ICU admission, standard coagulation markers were within normal limits, while TEG demonstrated hypercoagulability, but neither was associated with VTE. Repeat TEG one week after admission (n = 58) remained hypercoagulable but transitioned to a different pattern with increased clot strength. TXA was associated with reduced fibrinolysis on initial TEG (p < 0.05) but was not associated with VTE. CONCLUSION: Trauma ICU patients with RAP ≥ 10 are hypercoagulable at admission to ICU and remain so during recovery. They have a ≥ 25% rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers (measured on ICU admission) stratify high-risk patients who develop VTE from those who do not. LEVEL OF EVIDENCE: Prognostic study, level III.

Vasopressor use during emergency trauma surgery.

Most evidence suggests early vasopressor use is associated with death after trauma, but no previous study has focused on patients requiring emergency operative intervention (OR). We test the hypothesis that vasopressors are harmful in this population. Records from 746 patients requiring OR from July 2009 to March 2013 were retrospectively reviewed and stratified based on vasopressor use (epinephrine [EPI], phenylephrine, ephedrine, norepinephrine, dobutamine, vasopressin) or no vasopressor use. Vasopressors were administered to 225 patients (30%) during OR; 59 patients (8%) received multiple vasopressors. Patients who received vasopressors were older, more severely injured, had worse vital signs, and increased mortality rate (all P < 0.001). EPI was independently associated with mortality (odds ratio, 6.88; P = 0.001). If patients who received EPI were excluded, there was no difference in mortality between those who received vasopressors alone or in combination and those that did not (5 vs 6%, P = 0.523), although multiple markers of injury severity were worse. We conclude that vasopressor use is relatively common in the most severely injured patients requiring OR and is associated with mortality. EPI is most often used for cardiac arrest, whereas other vasopressors are used for their vasoconstrictive properties. This suggests that, except for EPI, vasopressors during OR are not independently associated with mortality.

Does traumatic brain injury increase the risk for venous thromboembolism in polytrauma patients?

BACKGROUND: Trauma is a major risk factor for venous thromboembolism (VTE). Traumatic brain injury (TBI) is generally considered to further increase the VTE risk, which should prompt routine thromboprophylaxis. However, the associated risk for intracranial hemorrhage often delays anticoagulants. We test the hypothesis that TBI associated with polytrauma results in a higher rate of VTE than polytrauma without TBI. METHODS: From August 2011 to June 2013, a prospective observational trial with informed consent was performed in 148 intensive care unit (ICU) patients with a Greenfield Risk Assessment Profile score of 10 or greater. RESULTS: Demographics, Greenfield Risk Assessment Profile scores, the incidence of polytrauma, and mortality were similar, but TBI patients had worse Injury Severity Scores (ISS) (32 vs. 22), longer ICU lengths of stay (21 days vs. 12 days), more hypercoagulable thromboelastogram values on admission (94% vs. 79%), more received unfractionated heparin prophylaxis (65% vs. 36%), and the prophylaxis start date was more than a day later (all p < 0.05). Nevertheless, the VTE rate with TBI was similar to that without TBI (25% vs. 26%, p = 0.507). Furthermore, VTE occurred at similar time points after ICU admission with and without TBI. In both groups, about 30% of the VTEs were detected within 2 days of ICU admission and 50% of the VTEs occurred within 10 days of admission despite chemical and mechanical thromboprophylaxis. CONCLUSION: In complex polytrauma patients who survived to ICU admission and who were prescreened for high VTE risk, TBI did not further increase the risk for VTE. The most likely explanation is that no single risk factor is necessary or sufficient for VTE development, especially in those who routinely receive chemical and mechanical thromboprophylaxis. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Hypercoagulability after burn injury.

BACKGROUND: Hypercoagulability is a homeostatic response to trauma, but relatively little information is available about coagulation changes after burn injury. Therefore, we tested the hypothesis that burn patients are hypercoagulable at admission and/or during recovery. METHODS: A prospective observational trial was conducted at an American Burn Association verified Burn Center. Thromboelastography (TEG) was performed on blood drawn from indwelling catheters upon admission and weekly for those who remained hospitalized. Routine and special coagulation tests were performed on stored samples. Data are expressed as median (interquartile range). RESULTS: Twenty-four patients (88% male) were enrolled, with a median age of 49 (20) years and a median total body surface area burn of 29% (23%); 21 experienced thermal burns (4 inhalational injuries), and 3 had electrical burns. There were no significant differences in TEG or coagulation assays between patients with thermal versus electrical burn injury, but there were significant differences between men versus women and between those with or without inhalational injury. Sixteen patients had repeat samples 1 week after intensive care unit admission. The repeat TEG was more hypercoagulable (all p < 0.05). Fibrinogen and natural anticoagulation proteins (protein C, protein S, and antithrombin III) were also increased (all p < 0.05). Two patients (8%) developed venous thromboembolism (VTE); TEG reaction time, fibrinogen, and partial thromboplastin time were decreased (all p < 0.05) at admission compared with those with no VTE. All changes occurred despite pharmacologic thromboprophylaxis. There was no significant correlation between TEG and total body surface area or between TEG and fluid balance. CONCLUSION: In general, burn patients have normal coagulation parameters at admission but become hypercoagulable during recovery. However, those who are hypercoagulable at admission may have an increased risk of VTE. Additional monitoring and/or thromboprophylaxis may be indicated. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III.

Vasopressin for cerebral perfusion pressure management in patients with severe traumatic brain injury: preliminary results of a randomized controlled trial.

BACKGROUND: After traumatic brain injury (TBI), catecholamines (CAs) may be needed to maintain adequate cerebral perfusion pressure (CPP), but there are no recommended alternative vasopressor therapies. This is an interim report of the first study to test the hypothesis that arginine vasopressin (AVP) is a safe and effective alternative to CAs for the management of CPP in patients with severe TBI. METHODS: Since 2008, all TBI patients requiring intracranial pressure monitoring at this Level 1 trauma center have been eligible for a randomized trial to receive either CA or AVP if vasopressors were required to maintain CPP greater than 60 mm Hg. RESULTS: To date, 96 patients have been consented and randomized. Demographics, vital signs, and laboratory values were similar. As treated, 60 required no vasopressors and were the least severely injured group with the best outcomes. Twenty-three patients received CA (70% levophed, 22% dopamine, 9% phenylephrine) and 12 patients received AVP. The two vasopressor groups had similar demographics, but Injury Severity Score (ISS) and fluid requirements on intensive care unit Day 1 were worse in the AVP versus the CA groups (all p < 0.05) before treatment. These differences indicate more severe injury with accompanying hemodynamic instability. Nevertheless, adverse events were not increased with AVP versus CA. Trends favored AVP versus CA, but no apparent differences were statistically significant at this interim point. There was no difference in mortality rates between CA and AVP. CONCLUSION: These preliminary results suggest that AVP is a safe and effective alternative to CA for the management of CPP after TBI and support the continued investigation and use of AVP when vasopressors are required for CPP management in TBI patients. LEVEL OF EVIDENCE: Therapeutic study, level II.

Frequency of adjustments and weight loss after laparoscopic adjustable gastric banding.

Laparoscopic adjustable gastric banding is an effective procedure for weight loss. Long-term follow-up and band adjustments are crucial to achieve sustained weight loss, but the optimal frequency is unknown. We compare the weight loss of two patient groups adjusted at different frequencies. A 24-month analysis was conducted to 280 patients (156 from an academic center and 124 from an outpatient surgery center). Each center's patients were stratified into 6-month groups according to the length of follow-up. These groups were compared between the settings for average adjustments per month and percent excess weight loss (%EWL). Patient subgroup 0-6 months had 0.6 adjustments/month (adj/mo) and 18.3% EWL at AC compared to 0.7 adj/mo and 19.1% EWL at OC. Subgroup 6-12 months had 0.4 adj/mo and 27.2% EWL at AC compared to 0.5 adj/mo and 33.4% EWL at OC. Subgroup 12-18 months had 0.3 adj/mo and 25.3% EWL at AC compared to 0.5 adj/mo and 45.6% EWL at OC. Subgroup 18-24 months had 0.3 adj/mo and 30.9% EWL at AC compared to 0.3 adj/mo and 42.2% EWL at OC. Analysis of variance crossing 6-month groups with facility produced significant effects for groups (F = 15.52, df = 4.290, p < 0.001), center (F = 14.28, df = 1.290, p < 0.001), and the center-by-group interaction (F = 3.01, df = 4.290, p < 0.02). Our data suggest that more frequent adjustments result in increased EWL, but optimal frequency remains unknown. We believe that the difference noted between the clinics stems from accessibility to adjustments. Additional data, such as %EWL at smaller monthly intervals and the point of diminishing results, should be investigated in future studies.